A critical review of the afferent pathways and the potential chemical mediators involved in cardiac pain

0306-4522/92 $5.00 + 0.00 PergamonPress Ltd Q 1992 IBRO

NeuroscienceVol. 48, No. 3, PP. 501-524, 1992 Printedin Great Britain

COMMENTARY

A CRITICAL REVIEW OF THE AFFERENT PATHWAYS AND THE POTENTIAL CHEMICAL MEDIATORS INVOLVED IN CARDIAC PAIN S. T. MELLER* and G. F. GEBHART Department of Pharmacology,

Bowen Science Building, College of Medicine, University of Iowa, Iowa City, IA 52242, U.S.A. CONTENTS 501

1. INTRODUCTION 2. BACKGROUND 3. AFFERENT PATHWAYS CONVEYING CARDIAC PAIN 3.1. Sympathetic afferents 3.1.1. Superior cervical ganglion 3.2. Vagal afferents 3.2.1. Anterior vs inferior-posterior 3.2.2. Convergence 3.2.3. Vagal afferents and antinociception 3.3. Other potential pathways 4. CHEMICAL MEDIATORS OF CARDIAC PAIN 4.1. Bradykinin 4.1.1. Behavioral effects 4.1.2. Afferent activation 4.1.3. Present in significant concentrations? 4.1.4. Noxious? 4.2. Serotonin 4.2.1. Behavioral effects 4.2.2. ABerent activation 4.2.3. Present in significant concentrations? 4.2.4. Noxious? 4.3. Adenosine 4.4. Histamine 4.5. Prostaglandins 4.6. Potassium 4.7. Lactate 4.8. Synergism 5. CORONARY OCCLUSION 6. SUMMARY 7. CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES

“Nobody believes that all pain originating in and around the heart is always due to the same cause”. Reid and Andrus, 1925.‘s2

*To whom correspondence should be addressed. ADN, aortic depressor nerve; DRG, dorsal root ganglion; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; MCG, middle cervical ganglion; NG, nodose ganglion; nTS, nucleus of the solitary tract; RCA, right coronary artery; RLN, recurrent laryngeal nerve; 5-HT, S-hydroxytryptamine; SCG, superior cervical ganglion; SLN, superior laryngeal nerve; SIT, spinothalamic tract.

Abbreviafions:

502 503 503 507 507 508 510 510 510 511 511 512 512 513 513 513 513 513 514 514 514 515 515 515 515 516 516 517 517 517 517

1. INTRODUCTION

Ischemia of visceral organs, especially the heart, is often a painful and potentially life-threatening condition. Myocardial ischemia is typically accompanied by either sensations of discomfort or pain in the chest, clinically described as angina, and in more extreme cases is associated with a myocardial infarction. The term angina pectoris was first used by Heberdeen73 to describe a disorder of the breast accompanied by a sense of strangling and anxiety. Over the following two centuries there have been numerous descriptive passages relating to angina and

502

S. T.

MELLER and G.

heart pain, and considerable investigation into the underlying mechanisms, which has led to the belief that ischemia of the heart is the cause of pain; i.e. there is an imbalance between oxygen supply and demand (for reviews, see Refs 64, 115, 164). It is now well established that humans suffering from atherosclerosis and coronary artery disease leading to a narrowing of the lumen of one or more of the four major coronary arteries supplying the heart [right (RCA), main left, left anterior descending (LAD), or left circumflex arteries (LCX)] suffer from myocardial ischemia (due either to an increased oxygen demand or a decreased oxygen supply). Considering the importance in understanding the mechanisms of cardiac pain, the goals of this paper are two-fold: first, to review the afferent pathways responsible for the transmission of sensations associated with myocardial ischemia, and second, to review the potential chemical and mechanical events which might lead to activation of cardiac nociceptive afferents. Just what specific events might lead to the activation of nociceptive afferents from the heart remains unclear. Nevertheless, there is significant literature, described below, which suggests that cardiac sympathetic afferents and bradykinin are intimately involved. However, there is also evidence, contrary to popular belief and opinion, that other afferents and other chemicals may be involved. Therefore, it is the aim of this paper to present and evaluate this evidence and to speculate on the potential contribution of these other systems. It is certainly not our intention to suggest that sympathetic afferents are not important, merely to suggest that other systems also contribute and may be important to mechanisms of cardiac pain. To this end, it is acknowledged that some conclusions drawn from the evidence reviewed may be speculative, but it is the investigation of ideas and speculation that may help us to uncover the underlying mechanisms of cardiac pain.

F. GEBHART

(see Fig. 1). Notwithstanding this extensive clinical literature, the general consensus, founded essentially on a small number of experimenta1176*2’3 and clinical is that complete relief from angina is studies, ‘03~2’o.213 achieved by removal of the lower cervical and upper thoracic sympathetic ganglia, or transection of the corresponding spinal dorsal roots. During a review of the literature, it became apparent to us that afferents from the heart other than those in sympathetic afferent nerves may also be important for conveying sensations related to myocardial ischemia and cardiac pain, A critical reevaluation of the clinical literature clearly indicated that (i) in all clinical studies, irrespective of the surgical manipulation, there was consistently a group of patients in whom transections of cardiac sympathetic afferents afforded no relief from angina, and (ii) there were patients who were relieved of angina by surgical transections of non-sympathetic (vagalassociated) afferents. In addition, there have been recent reservations expressed about the efficacy of sympathectomy for the permanent relief from an~ina,49,B9,170 Therefore, if removal of sympathetic afferents is not always effective (in at least l&20% of all cases), another afferent pathway is clearly implicated. Accordingly, stimulation of the cervical or thoracic vagus in humans has been reported to produce deep, poorly localized, burning sensations in the chest,69.2” or severe pain in the breast”’ and transection of vagal-associated fibers has been reported to effectively relieve angina in some cases Further, removal of the superior cerviL .35.45,9B.208 cal ganglion (SCG), which contains only nonsympathetic afferents (probably vagal), results in relief from angina in 3@35% of complete cases,2B.45A8.iG0 Experimentally, however, the potential role of vagal afferents in cardiac pain has not been extensively studied and the major research direction has continued to focus on the role of sympathetic afferents. There are many reports showing that either pathological conditions or experimental manipulations 1. BACKGROUND predominantly involving the anterior surface of the heart usually result in activation of sympathetic Over the past century, there have been a large afferents leading to reflex sympathetically mediated number of surgical studies aimed at defining and/or hypertenresponses (i.e. tachycardia the precise anatomical pathways responsible for ln con_ ' 9.21,28,30,34,35,45A8,59,74,87,90.100,103 sion). 15.29.106,110,1i2,113,136,142.159,173.174,l93,l94,~2~2~ cardiac pam trast, either patholo~cal conditions or ex~~mental (Table 1) and it has become widely accepted that involving the inferior-posterior manipulations pain arising from the heart is conveyed to the surface of the heart predominantly activate vagal central nervous system by sympathetic afferents 6.9,21-23,25,27,M,59,74,87,90,103,111,137,138,173,174,176,191,212.213 afferents resulting in reflex vagally mediated (i.e. bradycardia and/or hypotenCardiac sympathetic afferents have been found to (i) responses ~~~~),3~'10~139,141.142,159.l~.187.~~.205 Almost all Of those re_ travel in the middle cardiac nerve to enter the middle ports which exclude a cont~bution of vagal afferents cervical sympa~etic ganglion, where they project to in the central transmission of sensations associated both the lower cervical and upper thoracic spinal with myocardial ischemia generally involve expercord, (ii) pass by way of the inferior cardiac nerve, imental manipulations of the pericardium and arterthrough the stellate ganglion, to enter the upper ies preferentially supplying the anterior surface of the thoracic spinal cord, or (iii) to project directly to the heart 6,22.23,25.27.59,103,111,173.174.176.21~~2l3 Considering the upper and middle thoracic spinal cord through the upper and middle thoracic sympathetic ganglia2’0*2’2 abundance of reports on sympathetically mediated

Mechanisms of cardiac pain

503

Table 1. Summary of the various surgical manipulations which have been performed in attempts to relieve the pain associated with angina

success Ref.

Treatment

1. Thoracic sympathectomy 87 symp. 191 symp. 30 symp. 90 symp.

Level mid. + mid. + all all

inf. cerv. + T,-T,? inf. cerv. + T,-T,? cerv. + T,-T4? cerv. + T,-T,?

n

++++

2 1 1 1

100.0 100.0 100.0 0.0

+++

0.0 0.0 0.0 100.0

18.5 8.7

7.4 13.1

0.0

7.0 0.0

all cerv. T,-T,

27 23

47.7

30.5

103 211

symp. symp.

T,-T,

71 8

43.7 0.0

87.5

alcohol

T,-T, TI-T, T,-T, T,-L TIC% T,-T4 T,--L T,-T, T,-T, Tr’L

75

56.0

symp. alcohol

31

symp.

210

symp. alcohol rhizot.

9

symp.

21

symp.

138 symp. 74 symp. 2. Superior cervical ganglion (SCG)

T,-T,? SCG

62.9 40.8 34.5

8.0

24

80.0

20.0

28

80.0

20.0

30 17 77

56.7

26.7 35.3

56.0 50.0

8

75.0

50.0

50.0

5 8

50.0

45

sump.

SCG

29

34.4

48 100 3. Vagal

symp. symp.

SCG SCG

52 94

30.7 62.7

208

depressor

-

6

45

depressor

-

12

25.0 11.5

26.9 100.0

SCG

8.0

0.0

53.8

26 2

21.0

7.0

2

52

16.7

47.1

symp. symp.

34 28

+

0.0 0.0 0.0 0.0

symp. alcohol

59

++

0.0 0.0 0.0 0.0

45 213

T,-T,

Failure

0.0

0.0 0.0

25.0

12.5

80.0

0.0 50.0 20.0 0.0

37.9

13.8

30.7 6.4

13.4 9.6

2.2

80.0

20.0

75.0

17.0

0.0

symp., sympathectomy; alcohol, paravertebral injection of alcohol; rhizot., dorsal rhizotomy; depressor, section of the depressor vagus nerve; mid. + inf. cerv., middle and inferior cervical sympathetic ganglia; + + + + to + , range from complete success to complete failure; + + + , greater than 50% success; + + , less than 50% success.

cardiovascular reflexes from this region, these manipulations may be primarily activating, and thus preferentially studying, sympathetic afferent mechanisms (cardiovascular and nociceptive). In contrast, there

are no experimental reports of which we are aware regarding nociceptive mechanisms exclusively involving manipulations of the inferior-posterior surface of the heart, but considering the predominantly vagally mediated cardiovascular reflexes which can be elicited from this region, it is not improbable that there may also be a vagal contribution to the transmission of sensations associated with myocardial ischemia, at least from this region of the heart. It is likely, however, even if the ischemic episode is restricted to only one surface of the heart, both sympathetic and vagal afferents are probably activated, and the predominant cardiovascular and nociceptive responses may be the result of the number and type of afferents present and their spatial and temporal activation.

3. AFFERENT PATHWAYS

CONVEYING

CARDIAC

PAIN

Based on experimenta1’76*213 and clinical reof surgical interventions to relieve anports ‘032102’3 gina (Table l), it has become widely accepted that cardiac sympathetic afferents are solely responsible for signaling pain arising from the heart due to ischemia 6,9,21,25,27,30,59,87,90,103,111,1)7~173,l74~l76~19l,2l~213 3.1. Sympathetic a&en ts In attempts to control the pain associated with angina and myocardial infarction, varied surgical manipulations of the sympathetic nervous system have been performed, ranging from removal of the SCG, stellate ganglion, or the cervicothoracic trunk, to dorsal rhizotomies from the level of the lower cervical to the middle thoracic spinal cor~9,21,28,30.31,~,35,45,~,59.74.87.913 (=

Table 1). Of those reports, a number have suggested that only sympathetic afferents are responsible for the

S. T. MELLERand G. F. GEBHAR~

:tic

m

SCG -

Fig. 1. Summary diagram of the pathways by which nociceptive cardiac afferents may reach the central nervous system. Nociceptive afferent fibers travel from the heart through the cardiac plexus immediately dorsal to the heart. From here, vagal afferent fibers travel primarily to the nucleus of the solitary tract (nTS) in the dorsal medulla from where information is relayed both rostrally and caudally. Other vagal-associated afferents travel within the aortic depressor nerve (ADN) and the recurrent laryngeal nerve (RLN), which joins the superior laryngeal nerve (SLN) near the level of the nodose ganglion (NG). The cell bodies of all these vagal-associated afferents lie in the nodose ganglion. Other vagal-associated afferents pass (possibly) by way of the superior cardiac nerve (superior cardiac n.) to enter the SCG where they travel by an undefined pathway to enter the nucleus of the solitary tract. Sympathetic afferents from the heart travel in the middle cardiac nerve (middle cardiac n.) to enter the middle cervical sympathetic ganglion (MCG), where they project to both the lower cervical and upper thoracic spinal cord (predominantly T,), or pass by way of the inferior cardiac nerve (inferior cardiac n.) through the stellate ganglion (stellate), to enter the upper thoracic spinal cord (T,). Alternatively, sympathetic afferents may project directly to the upper, middle and lower thoracic spinal cord (‘T2-Ts) through the upper, middle and lower thoracic sympathetic ganglia. The cell bodies for these sympathetic afferents lie in the dorsal root ganglia (DRG). These nociceptive afferents enter the spinal cord to terminate predominantly in dorsal horn spinal laminae I, II and V where they synapse on spinothalamic tract cells to convey information to the thalamus by the spinothalamic tract (STT). Finally, there may be afferent fibers from the heart that do not run with the classically described sympathetic and vagal bundles (extra-vagal extra-sympathetic fibers).

transmission of pain arising from the ischemic heart.59*‘03,176.2102’3 However, these clinical studies consistently show that only 5(MO% of patients report complete relief from angina following sympathectomy, while 3040% of patients report only partial relief and IO-20% of all patients report no relief at

all. Generally, in these studies there is no explanation given for the failure to completely relieve angina. There is also no explanation for the partial failure rate of sympathectomy, although incomplete surgical sympathectomies have been suggested to be one possible explanation.

Mechanisms of cardiac pain Several key studies are widely cited to document that pain from the heart is conveyed only by sympathetic afferents. The first of these is an experimental study by Sutton and Leuth’” who reported that 3-5 h after a silk ligature had been placed around the left anterior descending coronary artery (the dogs were reported to be completely recovered from ether anesthesia), traction of the ligature in eight of 11 dogs, sufficient to occlude the vessel, produced discomfort and restlessness. Of these eight dogs, administration of 3 mg of atropine to one, and bilateral transection of the vagi in a second dog, did not alter the response to traction of the ligature. However, in the remaining three dogs, tested seven to 14 days following removal of the annulus of Vieussens (which corresponds to transection of sympathetic afferents passing from the heart through the stellate ganglion), there were no behavioral changes observed when traction was applied to the ligature. Using the same surgical approach, White et aZ.‘13 reported that traction of the left anterior descending coronary artery in four dogs caused immediate stiffening of the limbs and, if the traction was maintained for l&l 5 s, signs of restlessness were observed. The authors interpreted these behavioral reactions to coronary occlusion as evidence of cardiac pain. Of the total 21 dogs in their experiments, attempts to interrupt the presumed nociceptive afferent pathways by surgical intervention were made in four animals. In three of these four dogs, the restlessness was abolished by bilateral removal of the stellate and upper four thoracic sympathetic ganglia in one dog, by bilateral transection of the upper five dorsal and ventral spinal roots in the second dog and by bilateral transection of the upper five dorsal roots in the third dog. In the one remaining dog, bilateral transection of the vagi failed to abolish the restlessness produced by traction of the coronary artery. From these results, White et aL213 concluded that cardiac sympathetic afferents, especially to T,-T4, constitute the only pathway for cardiac pain. In a clinical study of 23 patients, included in the report described above, White et aLz13reported that the paravertebral injection of alcohol into the upper four or five thoracic ganglia and their rami resulted in relief from angina in 11 patients (47.7%) and greater than 50% relief in seven patients (30.5%). However, complete failure in three patients (13.1%), and only a small degree of relief in an additional two patients (8.7%) was reported. Thus five of 23 patients (21.8%, while having the same procedure as those who experienced relief, failed to gain any significant relief from angina. In contrast to the results of White et aL2” Lindgren and Olivecrona’03 reported that transection of the five superior dorsal roots (T,-T,) failed to give complete relief from angina to five of seven patients. Nevertheless, they did find complete, or nearly complete, relief in 31 of 71 patients (43.7%) who had either bilateral, left-sided or right-sided cervicotho-

505

racic (stellate plus upper four thoracic) ganglionectomies. In this study, if pain was only left-sided, only a left cervicothoracic ganglionectomy was performed and, if the pain was right-sided, a right-sided cervicothoracic ganglionectomy was performed. If pain was reported bilaterally a bilateral cervicothoracic ganglionectomy was performed. In addition, if pain migrated to the non-operated side following unilateral removal of the ganglia, then ganglia on the other side were removed. Therefore, in 34 of the 71 patients (47.8%) who had either unsatisfactory results (five patients; 7.0%) or a reduction of the severity in attacks (29 patients; 40.8%), pain was not effectively relieved by removal of the upper four to five thoracic ganglia on the side reported to have pain. The mortality rate was 8.5% (six patients). In addition, all 71 patients reported that emotion or exercise postoperatively still produced sensations of choking or slight pain. If only cardiac sympathetic afferents were responsible for the transmission of pain associated with angina, it would be expected that complete transection or removal of cardiac sympathetic afferents would afford complete relief in almost all patients. However, review of the clinical studies by White et aL213and Lindgren and 01ivecronaro3 reveals that after cervicothoracic sympathetic blockade, or surgical removal, complete relief from angina was reported in only 47.7% and 43.7% of all patients, respectively. Failure was reported in 13.1% and 7.0% of all patients and only minor relief in 8.7% and 40.8% of patients, respectively. White’s review”’ concluded that sympathetic afferents were solely responsible for the transmission of cardiac pain. However, he also showed that there were patients who were not afforded any relief following cervicothoracic sympathectomy, but he attributed these results to incomplete denervation. As the stellate and first three to four thoracic ganglia were removed on the side of the body where the pain was located in almost all of the studies reviewed, there either must be another significant sympathetic afferent pathway from the heart (outside of C,-T,) or pain on one side of the body may be signaled by sympathetic afferents on the opposite side of the body. Neuroanatomical studies of sympathetic afferent pathways do not support the notion that there are significant contralateral projections, or that there are cell bodies in levels outside of C 6_T 81.96.147 In iddition to these widely cited papers, there are a number of less well cited studies which also have examined the role of sympathetic afferents in cardiac pain. Jonnesco,87 in two males, and TulIier,‘9’ in one male, found that they could relieve angina by resection of the middle and lower cervical and the upper four thoracic ganglia on the left side, while Briining3’ reported that relief from angina was possible following removal of all three cervical and the upper four thoracic sympathetic ganglia. Using the same surgical method, Kappisgo was unable to relieve any of the

506

S. T.

MELLER

andG. F.

pain associated with angina in one patient whose attacks were also accompanied by a strong sense of anxiety. White and Bland*” reported that surgical interruption of the upper four thoracic sympathetic ganglia gave adequate relief of pain in seven of eight patients, whereas paravertebral injections of alcohol into the upper four thoracic sympathetic ganglia gave complete relief in 42 of 75 cases (56%), moderate or no relief in 32 cases (42.5%) and one death (1.5%). Apthorp et al.’ reported a 75% success rate following sympathectomy (down to T,, T, or TJ, while White and Sweet,2’z in their classic neurosurgery text, reported that cervicothoracic sympathectomy abolished pain in 15 of 19 patients (although chest pain recurred in five of these patients). Although Palumbo and Lului3* reported complete relief from angina in almost all patients following resection of the stellate and the second to fifth thoracic ganglia, they suggested that the favorable results were due to an increased vascularization associated with vasodilation and increased blood flow, and not to transection of afferent pain pathways, as all of the patients in their study still experienced a warning signal on exercise and reported a pressure beneath the sternum and a shortness of breath. Henrad et a1.74 have recently reported on two cases of Prinzmetal angina following sympathetic denervation and found that effective relief was observed only in the patient with coronary vasospasm of the left anterior descending coronary artery; no effective relief was produced in the patient with coronary vasospasm associated with the right coronary artery (supplying the inferiorposterior surface of the heart), thereby suggesting that pain from different regions of the heart may be signaled by different afferent pathways. These reports clearly indicate that cardiac sympathetic afferents are involved in the transmission of nociceptive information from the heart. However, they fail to support the assertion that only cardiac sympathetic afferents are involved in cardiac pain. For example, the experimental reports by Sutton and Leuth176 and White et aL213 demonstrated that occlusion of vessels on the anterior surface of the heart (predominantly involving the left anterior descending coronary artery) produced behavioral responses that they considered to be consistent with the stimulus being noxious. However, the criteria of “discomfort and restlessness” that they used are not necessarily indicative of pain. Certainly, an increase in arterial pressure in humans is perceived as uncomfortable, but is not usually described as painful,‘@’ and is often associated with a hypoalgesia in experimental anima~s41.50.104,108,163,168,169,218,220 and humans

66.219 Remova,

of sympathetic afferents in these studies,‘76,2’3abolished the behavioral responses to coronary artery occlusion, whereas they were unaffected by bilateral vagotomy. This may not be surprising considering that manipulations involving the anterior surface of the heart often result in cardiovascular and nociceptive sympathetic reflexes and that vagal afferents may

GEBHART

predominate in the inferior-posterior region of the heart (a region untested in these studies) (see Section 3.2). Given the lack of detail in the surgical studies reviewed as to the site of the coronary lesion, it is thus not possible to correlate the location of the ischemic stimulus with the effectiveness of the surgical manipulation. However, it seems reasonably evident that there are three distinct groups of patients: a group who were afforded complete relief, a second group who received no relief from angina and a third group who obtained partial relief following sympathectomy. If one accepts that the cervicothoracic sympathectomies were complete and that sympathetic afferents are not the only afferent pathway from the heart signaling nociceptive information, then it seems quite reasonable to speculate and propose that the first group of patients may have had ischemia involving predominantly the anterior surface of the heart, and therefore angina was predominantly sympathetically mediated. The second group had ischemia involving predominantly the inferior-posterior surface of the heart, and therefore angina was predominantly vagally mediated. The third group had ischemia involving both surfaces of the heart, and therefore angina was mediated by both sympathetic and vagal efferents. This is a particularly important concept when evaluating the efficacy of surgical treatment. Although hard and fast delineations probably do not exist, this concept suggests that only 5&60% of patients may have cardiac pain mediated exclusively by sympathetic afferents, lO-20% by vagal afferents, and 3040% may have cardiac pain mediated by both afferent systems (this could certainly account for the partial relief of pain after sympathectomy or the re-occurrence of pain weeks or months after complete sympathectomy). It is also never considered that significant relief following surgery could be the result of a strong placebo effect of hospitalization or surgery, a decreased after-load on the heart (as there is a significant decrease in heart rate and blood pressure after sympathectomy’), or an increased revascularization due to increased coronary blood flow as a result of sympathectomy. 9~138In support of hemodynamic changes resulting in decreased sensations of pain, Braunwald et a1.26 and Courbier et al.” have suggested that electrical stimulation of the carotid sinus nerve relieves angina by increasing coronary blood flow and decreasing myocardial oxygen requirements by decreasing heart rate. Alternatively, stimulation may modify local circulation such that the chemical mediators are unable to gain access to cardiac afferents and the nociceptive signal can no longer be generated. In any event, it still leaves no obvious explanation for the lO-20% of all cases totally unrelieved by surgical intervention, or for the 30-40% of all patients who experience only partial relief, unless incomplete transections or misdirected sympathetic blocks occurred in all of these patients.

Mechanisms of cardiac pain We suggest that although sympathetic afferents from the heart do undoubtedly transmit a significant degree of afferent information related to cardiac pain under conditions predominantly involving the anterior surface of the heart, an extra-sympathetic afferent pathway from the heart is almost certainly implicated in sensations associated with myocardial ischemia, and may involve vagal afferents. 3.1.1. Superior cervical ganglion. In addition to removal of the middle and lower cervical sympathetic ganglia, either alone or in combination with upper thoracic sympathectomies, removal of the SCG alone also has been reported to afford complete relief from angina (Table 1). For example, Brown and Coffey** reported that four of eight patients with angina were relieved of all pain following removal of either the left, right, or both SCG and three of eight patients received some degree of pain relief. In addition, Leriche and Fontaineloo reported that removal of the SCG gave either complete relief, or marked improvement in 48 of 94 patients (51.0%) but pain returned within three months in 17 patients (18.1%). Removal of the SCG failed or gave only slight relief from pain in 11 patients (11.8%) while there was an unknown result in five patients (5.3%) and operative mortality in 13 cases (13.8%). Similar results were provided by Cutler” and Diaz-Sarasola” who reported complete failure in 13.8 and 13.4% of all patients, respectively. That is, Leriche and Fontaine,lm Cutler45 and Diaz-Sarasola4* found complete relief from angina following removal of the SCG in 51.0, 34.4 and 30.7% of all patients, respectively, while complete failure was reported in 11.8, 13.8 and 13.4% of all patients, respectively. In addition, Leriche and Fontaine’” reported that cervicothoracic ramisection (section of the sensory nerve fibers), including those associated with the stellate ganglion, was an effective method for providing relief from angina. They reported that unsatisfactory results, or failure, numbered less than 20%. They discussed the possibility, as suggested by Langley9* and Coffey et al. 35 that sympathetic fibers passing through the SCG were not sympathetic afferents, and that the sensory fibers passing through the SCG were probably vagal in origin. Leriche and Fontaine’” also reported that electrical stimulation of the SCG in man “produced pain with a very definite, sharp and limited topography”. While Davis and Pollock46 reported that SCG stimulation in the cat also produced symptoms consistent with activation of nociceptive afferents, they reported that only transection of the posterior roots of the trigeminal nerve was effective in abolishing the response, indicating that afferents in

*Vagal afferents are defined here as those afferents with their cell bodies in the nodose ganglion (e.g. main vagus, recurrent laryngeal nerve, superior laryngeal nerve, aortic depressor nerve and vagal afferents in the superior cardiac nerve). The precise definition used by others has not always been clear when reading the literature.

507

the SCG pass to the trigeminal nucleus. They did not, however, report whether the afferents were cardiac in origin. If removal of the SCG affords relief from anand electrical stimulation of this gina, 28~34*45~48~‘oo ganglion produces sensations of pain in humans,lw and if there are no sympathetic afferents passing through this ganglion,35*98~‘00 a role for extrasympathetic afferents (possibly vagal) in cardiac pain is clearly indicated. Since the late 1940s there have only been sporadic reports of sympathectomies performed for the relief of a~gi~a9,2l,3l,59,74,2lO,212 with success and failure rates similar to those reported by earlier investigators. In the light of the uncertainty of the completeness of transections, the high mortality rate (5-IO%), the lack of adequate control data, development of advanced pharmacological treatment and the advent of coronary bypass surgery, it is not surprising that cervicothoracic sympathectomy has been abandoned for more reliable treatments. 3.2. Vagal afferents* The potential role of vagal afferents in sensations associated with myocardial ischemia has not been extensively studied, although clinical studies in the early part of this century suggested an involvement35~45~‘W~‘3’~208 (see Table 1). Wenckebach*‘* reported that section of the “depressor vagi” on the left side in two patients and bilaterally in three patients resulted in complete relief from angina (one patient died), and Cutler45 reported significant relief in nine of 12 patients (75%) and intermediate relief in two of 12 patients (16.6%). There appears to be some argument as to whether there is a separate depressor nerve in humans (for discussion, see Refs 28, 152), and Wenchebach208 may have in fact severed vagal afferents which pass through the SCG (as suggested by Coffey et ~21.~~and Leriche and Fontaine’@‘). Additional evidence shows that direct electrical stimulation of the cervical or thoracic vagus in humans has been reported to produce deep, poorly localized, burning sensations,69.2’2or severe pain in the breast.‘33 Further, Reid and Andrus15* suggested, on the basis of the available literature, that “painful sensations may travel to the central nervous system by way of the cervical or upper thoracic spinal nerves and the vagus nerves”. Since those clinical studies in the early part of this century, there has not been any significant research examining an involvement of the vagus nerve in cardiac pain, although Cannon’* reported that stimulation of the vagus nerve below the recurrent laryngeal nerve (and therefore not including a significant number of vagal afferents from the heart) was not in the least disturbing to unanesthetized cats. However, when the vagus nerve was stimulated at the cervical level in unanesthetized cats, Cannon32 reported “that it caused such vigorous reflex coughing that it was impossible to determine other vagal effects”.

508

S. T. MELLERand G. F. GEBHARI

Recent support for a role of the vagus in cardiac that during myocardial infarctions, 48.0% of the pain has been put forward in clinica183~*sand experpatients exhibited hypotension and/or bradycardia imental studies.85,123James et ~1.‘~ and James*’ de- which correlated almost perfectly with the incidence scribe a mass of chemoreceptors in humans and dogs of inferior left ventricular wall infarctions (49.4%). lying between the origins of the aorta and the pulWebb et ~1.~‘~reported that 77% of all patients with inferior-posterior infarctions exhibited bradycardia monary artery which are supplied by branches from the left coronary artery. When activated (by seroand hypotension whereas only 32% of patients with tonin; 5-HT), these chemoreceptors are able to anterior infarctions showed these symptoms. Esente et aLs3recently reported that there is a large incidence double systemic arterial blood pressure through activation of vagal afferents. Further, it was suggesteds3.*’ of bradycardia and hypotension in the early phase of that this vagal afferent-mediated hypertensive myocardial infarction suggesting a vagal activation. chemoreflex is important in mediating some of the Indeed, spontaneous angina attacks initiated from cardiovascular changes in the pain associated with the inferior-posterior wall of the heart are characterangina or myocardial infarction. These chemorecepized by decreases in heart rate, blood pressure and an tors, while not located in cardiac tissue, are supplied increase in left ventricular diastole time (the period in by the left coronary artery. To the contrary, Thames which coronary perfusion takes place), whereas sponet ul.‘** reported, also in the dog, that this coronary taneous angina attacks initiated from the anterior or chemoreflex was not mediated by either classical anterior-lateral wall are characterized by increases in sympathetic or vagal afferent pathways. However, heart rate and blood pressure and a decrease in left they did not remove the SCG (a known source of ventricular diastole time.S8~‘42~‘59~‘87 Thames et ~1.‘~~ vagal afferents). Cornish and Zucker43 have also suggested that ischemia induced by occlusion of the reported that this S-HT-mediated coronary distal end of the left circumflex artery activates vagal chemoreflex is absent in primates. afferent receptors in the inferior-posterior wall of the Coleridge and colleagues 38-40,92’29 have documented dog heart. Walker et ~1.‘~~reported similar findings that there are many unmyelinated vagal afferents with chemical activation of vagal afferents by nicotine which serve an exclusive chemosensitive function. or veratridine. Weaver et cd.202also reported that While they suggested that these afferents play a role occlusions of the left circumflex coronary artery, in mediating some of the inhibitory cardiovascular which generally supplies part of the posterior aspect reflexes, given the circumstantial evidence that vagal of the left ventricle (Fig. 2) usually produced sympaafferents may mediate some of the sensations associtho-inhibition (perhaps vagally mediated), whereas occlusion of the left anterior descending coronary ated with myocardial ischemia, a role for vagal afferents in relaying nociceptive information cannot artery, which predominantly supplies the septum and the anterior aspect of the left and right ventricles be discounted. We have shown that intravenously administered S-HT results in a bradycardia and (Fig. 2) usually produced sympatho-excitation. hypotension (the Bezold-Jarisch reflex),‘22.‘23pseudVagal afferents can also be activated from the affective responses indicative of pain,‘22’23 and an anterior surface of the heart to produce marked hemodynamic effects.‘*‘6.83,84.85 Further, Kositskii aversive behavior assessed in a passive avoidance paradigm. i22All of these responses are mediated by et a1.94and Mikhailova et al.‘24 have reported significant increases in the firing rate of nodose ganglion cervical, and not subdiaphragmatic, vagal afferents cells to occlusion of the left anterior descending (Meller et al., unpublished observations). These coronary artery, indicating that vagal afferents may results also suggest that a vagal afferent-mediated also be activated from the anterior surface of the receptor activation may be important in mediating heart. pain from the cardiopulmonary region that, for There is also a very strong correlation between the example, could be associated with angina or myolocation of infarctions in the inferior-posterior aspect cardial infarction. 3.2.1. Anterior us inferior-posterior. A review of of the heart and the incidence of vagally mediated vomiting and nausea.2.4@,‘60Ahmed et a1.4 reported the literature suggested to us that the cardiovascular that 69% of patients with inferior-posterior wall effects, and the pain associated with angina, might depend on the differential location and activation of infarctions reported a history of nausea and vomitsympathetic and vagal afferents in the heart (Fig. 2). ing, whereas only 27% of patients with anterior wall infarctions complained of these symptoms. For example, anterior ventricular infarctions and Considering the reported preferential distribution vasospasms of the coronary arteries on the anterior of vagal afferents in the inferior-posterior region of surface of the heart usually result in sympatho-excitation and therefore hypertension and tachycardia (a the heart, the overriding effect of vagally mediated hypotension, bradycardia and nausea accompanying presumed sympatho-sympathetic reflex)‘05S”0*‘42~‘59 inferior-posterior wall infarctions and atherosclerotic whereas posterior ventricular infarctions and vaocclusions, it would not be unreasonable to suggest sospasms of the coronary arteries on the inthat vagal afferents may also mediate some of ferior-posterior surface of the heart usually result in the sensations associated with myocardial ischemia, hypotension and bradycardia (a presumed vagoreported especially considering the paucity of sympathetic vagal reflex). 3~110.139~142.159~160~205 Pantridge'

509

Mechanisms of cardiac pain

LAD

RCA

sternocostal

surface

diaphragmatic

surface

Fig. 2. Summary diagram of the major coronary arteries supplying the heart viewed from the stemocostal and diaphragmatic surfaces. This schematic figure clearly illustrates that the left anterior descending coronary artery (LAD) primarily distributes to the anterior surface of the heart along the septum and the medial portions of the anterior surface of the right and left ventricles. The left circumflex coronary artery (LCX), like the left anterior descending coronary artery, also has its origin from the left main coronary artery, and primarily distributes to the lateral margins of the left ventricle. The proximal branches of the left circumflex coronary artery distribute to the anterior surface of the left ventricle, while the distal branches of the left circumtlex coronary artery primarily distribute to the posterior regions of the left ventricle. In contrast, the right coronary artery (RCA) distributes principally to both atria and also to supply almost the entire posterior surface of the right and left ventricles.

In support of this, afferents in this region. 81~‘37~‘47 Henrard et uI.,‘~ as indicated earlier, reported that sympathetic denervation produced no relief in a patient with Prinzmetal angina associated with coronary artery vasospasm of the right coronary artery, which supplies the inferior-posterior surface of the heart. One of the major limitations to our better understanding of the afferent nociceptive pathways associated with myocardial ischemia is that almost all of the

reports involve chemical or mechanical manipulations of the anterior surface of the heart. As we have suggested, these studies may be predominantly activating, and thus preferentially studying, the afferent sympathetic system, although there is undoubtedly also a vagal contribution from these regions. There are only a few direct reports on chemical or mechanical activation of afferents on the inferior-posterior surface of the heart,‘87@‘J99 an area which is well supplied by vagal afferents.“*‘*‘,iw Perhaps those

510

S. T. MELLER and G. F. G~~IHART

patients who were not afforded any relief from angina following sympathectomy (often as high as 20%) may have had occlusions of the right or distal parts of the left circumflex coronary arteries which predominantly supply the inferior-posterior wall of the heart. In the cases of surgical failure by sympathectomy which have been reported, pharmacological or surgical manipulations of the vagal system may have been effective. Therefore, while not strictly delineated, we can speculate that the implications for clinical and experimental research are that angina may be primarily the result of sympathetic afferent activation on the anterior surface of the heart, while vagal afferents may be principally activated on the inferior-posterior surface. Failure to obtain complete relief following sympathectomy may reflect vagal afferent activation predominantly from the posterior surface of the heart. Retrospective clinical studies comparing the type and incidence of pain, the predominant cardiovascular response, and the location of the infarction or occluded vessels associated with angina, may aid in clarifying the role of vagal afferents in cardiac pain. 3.2.2. Convergence. Pain associated with angina or myocardial infarction is often referred to muscle and skin overlying the chest and extending to the shoulder, arm, upper back, neck and even to the head and lower jaw. Therefore, any afferent pathway conveying visceral pain from the heart must converge on cells in the central nervous system that receive information from these varied somatic regions. Several investigators have suggested that cardiac sympathetic afferents and somatic input from the upper limbs and the chest converge on spinothalamic tract cells in the spinal cord and therefore may provide an explanation for the referred pain often However, recent reports associated with angina. 6,8*22*23 have also found that somatic information from the thorax, forelimbs and hindlimbs have a high degree of convergence with vagal afferents on cells in the nucleus of the solitary tract’43.‘44and therefore also may provide a locus for referred pain of vagal origin. In addition, Terui and Koizumi’@ have shown that responses from both sympathetic and vagal afferents from the heart are modified by somatic nerve stimulation. Therefore, while convergence and referred pain have been more systematically studied with respect to the sympathetic nervous system, the nucleus of the solitary tract also possesses the necessary circuitry for somatic and visceral convergence. 3.2.3. Vagal aflerents and antinociception. Ammons et aL6,’ were the first to document that electrical stimulation of thoracic vagal afferents in the primate could attenuate responses of thoracic spinothalamic tract neurons to cutaneous noxious and non-noxious inputs as well as putative cardiac nociceptive input (e.g. intra-atria1 injection of bradykinin). These, and subsequent studies, 6o,62led them to propose that activation of vagal afferents during myocardial ischemia inhibits the rostra1 transmission of cardiac

nociceptive information conveyed to the thoracic spinal cord via sympathetic afferents and may provide an explanation for “silent” ischemia, particularly when the ischemic events are located in the inferior-posterior wall of the left ventricle. Parametric studies of vagal afferent-produced effects on spinal nociceptive transmission in the rat, however, reveal a biphasic effect of vagal stimulation: low intensities of vagal stimulation facilitate or enhance spinal unit responses to noxious cutaneous and noxious visceral stimuli while greater intensities of vagal stimulation inhibit nociceptive responses in an intensity-dependent manner.ls6 The inhibitory and facilitatory effects of vagal stimulation require a relay in the nucleus of the solitary tract:“’ descending inhibitory influences from the brainstem relay further in the pons and rostroventral medulla’s0~‘58 while vagal-produced facilitatory influences require a rostral, forebrain loop before descending the spinal cord in the ventrolateral quadrants.‘50’58 Similarly, chemical activation of vagal afferents also results in an inhibition of nociception at the level of the spinal cord. Systemic administration of veratrine,‘49 [Dala*]methionine enkephalinamide,’ morphine15’ or 5HT12’ all have been shown to produce inhibitory effects on spinal nociception that rely on the integrity of cardiopulmonary vagal afferents. While either electrical or chemical activation of vagal afferents inhibits spinal nociceptive transmission, and also produces inhibitory cardiovascular reflexes (e.g. Bezold-Jarisch reflex), these responses are “indirect”. That is, activation of vagal afferents by these stimuli require a brainstem relay for initiation of the outcomes described above. In addition, given the evidence provided above and the results of Ren et aZ.,‘56 it is clear that activation of vagal afferents also engages ascending systems to the forebrain that appear to facilitate the conscious appreciation of nociceptive stimuli. The inhibitory effects of vagal stimulation on the spinal cord can be interpreted in two ways. Activation of vagal afferents may simply engage descending systems that inhibit spinal nociceptive transmission, including cardiac pain. Alternatively, activation of vagal afferents may be nociceptive (i.e. “painful”) and inhibit spinal nociceptive transmission (including cardiac pain) by a mechanism analagous to counter-irritation (i.e. pain inhibits pain). As most work has been performed on anesthetized animals, these alternative considerations cannot be distinguished in such circumstances. Moreover, given the experimental evidence from electrical and chemical activation of vagal afferents, we speculate that both mechanisms may be functionally important. 3.3. Other potential pathways Besides the classically described sympathetic and vagal afferent pathways which course from the heart, there are several other potential pathways which may

511

Mechanisms of cardiac pain contribute to sensations experienced during myocardial ischemia. It is possible that afferents from the cardiac region which travel in the phrenic nerve may play a role. However, it is to be noted that the only source of phrenic afferents from the region of the heart arise from the pericardial sac and not from the heart per se125 and it is therefore unlikely that phrenic nerve afferents contribute in any significant way to the sensations experienced during myocardial ischemia and angina. It is also possible that sympathetic afferents may enter the spinal cord via the ventral roots. Thus, dorsal rhizotomies would be ineffective in transecting these afferents and they could conceivably account for the failures to relieve angina reviewed above. This is unlikely for several reasons. First, the majority of clinical reports have used transection of sympathetic nerve fibers, or removal of sympathetic ganglia and the sympathetic chain (usually from C8 to T4) in attempts to relieve angina. This still results in a lO-20% failure rate. These surgical manipulations would have disrupted sympathetic afferents which would ultimately travel in either the ventral or dorsal roots of the spinal cord. Second, the numbers of putative nociceptive afferents entering the spinal cord via the ventral roots are not as great as initially thought because some of the ventral root afferents loop back into the dorsal root and some of the afferents are likely to arise from the pia mater under the spinal cord.*16 As a result of surgical manipulations, neuromas may result which could continue to cause pain from the site of the transection. While this is a distinct possibility in those patients who report the recurrence of pain several weeks to months following surgery, it would not contribute to the initial pain associated with myocardial ischemia which preceded surgery. Therefore, failure to relieve pain immediately after surgery is unlikely to be due to the development of neuromas. Another possible explanation for the lack of effectiveness of cervicothoracic sympathectomy to relieve angina is that the angina-like symptoms may originate in an organ other than the heart, such as the gall-bladder or esophagus, or even in the overlying chest muscles. While pain of esophageal origin is indistinguishable from the chest pain associated with myocardial ischemia on the basis of description alone, complete examination by the physician using electrocardiographic examination, stress tests, and angiography enables the two disorders to be distinguished. Inflammation of the upper costal cartilages associated with anterior chest wall syndrome or costochondritis, results in severe chest pain which can be confused with pain of cardiac origin. However, pressure on the sternum or pectoral muscles evokes pain in these patients, but does not produce any sensations in patients with angina. Various syndromes associated with obstruction of the biliary system produce poorly localized pain in the mid-

epigastrium and may be referred to the shoulder and right upper quadrant. However, in contrast to angina, local tenderness is almost always noted in the upper right quadrant and deep palpation increases the sensations. Therefore, while these syndromes may be initially confused with angina, complete examination by the physician will, in almost all cases, result in the correct diagnosis and these syndromes are therefore unlikely to contribute to the lO-20% of patients afforded no relief, or the 30-40% of all patients afforded only partial relief, following cervicothoracic sympathectomy. To summarize, sympathetic afferents are unquestionably important in signaling cardiac pain. However, if (i) cervicothoracic sympathectomy does not completely abolish the pain associated with ischemia of the heart in a significant proportion of patients, (ii) removal of the SCG is effective in some cases, (iii) section of vagal-associated fibers can be effective in some cases, and (iv) electrical stimulation of vagal afferents results in sensations of chest pain in humans, then the role of vagal afferents in relaying sensations associated with myocardial ischemia requires further evaluation. 4. CHEMICAL

MEDIATORS

OF CARDIAC

PAIN

There have been numerous studies on the role of potential chemical mediators of cardiac pain. However, many of these studies have been based on the premise that cardiac sympathetic fibers are the only afferent source of nociceptive information to the central nervous system from the heart.6,22,23,25.13’,‘73,174 In light of the evidence that non-sympathetic, likely vagal afferents may be involved in sensations associated with angina, we have reviewed evidence for activation of both vagal and sympathetic afferents by bradykinin and 5-HT, and also consider the potential roles of lactate, potassium, adenosine, prostaglandins and histamine in cardiac pain. 4.1. Bradykinin Bradykinin most likely

is generally considered to be the chemical mediator of cardiac

pain.6,15,*2~*3,*5,60,131,173,174 Indeed,

it

is

by

far

the

most commonly used chemical for experimental activation of cardiac sympathetic afferents 6,15,22,23,25,29,56.60,62,106,109,131,172-I74 However, while bradykinin clearly results in activation of cutaneous nociceptive afferents, its precise role in cardiac pain remains unclear. Supporting evidence that either epicardial, intraatria1 or intracoronary administration of bradykinin is a noxious stimulus is of three kinds. First, it has been reported that the intracoronary administration of bradykinin produces pseudaffective reactions, including vocalization, in lightly anesthetized dogs.70 Second, bradykinin activates sympathetic afferents”2,1’3,‘29,‘36,‘74,‘92 and third, there is a significant increase in coronary sinus concentration of

512

S. T.

MELLER

and G. F. GEBHARI

tissue at least, bradykinin apparently exerts its effect bradykinin approximately 2-5 min following acute indirectly through the release of other mediators occlusions of the left anterior descending coronary artery.‘*,93 which sensitize primary afferent nociceptors rather than by a direct action on nociceptors.“” 4.1.1. Behavioral effects. Guzman et al.” reported In the heart, the intra-atrial, intracoronary or that the intra-arterial injection of bradykinin into a epicardial application of bradykinin in cats and number of vascular beds, including the coronary monkeys has also been reported to produce its effects circulation, caused vocalizations in lightly chloraloseafter a relatively long latency (usually around anesthetized dogs and cats. Injections directly into 15-20 s8,15,22,25,60,106,112,136,1S4 the left coronary artery caused a small increase in and one of the reasons for arterial blood pressure, hyperpnea, and vocalization, this delay in onset of action may be due to the time whereas injections into the pulmonary artery or needed for it to distribute to the receptors in the coronary circulation. However, considering that the descending aorta failed to produce vocalization. This transcardiac perfusion time in the cat and monkey is initial report provided important evidence that only on the order of 700 and 600 ms, respectively, and bradykinin may be involved in cardiac nociceptive mechanisms. In support of this, Malliani et al.“’ and the plasma half-life of bradykinin is around 15 s,lg3 Pagani et a1.‘36 also reported that the injection of this conclusion requires experimental verification. An bradykinin (up to 2pgg/kg) within the first few days alternative possibility is that the responses to intraafter surgery into the left coronary artery (left anatrial, intracoronary or epicardial application of terior descending or left circumflex coronary arteries) bradykinin require a cascade of events (e.g. the of the conscious dog produced a transient hypotenrelease of prostaglandins) (see Ref. 20). There are, sion and bradycardia accompanied by vocalization however, no reports of which we are aware on the and agitation. However, one to three weeks after actions of bradykinin on presumed cardiac nociceptors in the presence of inhibitors of prostaglandin surgery, bradykinin produced a dose-dependent pressor response, tachycardia, and hyperpnea in the synthesis such as non-steriodal anti-inflammatory absence of any discernible signs of discomfort (no agents. 4.1.2. Aferent activation. There are many reports vocalizations or struggling). This study suggested that on the relex effects of epicardial application or intraother agents released during surgery may sensitize atria1 or intracoronary injection of bradykinin which Ad- or unmyelinated C-fiber afferents to the actions have established that bradykinin activates cardiac of intracoronary or pericardially applied bradykinin. sympathetic afferents; the responses to bradykinin are That is, bradykinin alone may not be noxious, but essentially unchanged following bilateral transection requires the sensitization of nociceptive and cardiovascular afferents by other agents in order to elicit its of the vagi23,112.136~173and are completely abolished by deafferentation of sympathetic afferents.s6’07”3~‘32In full actions (for reviews, see Refs 76, 172). In line with these studies, bradykinin was either applied epithis, bradykinin infusions into the coronary arteries cardially to, or injected into coronary arteries on the of humans have not been reported to precipitate anterior surface of the heart, an area well supplied by angina-like symptoms. I48Further, the cardiovascular reflex effects of bradykinin have been reported to be sympathetic afferents, or injected into the left atrium, where it would distribute to the entire coronary potentiated following prior application of prostatree and preferentially activate sympathetic afferents, and elevated concentrations of glandins ‘8~‘29~‘72~‘73 which are more numerous on the anterior surface prostaglandins have been found in patients with of the heart. None of these studies have restricted unstable angina, ischemic heart disease,‘9~79’02~2’s and in studies of experimentally induced anoxia.‘4~52~209the application of bradykinin to the epicardium or administered it into the coronary arteries supplying In addition, experimental studies also document regions of the inferior-posterior surface of the that bradykinin-induced changes in sympathetic heart, where predominantly vagal reflexes can be nerve activity or cardiovascular function are reduced, ~~~~~~,3~llO~l39~~4l~l42~‘59~~60,205 Although, as indicated or abolished, by pretreatment with aspirin’923’93or above, bradykinin applied to the anterior surface of indomethacin.‘74’75 the heart is also capable of activating cardiac vagal In cutaneous tissue, the application of bradykinin reCeptors92,10’.ls4.19~ and may mediate some of the has been reported to cause a release of prostaglandepressive actions attributable to intracoronary injecdins99’*3’84and to produce a hyperalgesia.‘83’84 The tions of bradykinin92~‘07’54~‘72~‘9* This also suggests bradykinin-induced hyperalgesia is not immediate, that there is a significant interplay between vagal and but has a relatively long latency to effect (usually sympathetic afferents from the heart which may be around 4-5 min) and it has been suggested that this occurring at supraspinal sites, or at the level of the delayed response may be dependent on the release of prostaglandins rather than a direct effect of spinal cord, and that the cardiovascular, and perhaps nociceptive, effects would depend on which afferents bradykinin on nociceptive afferents.‘83’84 In line with were preferentially activated. this is the finding that not only is bradykinin-induced Nishi et al.13’ reported that responses of A6-fibers cutaneous hyperalgesia blocked by sympathecin the inferior cardiac sympathetic nerve were intomy lo’ but it is also blocked by non-steroidal anticreased by mechanical probing, heat and topical inflammatory drugs.W’O’ Therefore, in cutaneous

Mechanisms of cardiac pain application or intravenous administration of chemical agents (including bradykinin), suggesting that some of the receptors in the heart are polymodal. Baker et al.” confirmed that A6- and C-fiber afferents of polymodal receptors in the heart respond to light touch and probing, as well as to either topically applied or intra-arterially administered bradykinin. However, this is not definitive evidence that they serve a nociceptive function. In contrast to the study by Nishi et al., H’ Baker et a1.l5 found a small number of A6- and C-fibers (18 out of 191) that responded only to bradykinin and not to mechanical stimulation, although mechanical stimulation is obviously limited to the external surface. The spontaneous activity of these fibers (0.3 + 0.3 impulses/s) was low, but still within the range normally seen”‘!j and they therefore were not silent. The existence of normally silent fibers had been previously suggested by Uchida and Murao”’ who reported that there was a recruitment of silent fibers capable of conveying noxious information. However, Malliani et al.“’ suggested that the thresholds for activation of the fibers conveying information pertaining to the mechanical actions of the heart were changed due to alterations in cardiovascular function. Although Brown and Malliani29 claimed that there were silent cardiac afferent fibers, a subsequent report from their laboratory’06 stated the apparent presence of silent fibers was due to a low baseline arterial pressure brought about by spinal transection, which probably held some of the mechanoreceptors below threshold. From this, they concluded that there did not appear to be fibers in cardiac sympathetic afferents which are recruited by the application of bradykinin to the heart. Therefore, although bradykinin activates sympathetic afferents, there is no compelling evidence that these afferents are specifically nociceptive and they may be more importantly involved in cardiovascular regulation of the heart and the coronary circulation, as suggested by Felder and Thames,56 Malliani et al.“’ and Pagani et a1.‘36 4.1.3. Present in signiJicant concentrations? There are reports of increases in the concentration of bradykinin in coronary sinus blood approximately 2-5 min following acute occlusions of the left anterior descending coronary artery,72,93 suggesting that a potentially noxious event results in the release of bradykinin. However, considering the abundant reports of cardiovascular reflexes produced by intracoronary injections of bradykinin,“2*“3*‘36~‘73~‘74 it is perhaps not surprising that there is an elevated concentration of bradykinin in coronary sinus blood during, and following, an ischemic episode. 4.1.4. Noxious? The crux of any argument that a substance like bradykinin is noxious is that it must produce behavior consistent with it being a painful stimulus. There is only one report of which we are aware in support of this.‘OThere are, however, several reports indicating that bradykinin alone does not produce pain in chronic experimental animals”2,‘36 or

513

humans.‘4* Thus it seems prudent that caution be taken when reflexes monitored in deeply anesthetized animals to either epicardial application, or intraatria1 or intracoronary administration of bradykinin, are interpreted as indicative of pain and the result of direct activation of cardiac nociceptors. In the absence of conclusive evidence, only claims concerning cardiovascular reflexes activated by bradykinin and mediated by cardiac sympathetic afferents should be made. Although bradykinin has been in vogue as an important mediator of cardiac pain for more than 20 years, and while there certainly is evidence to suggest a role for this substance in cardiac pain, there is also considerable evidence that this chemical by itself may play only a supporting role. 4.2. Serotonin 4.2.1. Behavioral effects. Consistent with a cardiac nociceptive role for 5-HT is the report by Guzman et af.‘Othat intracoronary injections of 5-HT produce pseudaffective responses (including vocalizations) in lightly anesthetized dogs. Additional support comes from James et al.” who found that 5-HT injected into the left atrium of conscious dogs caused them to exhibit distinct pseudaffective reactions indicative of angina. The dogs showed behaviors suggestive of pain, stretching of the forelimbs, anxiety and apprehension, whining and tremors. Intravenously administered 5-HT also produces sensations of pain in humans,“’ distinct pseudaffective responses in rats’22x’23and monkeysI and an avoidance behavior in rats.‘22 Since circulating 5-HT is degraded within 1 min under normal circumstances by blood vessels and the lungs,22’ and between 70 and 90% of intravenously administered 5-HT is degraded during one pass through the pulmonary circulation,88~‘89~2’4 intravenously administered 5-HT likely activates afferents from either the heart and/or lungs. When administered in this way, the pseudaffective responses to intravenous 5-HT that have been reported in the rat12: are the result of activation of cardiopulmonary vagal afferents, and not afferents from the gut, as these behavioral responses are absent following bilateral cervical vagotomy and are unaffected by subdiaphragmatic vagotomy (Meller et al., unpublished observations). Considering that 5-HT (i) activates vagal afferents (and other afferents which may be important to cardiac sensation, including sympathetic afferents) (for review, see Ref. 83), (ii) produces behavioral responses indicative of pain in several species,‘4~70~85~‘23 including humans,s0 and (iii) is found in increased concentrations at sites of pathological occlusion,“~g7 or following experimental coronary occlusion, or during/after angina,‘46*‘67,‘95 it seems reasonable to suggest that 5-HT may be involved as one of the potential mediators of cardiac pain. 4.2.2. Afferent activation 5-HT has been shown to have a potent depolarizing effect on vagal afferent cell bodies in the nodose ganglion’3*‘6’~‘65~17’~2~ and on

514

S. T.

MELLER and

unmyelinated C-fibers in the cervical vagus.13’ 5-HT also activates extrasynaptic 5-HT receptors in the main vagal trunk14’ and is a potent activator of vagal afferents located on the anterior, or inferior-posterior surface of the heart where it produces marked hemodynamic effects (for review, see Ref. 83). From these reports, it is likely that 5-HT is able to activate vagal afferents. Speculation on the latency from the time of administration of 5-HT to the resultant hemodynamic and depolarizing effects being relatively short suggests a role for 5-HT in cardiac (1-3 s)83~‘23,‘85,188 pain. It has been suggested that myocardial infarction and various forms of angina may be due to vasospasm (for review, see Ref. 68). Indeed, vasospasm has been observed many times under arteriographic examination and is usually associated with a decrease in heart rate.5’~‘41~‘42 The most pronounced vasospasm is observed when contrast medium is injected into the arteries supplying the inferior wall of the left ventricle.‘4’ In line with this, there is evidence to suggest that 5-HT is intimately involved in the genesis of coronary vasospasm, as well as in thrombus formation in association with atherosclerosis. 42.3. Present in signiJicunt concentrations? Experimentally, 5-HT activates vagal afferents from the heart. The key question, however, is: is the concentration of 5-HT in the coronary arteries sufficient to activate vagal afferents during angina or coronary artery disease? In normal individuals, plasma 5-HT concentrations are low,” and much of the vascular source of plasma 5-HT is from platelets. During coronary artery disease, thrombus formation and hyperaggregation of platelets can lead to an increased platelet uptake and an increase in 5-HT in the plasma. Additionally, it has been reported’6,‘96 that aggregating platelets, found commonly in coronary artery disease, contract isolated human coronary arteries through the release of 5-HT and thromboxane (which act on thromboxane receptors on the smooth muscle,19(’ or on 5-HT, receptors on the endothelium42), further indicating a potential role for 5-HT in vasospasm. Correspondingly, there is a significant increase in platelet uptake of 5-HT in patients with a history of ischemic heart disease or myocardial infarction.‘46 Plasma 5-HT concentrations were also found to be markedly elevated in patients with a recent myocardial infarction compared to plasma 5-HT concentrations in postoperation patients or normal controls.‘67 Not only are platelet and plasma concentrations of 5-HT elevated, but 5-HT concentrations have been found to be markedly elevated (18-27 times) at sites of fixed coronary artery obstruction and endothelial inConsistent with an elevated plasma conjury. 11.97.215 centration, Jamesa reported that up to 2OOOpg of 5-HT can be released from 1 ml of blood. Not surprisingly, an increase in 5-HT has been found in coronary sinus blood of patients with coronary artery disease’95 or ultrastructural changes in the shape of

G. F.

GEBHART

platelets during atria1 pacing.16” However, as with bradykinin, it still remains to be answered whether the elevated concentrations of 5-HT found under various pathological conditions are sufficient to produce cardiac pain. A recent study4’ reported that ketanserin (a 5-HT, receptor-selective antagonist) failed to prevent variant angina, which is predominantly caused by vasospasm. In this study, four of five patients were found to have occlusions of coronary arteries predominantly on the anterior surface of the heart which was assessed by angiography and changes in the electrocardiogram. Additionally, Mata-Bourcart et u/.‘~’ reported a failure of ketanserin to prevent ergonovine-induced attacks of variant angina. However, of the six patients in this study, three had angina associated with the anterior region of the heart and three had angina associated with the inferiorposterior region of the heart (assessed by coronary arteriography). Their results are difficult to interpret as two of the six patients recorded no attacks prior 10, or after, ketanserin therapy. Discounting these two patients, there were two patients considered to have occlusions on the anterior surface of the heart who showed a significantly greater number of attacks per day (3.0 vs 5.5) after ketanserin administration, whereas the two patients considered to have occlusions on the inferior-posterior-anterior surface of the heart showed significantly fewer attacks per day (1.6 vs 0.7) after administration of ketanserin. These results are not conclusive, but they do suggest that 5-HT released in vessels on the inferior-posterior surface of the heart may be involved in the genesis of angina. 4.2.4. Noxious? Taking into account that 5-HT produces pseudaffective responses in animals and reports of pain in humans, that it activates cardiopulmonary vagal afferents, that it is present in the heart in sufficient concentrations under conditions of ischemia or coronary artery disease, and considering its predominant role in mediating cardiovascular responses from the inferior-posterior regions of the heart, it would not be unreasonable to speculate and suggest that 5-HT may play a role in cardiac pain. 4.3. Adenosine Since the role of adenosine in cardiac pain has recently been reviewed by SylvCn,“’ only a summary of its proposed actions is presented here. During of adenosine are ischemia, increased amounts formed63.‘77 and coronary sinus concentrations of adenosine are elevated following myocardial ischemia.‘55 Adenosine is also produced by conditions of experimentally induced hypoxia.52 Intravenously administered adenosine provokes pain in normal healthy volunteers”’ and in patients with ischemic heart disease.lgO Adenosine also produces a dosedependent’79 central chest pain radiating towards the neck, arms and abdomen in the absence of ischemic electrocardiographic changes, whereas intravenously

Mechanisms of cardiac pain administered inosine (the major first metabolite of adenosine) does not produce chest pain or respiratory reactions.‘53 Following the intravenous administration of adenosine, chest pain was reported to begin shortly after the initial increase in coronary sinus flowis’ with respiratory stimulation preceding chest painzO’ Theophylline (a competitive antagonist at adenosine receptors) decreases both the degree of hypapnea and chest pain produced by adenosine in healthy humans.“’ Dipyridamole, which blocks the transport of adenosine through the cell membranelM and thereby increases extracellular concentrations of adenosine, has been shown to increase adenosine-induced hyperventilation and chest pain in healthy volunteers.“’ Sylvtn”’ has suggested that adenosine activates neural receptors directly to produce the pain as there were no changes in the electrocardiogram, and similar degrees of exercise-induced vasodilation do not produce chest pain. Accordingly, it has been reported that in the cat, intravenous adenosine sensitizes myelinated and unmyelinated vagal afferents.33”62 From the available evidence, it is clear that adenosine is implicated in the genesis of cardiac pain; however, the specific receptors and afferents which are activated remain unclear. 4.4. Histamine Direct reports on the involvement of histamine in the genesis of cardiac pain are few. Guzman et al.” reported that the intracoronary injection of histamine, like bradykinin and 5-HT, produced pseudaffective reactions in dogs and Ginsburg et aL6’ reported that intravenously administered histamine produced coronary artery vasospasm in four of 12 patients. The subsequent administration of cimetidine (an H, receptor antagonist) prevented the unpleasant side-effects of histamine, which include some angina-associated symptoms. It has also been reported that histamine activates cardiac sympathetic afferentsi3’ as well as cells in the nodose ganglion.” Therefore, although histamine may be able to directly activate cardiac afferents when applied exogenously, and while histamine is produced, stored and is able to be released from mast cells in the myocardium ‘2,65,“g120there is some controversy as to whether significant amounts of histamine are released during myocardial ischemia.‘20*2’7Just what role histamine may play in cardiac pain remains unclear. 4.5. Prostaglandins Prostaglandins have been shown to sensitize cutaneous primary afferent nociceptors by a direct action.57*183*‘84 Therefore, while not causing anginalike symptoms themselves, ‘02,‘26 they may act to lower the threshold of cardiac nociceptive afferents. Intravenous infusions of PG12 have even been reported to prolong the time between angina attackszO and to reduce, or abolish, attacks of spontaneous angina.ig2 However, inhibitors of prostaglandin synthesis (e.g.

515

aspirin and indomethacin) do not affect the severity or discomfort of angina. iz6 Therefore, while prostaglandins may sensitize nociceptive afferents to the actions of potential algesic agents (e.g. potassium, lactate, histamine, adenosine, bradykinin or 5-HT), prostaglandins by themselves are apparently not a direct mediator of cardiac pain. While exogenously applied prostaglandins have been shown to directly activate predominantly vagal afferents related to cardiovascular contro1,7”78,‘72a sensitizing function has also been put forth with respect to cardiovascular-related cardiac afferents.‘7~78~‘29*‘72~‘74 The reflex cardiovascular effects of bradykinin have been reported to be potentiated following prior application of prostaglandins’7~77~129~‘72~‘74 and elevated plasma concentrations of PGE,, PGF2,, TXA, and PGI, have been found in patients with unstable angina, during a myocardial infarction’9,79*‘26,2’5 and in anoxia-induced experimental studies.24,52,209 Although the exact function of these substances is not clear, it would not be unreasonable to suggest that they may be released locally to function in maintaining homeostasis by increasing coronary blood flow and decreasing the incidence of myocardial arrhythmias,‘26 in some instances to suppress pain transmission (i.e. PG12), and in other instances to aid in signaling to the organism of impending damage (possibly by sensitizing nociceptive afferents to both chemical and mechanical stimuli). 4.6. Potassium Several studies have shown that there is a rapid increase in the extracellular concentration of potassium in myocardial tissue after the onset of ischemia (for review, see Ref. 207). As with lactate, when potassium is released in sufficient concentrations it could act nonspecifically to depolarize both vagal and sympathetic afferent fibers. Potassium has been shown to produce pseudaffective responses in dogs when administered into the coronary circulation,” and chest pain and electrocardiographic changes when injected into the coronary circulation of patients with coronary artery disease.206 However, in human studies, ischemia induced by inflation of angioplastic balloons for more than 15 s produced an increase in potassium concentration in the coronary sinus which was neither sufficient to induce changes in the electrocardiogram nor produce chest pain.*07 While ischemia usually lasts for several minutes to hours, plasma potassium concentrations do not reach significantly greater levels. Therefore, within the physiological range of potassium released during ischemia, extracellular potassium by itself may not be sufficient to induce angina. 4.7. Lactate Lactate is released from myocytes in response to myocardial ischemia. In experimentally induced

516

S.

T. MELLER and G. F. GEBHART

hypoxia, it can be shown that extracellular concentrations of lactate increase markedly in myocardial tissues2 and alterations in myocardial lactate concentrations have routinely been used to indicate myocardial ischemia during pacing-induced stress.‘28.‘40In these patients, increased lactate concentrations have been found 15 s after pacing, but these concentrations return to normal within l-2 min.ls5 Intracoronary injections of lactic acid can elecit a pseudaffective reaction in lightly anesthetized dogs”’ or cats.12’ However, the intracoronary injection of lactate only excites unmyelinated C-fiber sympathetic afferents at a non-physiological pH (3.64.6),‘94 whereas the pH of coronary sinus blood only falls from 7.4 to 7.25 during myocardial ischemia.‘3’ Therefore, changes in plasma pH within the physiological range seen by the heart or alterations in lactate concentration within the myocytes do not appear to be sufficient to produce cardiac pain. However, local changes in pH at the afferent ending sufficient to alter the excitability of the afferent terminal but not to alter plasma pH may possibly contribute to cardiac pain. 4.8. Synergism Handwerker and Reeh,” in in vitro studies of cutaneous nociceptors, have examined activation of Ad- and C-fiber afferents in the skin by a variety of substances including bradykinin, S-HT and histamine. While these and other substances activated the nociceptive afferents studied, they found that a “Soup” containing bradykinin, 5-HT, PGE,, histamine and K+ at concentrations intended to mimic those occurring naturally, induced responses more frequently than did bradykinin or 5-HT alone. Although such a soup has not been described for studies related to cardiac afferents, it may be a better and more rational strategy to develop and study the effects of a soup optimized for activation of cardiac afferents by systematically examining synergism between each of these potential chemical mediators. 5.

CORONARY

OCCLUSION

As myocardial ischemia is the major precipitating factor in angina,“~“5~‘” coronary artery occlusion has been widely used in experimental studies to reproduce the ischemic stimulus considered to underly angina. Many researchers have argued, therefore, that occlusions of the major coronary arteries should produce pseudaffective reactions in animals.27.60~6’~‘76~2’3 While there certainly is evidence that coronary occlusion can produce pseudaffective reactions in experimental animals 27~176,213 there are at least two concerns that have a&en. First, there is apparently a significant contribution to these pseudaffective responses by mechanical traction on the coronary artery. TWO studies have dissociated the stimulus of mechanical traction from occlusion91,“6 and shown that coronary occlusion without traction does not produce pseudaffective responses. For example, Sutton and Leuth176

noted that accidental transection of a coronary vessel during experimental coronary artery occlusion resulted in the cessation of the pseudaffective have been carried response. Second, studies 27960,61,176J13 out either in lightly anesthetized or conscious animals within hours after surgery. Maseri et al.,“’ in addition to the studies by Katz et al.” and Martin and Gordham,‘16 reported that coronary occlusion in awake dogs after complete recovery from surgery failed to eleicit pseudaffective or pain-like reactions in many cases, even when the occlusion produced an infarction. Considering that administration of bradykinin into the coronary circulation produces pseudaffective reactions only in the first few hours to days following sUrgery,70J~2,136 while no behavioral responses are apparent in the same animal two weeks after surgery “2~‘36the possible contribution of post-surgical, experimentally induced changes to the responses produced by coronary artery occlusion must be clarified. Whether chemical mediators present post-surgically might contribute to a “sensitization” of afferents to the occlusive stimulus has not been systematically examined. In acute experimental conditions using anesthetized animals, coronary artery occlusion has been shown to activate cardiac sympath~~~~27.55.61.95,114,190,193.202 and vagal afferents94,‘24.187*‘90~2~ and responses are generally dependent on the anterior or inferior-posterior location of the occlusion *‘,61.95.114,18’,190.193.19’~202 In addition there are con_ siderable metabolic adjustments during ischemia, including changes in bradykinin,72x93 5-HT,‘1,83.97.‘95 prostaglandins,l9,24,5*.‘9,209.2l5 lacadenosine,‘j’.“’ tate 52~128~‘39~‘55 potassium2” and histamine concentratfons.12’ In humans, myocardial ischemia and associated metabolic changes are usually present prior to reports of sensations of pain, and in experimental studies there is generally reported to be a 5540-s latency from the time of coronary occlusion to alterations in vagal or sympathetic nerve activity. In light of earlier evidence, these experimental studies are suggestive of the release of some chemical mediator(s) following occlusion that activate afferents involved in cardiovascular control and nociceptive transmission. In support of this, Zucker et al.222have shown that, in anesthetized animals, the cardiovascular reflexes to coronary artery occlusion were abolished by pretreatment with the non-steroidal anti-inflammatory drug indomethacin. It is still not known which of the potential chemical mediators released during occlusion are able to evoke painful sensations, although activation of vagal and/or sympathetic afferents is likely to depend on (i) the location of the occlusion, (ii) the sensitization and activation of these afferents by several, if not all, of the putative algesic agents acting simultaneously, and (iii) cardiovascular reflexes which alter coronary blood flow and subsequent distribution of these various putative algesic agents.

517

Mechanisms of cardiac pain 6. SUMMARY

There is considerable evidence that on the anterior surface of the heart (which is usually supplied by the left anterior descending and the proximal part of the left circumtlex coronary arteries), sympathetic efferent reflexes characterized by tachycardia and/or hypertension predominate following experimental or pathological perturbations. These cardiovascular reflexes are accompanied by an increase in presumed nociceptive afferent traffic and, in ~atholo~cal condition, by pain. In these experiments, there is generally no effect of vagotomy on afferent nerve traffic, and lower cervical and upper thoracic sympathectomies help provide relief from angina. On the other hand, experimental or pathological perturbations involving the infe~or-~ste~or surface of the heart (supplied by the right and distal parts of the left circumflex coronary arteries), are characterized by vagal efferent reflexes, resulting in bradycardia and/or hypotension. These reflexes are accompanied by an increase in vagal afferent nerve traffic and, in patholo~cal conditions, by pain. In these experiments, vagotomy generally abolishes such cardiovascular reflexes, and lower cervical and upper thoracic sympathectomies are not effective in the relief from angina. Although cardiac sympathetic afferents are unquestionably involved in the central transmission of nociceptive information from the heart, it is also likely that there is a cont~buting role from the vagus in cadiac pain. It is important experimentally to understand the natural stimulus that gives rise to angina. In the clinical situation, a decrease in coronary blood flow or an increase in the metabolic demands of the my~ardi~ due to increased work are obvious precipitating factors which lead to myocardial ischemia. In the experimental situation, occlusion of the coronary arteries is often used as a stimulus which mimics myocardial ischemia. As people who frequently experience angina have varying degrees of coronary artery disease, it is difficult to accept that the state of the coronary arteries of the normal experimental animal bear any resemblance to the state of the coronary arteries under pathological conditions. That is, the gain of homeostatic reflexes, the basal concentrations of neuroactive substances in the plasma, the myocardium and the afferent terminals, the excitability of the afferents, access of chemical mediators (e.g. bradykinin, .5-HT, adenosine, histamine, prostaglandins, potassium, lactate), to afferents, and the overall function of the animal are all significantly different. We have no idea how control mechanisms have been altered in the person with severe coronary artery disease compared to the normal patient or the “normal” experimental animal.

Ideally, when trying to understand the mechanisms of cardiac pain in experimental animals, we should try to conduct these experiments in models which approach the ~tholo~~l situation in humans. Although such models have been described?? the extent to which they are appropriate for study of the issues raised here is not known. Just what the chemical mediators are is a critical question to be answered in elucidating the mechanisms of cardiac pain. Many attempts have been made to correlate a change in pH, lactate, potassium, adenosine, bradykinin, prostaglandins, histamine or S-HT concentrations with cardiac pain. However, since there is no evidence that any one putative endogenous algesic agent is released during ischemia in the absence of others being released, then it seems evident and logical to propose that activation of afferents may be by more than one substance. Attempts to correlate any single, particular agent with pain are limited, and should therefore only serve to provoke us to investigate the interactions of these substances in the experimental systems that we use.

7. CONCLUSIONS It is evident that the mechanisms underlying pain arising from the ischemic heart are not fully understood. This review of the literature suggests that multiple systems may be involved and we suggest that our limited knowledge of cardiac pain mechanisms is due, in part at least, to the restricted focus on (i) sympathetic afferents as the only afferent pathway mediating sensations associated with myocardial ischemia, (ii) bradykinin as the most important mediator of cardiac pain, (iii) experimental manipulations limited to only the anterior surface of the heart and (iv) non-pathological models for study.

“Indeed, the more we study angina pectoris the more we are inclined to believe that its causes are just as varied as are the causes of pain in any other region of the body, and that it is just as illogical to treat all angina by the same therapeutic procedure as it is to treat all pain in any other region by the same procedure.” Reid and Andrus, 1925.‘52 A~k~o~~edgerne~~s-she authors wish to thank Drs R. K. Bhatnagar, C. L. Cleland, D. D. Gutterman, S. J. Lewis and R. J. Traub for their comments on earlier versions of this manuscript. We especially wish to thank Dr A. Randich for his valuable critical commentary and suggestions for improvement. The authors also wish to thank Syrena Hepker and Kathy Andrews for secretarial assistance. Supported by DHSS grants NS 19912, DA 02879, NS 29844, HL 32295 and an unrestricted pain research grant from Bristol-Myers Squibb Co.

REFERENCES 1. Abboud F. M. and Thames M. D. (1983) Interaction of cardiovascular reflexes in circulatory control. In Handbook uf Physiology--The Cardiovascukzr System ill (eds Shepard J. T. and Abboud F. M.), pp. 675-753. Williams and

Wilkins, Baltimore, MD.

518

S. T. MELLERand G. F. GEBHART

2. Abrahamsson H. and Thor&n P. (1973) Vomiting and reflex vagal relaxation of the stomach elicited from heart receptors in the cat. Acta. physiol.‘scanb. 88, 433239. Adgey A. A. J., Geddes J. S., Mulholland H. C., Keegan D. A. J. and Pantridge J. F. (1968) Incidence, significance and management of bradyarrhythmia complicating acute myocardial infarction. Lancer 23, 1097-l 101. Ahmed S. S., Gupta R. C. and Brancato R. R. (1978) Significance of nausea and vomiting during acute myocardial infarction. Am. Heart J. 99, 671-672. Aicher S. A. and Randich A. (1988) Effects of intrathecal antagonists. on the antinociception, hypotension and bradycardia produced by intravenous administration of [D-Ala*]-methionine enkephalinamide (DALA) in the rat. Pharmac. Biochem. Behav. 30, 65-72.

6. Ammons W. S., Blair R. W. and Foreman R. D. (1983) Vagal afferent inhibition of spinothalamic cell responses to sympathetic afferents and bradykinin in the monkey. Circulation Res. 53, 603612. 7. Ammons W. S., Blair R. W. and Foreman R. D. (1983) Vagal afferent inhibition of primate spinothalamic neurons. J. Neurophysiol. 50, 926-940.

8. Ammons W. S., Girardot M.-N. and Foreman R. D. (1985) Effects of intracardiac bradykinin on T,-T, medial spinothalamic cells. Am. J. Physiol. 249, R147-R152. 9. Apthorp G. H., Chamberlain D. A. and Hayward G. W. (1964) The effects of sympathectomy on the electrocardiogram and effort tolerance in angina pectoris. Br. Heart J. 26, 218-226. 10. Artigas F., Sarrias M. J., Martinez E. and Gelpi E. (1985) Serotonin in body fluids: characterization of human plasmatic and cerebrospinal fluid pools by means of a new HPLC method. Life Sci. 37, 441447. II. Ashton J. H., Benedict C. R., Fitzgerald C., Raheja S., Taylor A., Campbell W. B., Buja L. M. and Willerson J. T. (1986) Serotonin is a mediator of cyclic flow variations in stenosed canine arteries. CirculaGon 73, 572-578. 12. Assem E. S. K. and Ezeamuzie I. C. (1989) Suxamethonium-induced histamine release from the heart of naive and suxamethonium-sensitized guinea-pigs: evidence suggesting spontaneous sensitization in naive animals, and relevance to anaphylactoid reactions in man. Agents Actions 27, 146-149. 13. Azami J., Fozard J. R., Round A. A. and Wallis D. I. (1985) The depolarizing action of S-hydroxytryptamine on rabbit vagal primary afferent and sympathetic neurons and its selective blockade by MDL 72222. Naunyn-Schmiedeberg’s Arch. Pharmac. 328, 423-429.

14. Bachman D. S. and Katz H. M. (1977) Physiologic responses to intravenous serotonin in the awake squirrel monkey. Physiol. Behau. 18, 987-990.

15. Baker D. G., Coleridge H. M., Coleridge J. C. G. and Nerdrum T. (1980) Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent-nerve endings in the heart of the cat. J. Physiol., Land. 306, 519-536. 16. Barron K. W. and Bishoo V. S. (1982) Reflex cardiovascular changes with veratridine in the conscious dog. Am. J. Physiol. 242, H810-H81;. . 17. Bassenge E. and Munzel T. (1988) Cardiac mechanisms for the development of angina pectoris pain. Z. Kardiol. 77, Suppl. 5, 5-14. 18. Beck P. W. and Handwerker H. 0. (1974) Bradykinin and serotonin effects on various types of cutaneous nerve fibres. Pjltigers Arch. 347, 207-222.

19. Berger H. J., Zaret B. L., Speroff L., Cohen L. S. and Wolfson S. (1977) Cardiac prostaglandin release during myocardial ischemia induced by atria1 pacing in patients with coronary artery disease. Am. J. Catdiol. 39, 481486. 20. Bergman G., Daly K., Atkinson L., Rothman M., Richardson P. J., Jackson G. and Jewitt D. E. (1981) Prostacyclin: haemodynamic and metabolic effects in patients with coronary artery disease. Lancer i, 569-572. 21. Birkett D. A., Apthorp G. L., Chamberlain D. A., Hayward G. W. and Tuckwell E. G. (1965) Bilateral upper thoracic sympathectomy in angina pectoris: results in 52 cases. Br. Med. J. 2, 187-190. 22. Blair R. W., Weber R. N. and Foreman R. D. (1982) Responses of thoracic spinothalamic neurons to intracardiac injection of bradykinin in the monkey. Circulation Res. 51, 83-94. 23. Blair R. W., Weber R. N. and Foreman R. D. (1984) Responses of thoracic spinoreticular and spinothalamic cells to intracardiac bradykinin. Am. J. Physiol. 246, HSO(tH507. 24. Block A. J., Feinberg H., Herbaczynska-Cedro K. and Vane J. R. (1975) Anoxia-induced release of prostaglandins in rabbit isolated hearts. Circulation Res. 36, 3442. 25. Bolser D. C., Chandler M. J., Garrison D. W. and Foreman R. D. (1989) Effects of intracardiac bradykinin and capsaicin on spinal and spinoreticular neurons. Am. J. Physiol. 257, HlS43-Hl5SO. 26. Braunwald E., Epstein S. E., Glick G., Wechsler A. S. and Braunwald N. S. (1967) Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. New Engl. J. Med. 24, 1278-1283. 27. Brown A. M. (1967) Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischemia. J. Physiol.. Lond. 190, 35-53. 28. Brown P. K. and Coffey W. B. (1924) Surgical treatment of angina pectoris. Report of eight additional cases and review of the literature. Archs Int. Med. 34, 417-445. 29. Brown A. M. and Malliani A. (1971) Spinal sympathetic reflexes initiated by coronary receptors. J. Physiol., Lond. 212, 685-705.

30. Briining F. (1923) Die operative Behandlung der Angina Pectoris durch Exstirpation des Hals-b Brustsymathicus und Bemerkungen iiber die operative Behandlung des abnormen Blutdrucksteigerung, Klin. Wschr. 2, 777-780 (cited in Ref. 35). 31. Burnett C. G. and Evans J. A. (1956) Follow-up report on resection of the angina1 pathway in thirty-three patients. J. Am. med. Ass. 162, 709-712. 32. Cannon B. (1933) A method of stimulating autonomic nerves in the unanesthetized cat with observations on the motor and sensory effects. Am. J. Physiol. 105, 366-372. 33. Cherniack N. S., Runold M., Prabhakar N. R. and Mitra J. (1987) Effects of adenosine on vagal sensory pulmonary afferents. Fedn. Ptoc. 46, 825. 34. Coffey W. B. and Brown P. K. (1923) Surgical treatment of angina pectoris. Archs Inl. Med. 31, 200-220. 35. Coffey W. B., Brown P. K. and Humber J. D. (1927) Angina Pectoris; The Anatomy, Physiology and Surgical Treatment. A. J. Dickerson, New Orleans. 36. Cohen R. A. (1986) Contractions of isolated canine coronary arteries resistant to S,-serotonergic blockade. J. Pharmac. rxp. Ther. 237, 548-552.

Mechanisms of cardiac pain

519

37. Colatsky T. J. (1989) Models of myocardial &hernia and reperfusion injury: role of inflammatory mediators in determining infarct size. In Pharmacological Methoak in the Control ofInj7ammation (eds Chang J. Y. and Lewis A. J.), pp. 283-320. Alan R. Liss, New York. 38. Coleridge H. M. and Coleridge J. C. G. (1980) Cardiovascular afferents involved in regulation of peripheral vessels. A, Rev. Physiol. 42, 413427. 39. Coleridge H. M., Coleridge J. C. G. and Hewe A. (1970) Thoracic chemoreceptors

electrophysiological

in the dog: a histological and study of the location, innervation and blood supply of the aortic bodies. Circulation Res. 26,

235-247. 40. Coleridge H. M., Coleridge J. C. G., Dangel A., Kidd C., Luck J. C. and Sleight P. (1973) Impulses in slowly conducting vagal fibers from afferent endings in the veins, atria and arteries of dogs and cats. Circulation Res. 33, 87-97. 41. Colville K. and Caphlin E. (1964) Sympathomimetics as analgesics: effects of methoxamine, methamphetamine, metaraminol and norepinephrine. Life Sci. 3, 315-322.

42. Connor H. E., Feniuk W. and Humphrey P. P. A. (1989) 5-Hydroxytryptamine contracts human coronary arteries predominantly via S-HT, receptor activation. Eur. J. Pharmac. 161, 91-94. 43. Cornish K. G. and Zucker I. H. (1983) Is there a serotonin-induced hypertensive coronary chemoreflex in the non-human primate? Circulation Res. 52, 3 12-3 18. 44. Courbier R., Torresani J., Houze J. P., Jouve A. and Henry E. (1971) Carotid sinus nerve stimulation in angina pectoris. J. Cardiovasc.

Surg. 12, 231-234.

45. Cutler E. C. (1927) Summary of experiences up-to-date in surgical treatment of angina pectoris. Am. J. Med. Sci. 173, 613624. 46. Davis L. and Pollock L. J. (1932) The role of the sympathetic nervous system in the production of pain in the head. Archs Neural. Psychiat.

27, 282-293.

47. De Caterina R., Carpeggiani C. and L’Abbate A. (1984) A double-blind, placebo-controlled study of ketanserin in patients with Pi&metal’s angina. Evidence against a role for serotonin in the genesis of coronary vasospasm. Circulation

69, 889-894.

48. Diaz-Sarasola R. (1927) Estado actual de1 tratamiento quirurgico de la angina de pecho. Arch. Cardiol. Hematol, p. 8 (cited in Ref. 100). 49. DOS S. J. (1978) Cardiac sympathectomy for angina pectoris. Ann. Thorac. Surg. 25, 178-179. 50. Dworkin B. R., Filewich R. J., Miller N. E., Craigmyle N. and Pickering T. G. (1979) Baroreceptor activation reduces reactivity to noxious stimulation: implications in hypertension. Science 205, 1299-1301. 51. Eckberg D. L., White C. W., Koschos J. M. and Abboud F. M. (1974) Mechanisms mediating bradycardia during coronary arteriography. J. clin. Invest. 54, 1455-1461. 52. Edlund A., Fredholm B. B., Patrignani P., Patron0 C., Wennmalm A. and Wennmalm M. (1983) Release of two vasodilators, adenosine and prostacyclin, from isolated rabbit hearts during controlled hypoxia. J. Physiol., Lond. MO, 487-501.

53. Esente P., Giambartolomei A., Gensini G. G. and Dator C. (1983) Coronary reperfusion and Bezold-Jarisch reflex (bradycardia and hypotension). Am. J. Cardiol. 52, 221-224. 54. Estrin J. A., Emery R. W., Leonard J. J., Nicoloff D. M., Swayze C. R., Buckley J. J. and Fox I. J. (1979) The Bezold reflex: a special case of the left ventricular mechanoreceptor reflex. Proc. natn. Acad. Sci. U.S.A. 76, 41464150. 55. Felder R. B. and Thames M. D. (1981) The cardiocardiac sympathetic reflex during coronary occlusion in anesthetized dogs. Circulation Res. 48, 685-692. 56. Felder R. B. and Thames M. D. (1982) Responses to activation of cardiac sympathetic afferents with epicardial bradykinin. Am. J. Physiol. 242, Hl48-H153. 57. Ferreira S. H. (1972) Prostaglandins, aspirin-like drugs and analgesia. Nature 240, 200-203. 58. Ferro G., Sacca L., Piscione F., Spinelli L., Spadafora M., Duilio C. and Chiariello M. (1988) Electromechanical events during spontaneous angina. Cardiol. 75, 90-99. 59. Flothow P. G. (1952) Sympathectomy for cardiac decompensation and coronary disease. Surgery 32, 796-802. 60. Foreman R. D. (1989) Organization of the spinothalamic tract as a relay for cardiopulmonary sympathetic afferent fiber activity. In Progress in Sensory Physiology (eds Autrum H., Ottoson D., Per1 E. R., Schmidt R. F., Shimazu H. and Willis W. D.), Vol. 9, pp. l-51. Springer, Heidelberg. 61. Foreman R. D. and Ohata C. A. (1980) Effects of coronary artery occlusion on thoracic spinal neurons receiving viscerosomatic inputs. Am. J. Physiol. 238, H667-H674. 62. Foreman R. D., Blair R. W. and Ammons W. S. (1986) Neural mechanisms of cardiac pain. Prog. Brain Res. 67, 227-242.

63. Fredholm B. B. and Sollevi A. (1986) Cardiovascular effects of adenosine. Clin. Physiol. 6, l-21. 64. Friesinger G. C. and Robertson R. M. S. (1985) Haemodynamics in stable angina pectoris. In Angina Pectoris (ed. Julian D. E.), pp. 25-37. Churchill Livingstone, Edinburgh. 65. Ghanem N. S., Abdullah N. A. and Assem E. S. K. (1989) The cardiac and renal effects of the complement fragment C5a des Arg are partly mediated by the release of histamine and arachidonic acid metabolites. Agents Actions 27, 138-141.

66. Ghione S., Rosa C., Mezasalma L. and Panattoni E. (1988) Arterial hypertension is associated with hyperalgesia in humans. Hypertension 12, 491497. 67. Ginsburg R., Bristow M. R., Kantrowitz N., Bairn D. S. and Harrison D. C. (1981) Histamine provocation of clinical coronary artery spasm: implications concerning pathogenesis of variant angina pectoris. Am. Heart J. 102, 819-822.

68. Gorlin R. (1982) Role of coronary vasospasm in the pathogenesis of myocardial ischemia and angina pectoris. Am. Heart J. 103, 598403.

69. Grimson K. S., Hesser F. G. and Kitchin W. W. (1947) Early clinical results of transabdominal celiac and superior mesenteric ganglionectomy, vagotomy, or transthoracic splanchnectomy in patients with chronic abdominal visceral pain. Surgery 22, 23&238. 70. Guzman F., Braun C. and Lim K. S. (1962) Visceral pain and the pseudaffective response to intra-arterial injection of bradykinin and other analgesic agents. Arch. int. Pharmacodyn. ThPr. 136, 353-384.

520

S. T. MELLERand G. F. GEBHART

71. Handwerker H. 0. and Reeh P. W. (1991) Pain and inflammation. In Advances in Pain Research and Therapy (eds Bond M. R., Woolf C. and Charlton J. E.), pp. 59-70. Raven Press, New York. 72. Hashimoto K., Hirose M., Furukawa S., Hayakawa H. and Kimura E. (1977) Changes in hemodynamics and bradykinin concentration in coronary sinus blood in experimental coronary artery occlusion Jap. Heart J. l&679-689. 73. Heberdeen W. (1772) Some accounts of a disorder of the breast. Med. Trans. R. Coil. Phys., Lond. 2, 5967*ited in Mathews M. B. (1985) Clinical diagnosis. In Angina Pectoris (ed. Julian D. E.), pp. 62-83. Churchill-Livingstone. Edinburgh. 74. Henrard L., Pierard L. and Limet R. (1982) Treatment of Prinzmetal’s angina with normal coronary vessels by thoracic sympathectomy. Arch. mal. Coeur. IS, 1317-1320. 75. Higashi H. (1986) Pharmacological aspects of visceral sensory receptors. In Progress in Brain Research (eds Cervero F. and Morrison J. F. B.), Vol. 67, pp. 1499161. Elsevier, Amsterdam. 76. Hintze T. H. (1987) Reflex regulation of the circulation after stimulation of cardiac receptors by prostaglandins. Fedn. Proc. 46, 73-80. 77. Hintze T. H., Kaley G., Martin E. G. and Messina E. J. (1978) PGIr induces bradycardia in the dog. Prosfaglundins

15, 712. 78. Hintze T. H., Martin E. G., Mesina E. H. and Kaley G. (1979) Prostacyclin (PGI,) elicits reflex bradycardia in dogs: evidence for vagal mediation. Proc. Sot. exp. Eiol. Med. 162, 96100. 79. Hirsh P. D., Hillis L. D., Campbell W. B., Firth B. G. and Willerson J. T. (1981) Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. New Engl. J. Med. 304, 685691. 80. Hollander W., Michaelson A. L. and Wilkins R. W. (1957) Serotonin and antiserotonins. I. Their circulatory. respiratory and renal effects in man. Circulation 16, 246255. 81. Hopkins D. A. and Armour J. A. (1989) Ganglionic distribution of afferent neurons innervating the canine heart and cardiopulmonary nerves, J. auton nerv. Sysf. 26, 213-222. 82. James T. N. (1986) Degenerative lesions of a coronary chemoreceptor and nearby neural elements in the hearts of victims of sudden death. J. Am. Coll. Cardiol. 8, 12A-21A. 83. James T. N. (1989) A cardiogenic hypertensive chemoreflex. An&h. Arm/g. 69, 633646. 84. James T. N., Hageman G. R. and Urthaler F. (1979) Anatomic and physiologic considerations of a cardiogenic hypertensive chemoreflex. Am. J. Curdiol. 44, 8522859. 85. James T. N., Rossi L. and Hageman G. R. (1988) On the pathogenesis of angina pectoris and its silence. Trans. Am. clin. Climarol. Assoc. 100, 8 l-99. 86. Johannsen U. J., Summers R. and Mark A. L. (1981) Gastric dilation during stimulation of cardiac sensory receptors. Circulation 63, 960-964. 87. Jonnesco T. (1920) Angine de potrine guirie par la resection du sympathetique cervicothoracique. Bull. Acad. Med. 84, 93-102. 88. Junod A. F. (1972) Uptake metabolism and reflex effects of “C-5-hydroxytryptamine in isolated perfused rat lungs. J. Pharmac. exp. Ther. 183, 341-355. 89. Kadowaki M. H. and Levett J. M. (1986) Sympathectomy in the treatment of angina and arrhythmias. Ann. Thorac. Surg. 41, 5722578. 90. Kappis M. (1923) Die operative Behandlung der Angina Pectoris. Med. Klin. 19, 165881662 (cited in Ref. 35).

91, Katz L. N., Mayne W. and Weinstein W. (1935) Cardiac pain-presence of pain fibers in the nerve plexus surrounding the coronary vessels. Arch. Int. Med. 55, 76&772. 92. Kauffman M. P., Baker D. G., Coleridge H. M. and Coleridge J. C. G. (1980) Stimulation by bradykinin of afferent vagal C-fibers with chemosensitive endings in the heart and aorta of the dog. Circulation Res. 46, 476484. 93. Kimura E., Hashimoto K., Furukawa S. and Kayakawa H. (1973) Changes in bradykinin level in coronary sinus blood after the experimental occlusion of a coronary artery. Am. Heart J. 85, 635-647. 94. Kositskii G. I., Mikhailova S. D. and Semushkina T. M. (1985) Unit activity of the ganglion nodosum in myocardial ischemia. Bull. exp. Med. Biol. 98, 1622-1624. 95. Kullman R. (1982) Cardiovascular reflexes controlling regional sympathetic outflow during coronary artery occlusion. Basic Res. Cardiol. 77, 5077519. 96. Kuo D. C., Oravitz J. J. and DeGroat W. C. (1984) Tracing of afferent and efferent pathways in the left inferior cardiac nerve of the cat using retrograde and transganglionic transport of horseradish peroxidase. Bruin Res. 321,

111-118. 97. Lamping K. G., Marcus M. L. and Dole W. P.. (1985) Removal of the endothelium potentiates canine large coronary artery constrictor responses to 5-hydroxyttyptamine in vivo. Circulation Res. 57, 4654. 98. Langley J. N. (1924) Sensory nerve fibers of heart and aorta in relation to surgical operations for relief of angina pectoris. Lancet 207, 955-956. 99. Lembeck F., Popper H. and Juan H. (1976) Release of prostaglandins by bradykinin as an intrinsic mechanism of its algesic effect, Naunyn-Schmieakberg’s Arch. Pharmac. 294, 69-73. 100. Leriche R. and Fontaine R. (1927) The surgical treatment of angina pectoris. What it is and what it should be. Am. Heart J. 3, 64967 1. 101. Levine J. D., Taiwo Y. O., Collins S. D. and Tam J. K. (1986) Noradrenaline hyperalgesia is mediated through interaction with sympathetic postganglionic neurone terminals rather than activation of primary afferent nociceptors. Nature 323, 1588160. 102. Lewy R. I., Weiner L., Smith J. B., Wallinsky P., Silver M. J. and Saira J. (1979) Comparison of plasma concentrations of thromboxane B, in Prinzmetals variant angina and classical angina pectoris. Clin. Cardiol. 2, 404406. 103. Lindgren I. and Olivecrona H. (1947) Surgical treatment of angina pectoris. J. Neurosurg. 4, 19-39. 104. Little H. J. and Rees J. M. (1978) Naloxone antagonism of sympathomimetic analgesia. In Characteristics and Function of Opioids (eds Van Ree J. M. and Terenius L.), pp. 433434. Elsevier, Amsterdam. 105. Littler W. A., Honour A. J., Sleight P. and Stott F. D. (1973) Direct arterial pressure and the electrocardiogram in unrestricted patients with angina-pectoris. Circulation 68, 125-134. 106. Lombardi F., Della Bella P., Casati R. and Malliani A. (1981) Effects of intracoronary administration of bradykinin on the impulse activity of afferent sympathetic unmyelinated fibers with left ventricular endings in the cat. Circulation Res. 48, 6997.5

Mechanisms of cardiac pain

521

107. Lombardi F., Patton C. P., Della Bella P., Pagani M. and Malliani A. (1982) Cardiovascular and sympathetic responses reflexly elicited through the excitation with bradykinin of sympathetic and vagal cardiac sensory endings in the cat. Circulation Res. 16, 57-65. 108. Maixner W., Touw K. B., Brody M. J., Gebhart G. F. and Long J. P. (1982) Factors influencing the altered pain perception in the s~n~neo~ly h~rtensive rat. Brain Res. 237, 137-145. 109. Malliani A. (1982) Cardiovascular sympathetic afferent fibers. Rev. Physiol. Biochem. Phurmac. 94, I l-74. 110. Malliani A. and Lombardi F. (1986) Circulatory markers of nervous activation during myocardial ischemia. Cbn. J. Cardiol. Suppl. A, 2, 40A-45A. 11I. Malliani A., Pagani M. and Lombardi F. (1984) Visceral versus somatic mechanisms. In Textbook of Pain (eds Wall P. D. and Melzack R.), pp. 100-109. Churchill-Livingstone, New York. 112. Malliani A., Pagani M., Pizzinelli P., Furlan R. and Guzzetti S. (1983) Cardiovascular reflexes mediated by sympathetic afferent fibers. J. auton. tterv. Syst. 7, 295-301. 113. Malliani A., Peterson D. F., Bishop V. S. and Brown A. M. (1972) Spinal s~pathetic cardiocardiac reflexes. Circulation Res. 30, 158-166. 114. Malliani A., Schwartz P. J. and Zanchetti A. (1969) A sympathetic reflex elicited by experimental coronary occlusion. Am. J. Physiol. 217, 703-709. 115. Marcus M. L. (1983) Effects of coronary occlusion on myocardial reperfusion in the coronary circulation in health and disease. In The Coronary Circulation in Health and Disease (ed. Marcus M. L.), pp. 191-220. McGraw-Hill, St LOlliS.

116. Martin S. J. and Gordham L. W. (1938) Cardiac pain: an experimental study with reference to the tension factor. Archs Int. Med. 62, 840-852. 117. Maseri A., Chierchia S., Davies B. J. and Glazier J. (1985) Mechanisms of ischemic cardiac pain and silent myocardial ischemia. Am. J. Med. 79, 7-l I. 118. Masini E., Fantozzi R., Blandina P., Brunelleschi S. and Mannaioni P. F. (1985) The riddle of cholinergic histamine release from mast cells. Prog. med. Chem. 22, 267-291. 119. Masini E., Gambassi F., Giannella E., Palmerani B., Pistelli A., Carlomagno L. and Mannaioni P. F. (1989) Ischemia reperfusion injury and histamine release in isolated guinea-pig heart: the role of free radicals. Agents Actions 27, 154-157. 120. Masini E., Giannella E., Bianchi S., Palmerani B., Pistelli A. and Mannaioni P. F. (1988) Histamine release in acute coronary occlusion-reperfusion in isolated guinea-pig heart. Agents Actions 23, 266269. 121. Mata-Bourcart L. A., Waters D. D., Bouchard A., Miller D. D. and Thtroux P. (1985) Failure of ketanserin, a serotonin inhibitor, to prevent spontaneous or ergonovine-induced attacks of variant angina. Can. J. Cardiol. 1, 168-171. 122. Mefler S. T., Lewis S. J., Brody M. J. and Gebhart G. F. (1991) The nociceptive responses to i.v. S-HT requires dual activation of 5-HT, and 5-HT, receptor subtypes. Brain Res. 561, 6168. 123. Meller S. T., Lewis S. J., Ness T. J., Brody M. J. and Gebhart G. F. (IVVO)Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. I. Characterization. Brain Res. 524, 90-100. 124. Mikhailova S. D., Semushkina T. M. and Kositskii G. I. (1986) Response of ganglion nodosum neurons to myocardial ischemia complicated by ventricular fibrillation. BUN.exp. Med. Biol. 101, 264-266. 125. Mitchell G. A. G. (1956) Cardiovascular Innervation, p. 222. E. & S. Livingston, London. 126. Moore P. K. (1985) Prostanoidr: Pharmacological, Physioiogical and CIinicaI Relevance, pp. 75-77. Cambridge University Press, Cambridge. 127. Moore R. M. and Sin~eton A, 0. Jr (1935) A pseudaffective reflex evoked by injections into the left coronary artery and the peripheral paths of the pain-fibers which are concerned. Am. J. Physiol. 1X3,99-100. 128. Neil1 W. A. (1968) Myocardial hypoxia and anerobic metabolism in coronary heart disease. Am. J. Cardiol. 22, 507-515. 129. Nerdrum T., Baker D. G., Coleridge H. M. and Coleridge J. C. G. (1986) Interaction of bradykinin and prostaglandin E, on cardiac pressor reflex and sympathetic afferents. Am. J. Physioi. 250, R815-R822. 130. Neto F. R. (1978) The depolarizing action of 5-HT on mammalian non-myelinated nerve fibres. Eur. J. Phurmuc. 49, 351-356. nerve fibers of the cat 131. Nishi K., Sakanashi M. and Takenaka F. (1977) Activation of afferent cardiac s~pathetic by pain producing substances and by noxious heat. P$Ggers Arch. 372, 53-61. 132. Nolan P. N., Luk D. E. and Staszewska-Barczak J. (1983) Reflex effects evoked from the parietal pericardium in the dog: comparison with responses from the visceral pericardium. Basic Res. Cardiol. 78, 654-664. 133. Odermatt W. (1923) Die chirurgische Behandlung der Angina Pectoris. Deutche Ztschr. f. Chir. 182, 341-354. 134. Olsson R. A. and Bilnger R. (1987) Metabolic control of coronary blood flow. Prog. cardiovasc. Dis. 29, 369-387. 135. Opie L. H., Owen P., Thomas M. and Samson R. (1973) Coronary sinus lactate m~surements in assessment of myocardial ischemia. Am. J. Cardiol. 32, 295-305. 136. Pagani M., Pizzinelli P., Furlan R., Guzzetti S., Rimoldi O., Sandrone G. and Malliani A, (1985) Analysis of the pressor sympathetic reflex produced by intracoronary injections of bradykinin in conscious dogs. Circulation Res. f&j, 175-183. 137. Pal P., Koley J., Bhattacharyya S., Gupta J. S. and Koley B. (1989) Cardiac nociceptors and ischemia: role of sympathetic afferents in cat. Jap. J. Physiol. 39, 131-144. 138. Palumbo L. T. and Lulu D. J. (1966) Anterior transthoracic upper dorsal sympathectomy; current results. Arch. Surg. 92, 247-257. 139. Pantridge J. F. (1978) Autonomic disturbances at the onset of acute myocardial infarction. In Narronal ~echun~ms in Cardiac Arrhythmias (eds Schwartz P. J., Brown A. M., Malliani A. and Zanchetti A.), pp. 7-17. Raven Press, New York. 140. Parker J. O., Chiong M. A., West R. 0. and Case R. B. (1969) Sequential alterations in myocardial lactate metaboli, S-T segments and left ventricular function during angina induced by atria1 pacing. Circulation 40, 113-131. 141. Perez-Gomez F. and Garcia-Aguado A. (1977) Origin of ventricular reflexes caused by coronary arteriography. Br. Heart J. 39, 967-973.

522

S. T. MELLERand G. F. GEBHART

142. Perez-Gomez F., Martin de Dios R., Rey J. and Garcia-Aguado A. (1979) Prinzmetal’s angina: reflex cardiovascular responses during episodes of pain. Br. Heart J. 42, 81-87. 143. Person R. J. (1989) Somatic and vagal afferent convergence on solitary tract neurons in cat: electrophysiological characteristics. Neuroscience 30, 283-295. 144. Person R. J., Domer K. J., Bedford T. G., Andrezik J. A. and Foreman R. D. (1986) Fastigial nucleus modulation of medullary parasolitary neurons. Neuroscience 19, 1293-1301, 145. Pike G. K. and Kerr D. I. B. (1987) The influence of temperature upon depolarizing responses of rat isolated vagus nerve to 5-hydroxytryptamine. Bruin Res. 413, 388-391. 146. Puri V. K., Rawat A., Sharma A., Mehrotra A., Hasan M., Shanker K., Verma M., Sinha J. N. and Bhargava K. P. (1986) Sulphinpyrazone and the platelet serotonergic mechanism in ischemic heart disease. Br. Med. J. 293, 591-593. 141. Quigg M., Elfvin L. G. and Aldskogius H. (1988) Distribution of cardiac sympathetic afferent fibers in the guinea pig heart labeled by anterograde transport of wheat germ agglutinin-horseradish peroxidase. J. uufon nero. Syst. 25, 107-l 18. 148. Raffenbeul W., Fliige T., Fiirsterman U. and Bosaller C. (1986) Coronary vasomobility with bradykinin versus nitroglprin in man. Circulufion 74, Suppl. II, 86. 149. Randich A., Simpson T. A., Hanger P. A. and Fisher R. L. (1984) Activation of vagal afferents by veratrine induced antinociception. Physiol. Psychol. 12, 293-301. 150. Randich A., Ren K. and Gebhart G. F. (1990) Electrical stimulation of vagal afferents. II. Central relays for behavioral antinociception and arterial blood pressure decreases. J. Neurophysiol. 64, 1115-l 124. 151. Randich A., Thurston C. L., Ludwig P. S., Timmermann M. R. and Gebhart G. F. (1991) Antinociceptive and cardiovascular responses produced by intravenous morphine: the role of vagal afferents. Brain Res. 543, 256-270.

152. Reid M. R. and Andrus Wm. D. (1925) The surgical treatment of angina pectoris. Ann. Surg. 81, 591-604. 153. Reid P. G., Watt A. H., Routledge P. A. and Smith A. P. (1987) Intravenous infusion of adenosine but not inosine stimulates respiration in man. Br. J. clin. Pharmac. 23, 331-338. 154. Reimann K. A. and Weaver L. C. (1980) Contrasting reflexes evoked by chemical activation of cardiac afferent nerves. Am. J. Physiol. 239, H316-H325. 155. Remme W. J., Van Den Berg R., Mantel M., Cox P. H., Van Hoogenhuyze D. C. A., Krauss X. H., Storm C. J. and Kruyssen D. A. C. M. (1986) Temporal relation of changes in regional coronary flow and myocardial lactate and nucleoside metabolism during pacing-induced ischemia. Am. J. Cardiol. 58, 1188-I 194. 156. Ren K., Randich A. and Gebhart G. F. (1989) Vagal afferent modulation of spinal nociceptive transmission in the rat. J. Neurophysiol. 62, 401415. 157. Ren K., Randich A. and Gebhart F. G. (1990) Modulation of spinal nociceptive transmission from nuclei tractis solitarii: a relay for effects of vagal afferent stimulation. J. Neurophysiol. 63, 971-986. 158. Ren K., Randich A. and Gebhart G. F. (1990) Electrical stimulation of cervical vagal afferents. I. Central relays for modulation of spinal nociceptive transmission. J. Neurophysiol. 64, 1098-l 114. 159. Robertson D.. Hollister A. S., Forman M. B. and Robertson R. M. (1985) Reflexes unique to myocardial ischemia and infarction. J. Am. CON. Cardiol. 5, 99B-104B. 160. Robertson R. M. and Robertson D. (1981) The Bezold-Jarisch reflex: possible role in limiting myocardial ischemia. Clin. Cardiol. 4, 75-79.

161. Round A. and Wallis D. I. (1986) The depolarizing action of 5-hydroxytryptamine on rabbit vagal afferent and sympathetic neurons in vitro and its selective blockade by ICS 205-930. Br. J. Pharmac. 88, 485494. 162. Runold M., Prabhakar N. R., Mitra J. and Chemiack N. S. (1987) Adenosine stimulates respiration by acting on vagal receptors. Fedn. Proc. 46, 825. 163. Saavedra J. M. (1981) Naloxone reversible decrease in pain sensitivity in young and adult spontaneously hypertensive rats. Brain Res 209, 245-249. 164. Sampson J. J. and Cheitlin M. D. (1971) Pathophysiology and differential diagnosis of cardiac pain. Prog. Cardiovasc. Dis. 13, 507-531.

165. Sampson S. R. and Jaffe R. A. (1974) Excitatory effects of 5_hydroxytryptamine, veratridine and phenyldiguanide on sensory ganglion cells of the nodose ganglion of the cat. Life Sci. 15, 2157-2165. 166. Seibold H., Galle J., Haferkamp 0. and Stauch M. (1981) Ultrastructure of platelets before and during atria1 stimulation. Differences in the coronary sinus and aortic blood in patients with angina pectoris. Klin. Wschr. 59, 237-243.

167. Shuttleworth R. D. and O’Brien J. R. (1981) Intraplatelet serotonin and plasma 5-hydroxyindoles in health and disease. Blood 57, 505-509. 168. Sitsen J. M. A. and de Jong W. (1983) Hypoalgesia in genetically hypertensive rats (SHR) is absent in rats with experimental hypertension. Hypertension 5, 185-190. 169. Sitsen J. M. A. and de Jong W. (1984) Observations on pain perception and hypertension in spontaneously hypertensive rats. Clin. exp. Hyperfens. A 6, 1345-1356. 170 Spodick D. M. (1983) Partial sympathetic denervation for variant angina pectoris. Am. J. Curdiol. 52, 1153. 171 Stansfeld C. E. and Wallis D. I. (1985) Properties of visceral primary afferent neurons in the nodose ganglion of the rabbit. J. Neurophysiol. 54, 245-260. 172 Staszewska-Barczak J. (1983) Prostanoids and cardiac reflexes of sympathetic and vagal origin. Am. J. Curdiol. 52, 36A45A. by bradykinin-induced 173 Staszewska-Barczak J. and Dusting F. J. (1977) Sympathetic cardiovascular . .reflex . _ initiated . _^ stimulation of cardiac pain receptors in the dog. Clin. exp. Pharm. Physiol. 4, 443-43~. 174. Staszewska-Barczak J., Ferreira S. H. and Vane J. R. (1976) An excitatory nociceptive cardiac reflex elicited by bradykinin and potentiated by prostaglandins and myocardial ischemia. Cardiovasc. Res. 10, 314-327. 175. Stebbins C. L., Smith R. C. and Longhurst J. C. (1985) Effect of prostaglandins on bradykinin-induced visceralcardiac reflexes. Am. J. Physiol. 249, H155-H163. 176. Sutton D. C. and Lueth H. C. (1930) Experimental production of pain on excitation of the heart and great vessels. Archs. Int. Med. 56, 827-867.

Mechanisms of cardiac pain

523

and molecular mechanisms. Puin 36, 177. Sylv&n C. (1989) Angina pectoris. Clinical characteristics, neu~physiolo~~ 145-167. 178. Sylven C., Beermann B., Jonzon B. and Brandt R. (1986) Angina peetoris-like pain provoked by intravenous adenosine in healthy volunteers. Br. Med. J. 293, 227-230. 179. Sylven C., Borg G., Brandt R., Eleermann B. and Jonzon B. (1988) Doseeffect relationship of adenosine provoked angina pectoris-like pain-a study of the psy~hophysi~ power function. Eur. Heart J. 9, 87-91. 180. Syldn C., Edlund A., Brandt R., Beermann B. and Jonzon B. (1986) Angina pectoris-like pains provoked by intravenous adenosine. Br. Med. J. 293, 1027-1028. 181. Sylven C., Jonzon B. and Edlund A. (1989) Angina pectoris-like pain provoked by iv. bolus of adenosine: relationship to coronary sinus blood flow, heart rate and blood pressure in healthy volunteers. Eur. Hear? J. 10, 48-54. 182. Szcaeklik A,, Szcaeklik J., Nizankowski R. and Gluszko P. (1980) Prostacyclin for acute coronary ins~cien~y. Artery 9, 7-11. 183. Taiwo Y. 0. and Levine J. D. (1988) Characterization of the arachidonic acid metabolites mediating bradykinin and noradrenaline hyperalgesia. Brain Res. 458, 402-406. 184. Taiwo Y. O., Goetzl E. J. and Levine J. D. (1987) Hyperalgesia onset latency suggests a hierarchy of action. Bruin RES. 423, 333-337. 185. Takahashi H. (1985) Cardiovascular and sympathetic responses to intracarotid and intravenous injections of serotonin in rats. Naunyn-Schmiedeberg’s Arch. Pharmac. 329, 222-226. 186. Terui N. and Koizumi K. (1984) Responses of cardiac vagus and sympathetic nerves to excitation of somatic and visceral nerves. J. auton. nerv. .Syst. 10, 73-91. 187. Thames M. D., Klopfenstein H. C., Abboud F. M., Mark A. L. and Walker J. L. (1978) Preferential dist~bution of inhibitory cardiac receptors with vagal afferents to the inferioposterior wall of the left ventricle activated during coronary occlusion in the dog. Circulation Res. 43, 512-519. 188. Thames M. D., Johannsen U. J. and Mark A. L. (1987) In search of afferent pathways of a cardiogenic hypertensive chemoreflex. Circulation 75, 6433650. 189, Thomas D. P. and Vane J. R. (1967) 5-Hydroxyt~~mine in the circulation of the dog. Nature 216, 335-338. 190. Thor&n P. N. (1976) Activation of left ventricular receptors with nonmedullated vagal afferent fibers during occlusion of a coronary artery in the cat. Am. J. Cardiol. 37, 10461051. 191. Tuffier T. (1921) Deskussionsbemerkung. Bull I’Acad. Med. Paris 86, 99 (cited in Ref. 35). 192. Uchida Y. and Murao S. (1974) Bradykinin-induced excitation of afferent cardiac sympathetic nerve fibers. Jap. Heart J. 15, 8491. 193. Uchida Y. and Murao S. (1974) Excitation of afferent cardiac sympathetic nerve fibers during coronary occlusion. Am. J. Physiol. 226, 1094-1099. 194. Uchida Y. and Murao S. (1975) Acid-induced excitation of afferent cardiac sympathetic nerve fibres. Am. J. Physioi. 228, 27-33.

195 van den Berg E. K., Schmitz J. M., Benedict C. R., Malley C. R., Willerson J. T. and Dehmer G. J. (1989) Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology. Circulation 79, 116124. 196. Verheggen R. and Schror K. (1986) The modification of platelet-induced coronary vasoconstriction by a thromboxane receptor antagonist. J. Cardiovasc. Pharm. 8, 483-490. 197. Vogt A., Vettertein F., Dal Ri H. and Schmidt G. (1979) Excitation of afferent fibres in the cardiac sympathetic nerves induced by coronary occlusion and injection of bradykinin. The influence of a~tyls~icyclic acid and dipyron. AI&S int. Pharmacodyn. Ther. 239, 8698. 198. Waldrou T. G. and Mullins D. C. (1987) Cardiorespiratory _ _-responses to chemical activation of right ventricular receptors. J. appl. Physiol. 63, 733-739. 199. Walker J. L., Thames M. D., Abboud F. M., Mark A. L. and Klopfenstein H. S. (1978) Preferential distribution of inhibitory cardiac receptors in left ventricle of the dog. Am. J. Physiol. 235, H188-HI92.

200. Wallis D. I., Stansfeld C. E. and Nash H. L. (1982) Depolarizing responses recorded from nodose ganglion cells of the rabbit evoked by 5-hydroxytryptamine and other substances. Neuropharmacology 21, 31-40. _ 201. Watt A. M. and Routledae P. A. (1985) Adenosine stimulates resniration in man. Er. J. c/in. Phurmac. 20, 503-506. 202. Weaver L. C., Danos L.-M., Oehl R. S. and Meckler R. L. (198>) Contrasting reflex influences of cardiac afferent nerves during coronary occlusion. Am. J. Physioi. 240, H62gH629. 203. Weaver L. C.. Frv H. K.. Meekler R. L. and Oehl R. S. (1983) Multiseamental sninal svmnathetic reflexes oriainatinp: . ” from the heart. km. J. ihysiol. 245, R345-R352. . ’ * _ _ 204. Weaver L. C., Meckler R. L., Fry H. K. and Donohue S. (1983) Widespread neural excitation initiated from cardiac spinal afferent nerves. Am. J. Physiol. 245, R241-R250. 205. Webb S. W., Adgey A. A. and Pantridge J. F. (1972) Autonomic disturbance at onset of acute my-dial infarction. Br. Med. J. 3, 89-92. 206. Webb S. C., Canepa-Anson R., Rickards A. F. and Poole-Wilson P. A. (1983) High potassium concentration in a parenteral preparation of glyceryl trinitrate. Need for caution if given by intracoronary injection. Br. Heart J. SO, 395-396. 207. Webb S. C., Canepa-Anson

208. 209. 210.

211. 212.

213.

R., Rickards A. F. and Poole-Wilson P. A. (1987) My~rdiai potassium loss after acute coronary occlusion in human. J. Am. Coil. Card&l. 9, 1230-1234. Wenckebach K. F. (1923) Dutsch-Zmernisten Kongress, Vienna, April (cited in Ref. 35). Wennmalm A., Chanh P. H. and Junstad M. (1974) Hypoxia causes prostaglandin release from perfused rabbit hearts. Acta physiol. stand. 91, 133-l 35. White J. C. (1957) Cardiac pain. Anatomic pathways and physiology mechanisms. Circulation 16, 644-655. White J. C. and Bland E. F. (1948) The surgical relief of severe angina pectoris. Methods employed and end results in 83 patients. Medicine 27, 142. white J. C. and Sweet W. M. (1969) Pain and the Neurosurgeon. A Forty-year Experience, p. 560. Charles C. Thomas, Springfield, IL. White J. C., Garrey W. E. and Atkins 3. A. (1933) Cardiac innervation. Experimental and clinical studies. Arch. Surg.

26, 765-786.

524

S. T. MELLERand G. F. GEBHART

214. White M. K., Hechtman H. B. and Shepro D. (1986) Canine lung uptake of plasma and platelet serotonin. ~Uicrouusc. Res. 9, 230-241. 215. Willerson J. T., Hillis D., Winniford M. and Buja M. (1986) Speculation regarding mechanisms responsible for acute ischemic heart disease syndromes. J. Am. CON. Cardiol. 8, 245-250. 216. Willis W. D. (1985) The Pain System. The Neural Basis of Nocicepfive Transmission in the Mammalian Nervous System, p. 139. Karger, New York. 217. Wolff A. A. and Levi R. (1988) Ventricular arrhythmias parallel cardiac histamine efflux after coronary artery occlusion in the dog. Agents Actions 25, 296-306. 218. Zamir N. and Segal M. (1979) Hypertension induced analgesia: changes in pain sensitivity in experimental hypertensive rats. Bruin Res. 160, 17&173. 219. Zamir N. and Shuber E. (1980) Altered pain perception in hypertensive humans. Brain Res. 201, 471474. 220. Zamir N., Simantov R. and Segal M. (1980) Pain sensitivity and opioid activity in genetically and experimentally hypertensive rats. Brain Res. 184, 299-310. 221. Zinner M. J., Kasher F. and Jaffe B. M. (1983) The hemodynamic effects of IV infusions of serotonin in conscious dogs. J. Surg. Res. 34, 171-178. 222. Zucker 1. H., Panzenbeck M. J., Hackley J. F. and Haiderzad K. (1989) Baroreflex inhibition during coronary occlusion is mediated by prostaglandins. Am. J. Physiol. 257, R216-R223. (Accepted 18 November 1991)