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Role of the autonomous nervous system in the genesis of pulmonary hypertension in heart disease
ROLE OF THE AUTONOMOUS NERVOUS SYSTEM IN THE GENESIS OF PULMONARY HYPERTENSION IN HEART DISEASE DENIS F. J. HALMAGI’I, M.D.,*
From the Department Sydney
SYDNEY, AUSTRALIA
of Medicine,
lTniversity
of
(Received for publication Feb. 9, 1959)
AST new territories of cardiology were opened up by Bloomfield and assoV ciates5 when they first pushed a catheter intentionally into the human pulmonary artery. Not only was one of nature’s closely guarded secrets revealed but the pulmonary bed became one of the most easily accessible segments of the human circulation. It was soon learned that pulmonary hypertension is a frequent and important feature in many types of heart disease and that different pathogenetic types of pulmonary hypertension exist (Fig. 1). The role of the nervous system is one of the main controversial points in the genesis of pulmonary hypertension. The roots and causes of this controversy have been described by Lilienthal and Riley36 with an admirable clarity: There is in historical perspective a recurrent pattern in the development of concepts concerning special circulations. In the earlier stages of investigation the experimental technics available for isolation and measurement of the circuit under study are relatively crude and unwitting damage is done to the controlling mechanisms. During this period the conclusion is oftimes drawn that the special circulation mirrors in a passive way the pressures and flows imposed on it by the systemic circulation. With progressive refinement of experimental technics there begin to appear observations which suggest that active vasomotion does occur in response to a host of neural and chemical stimuli. The growth of our knowledge concerning the cerebral and hepatic circulations are examples of this pattern. For many years this same question has confronted students of the pulmonary circulation and to this day the dilemma has not been resolved with any finality.s6 The importance of static factors in the genesis of pulmonary hypertension is generally accepted. A stenosed mitral valve or a large interventricular septal defect can obviously be the main cause of pulmonary hypertension. Microscopic changes in the lung vessels, consisting of intimal proliferation and atherosclerotic deposits, and thromboembolic obliteration of several branches, are of equal importance. These changes not only decrease the capacity of the pulmonary vascular bed but also severely impair its biophysical characteristics.8,42 This is why anatomic changes appeared amply sufficient to explain the increase in pulmonary arterial pressure to some observers.iO It is not very difficult, however, *Adolph
Basser
Senior Research
Fellow
of the Royal 525
Australasian
College of Physicians.
J. Chron. Dis. May, 1959
HALMAGYI
to find anatomic observations which fail to support this view. In some cases of idiopathic pulmonary hypertension with an extremely high pressure, no microscopic anomalies were detected in the lung vessels.52 A poor correlation was found between microscopic changes in the pulmonary arterioles and the increase in arteriolar resistance in mitral stenosis.s~24 The thickening of the medial musculature of the pulmonary arterioles, hitherto regarded as real muscular hypertrophy, has been revealed as the consequence of pre-existing vasoconstriction 17,34.43,44,45
OBSTRUCTED
Fig. l.-Pathogenesis of pulmonary hypertension. White circles represent the three possible general causes of pulmonary hypertension while the resulting diseases are shown as black circles. By shifting the black circles in different directions one can illustrate the varying extent to which one of the three mechanisms participates in the genesis of pulmonary hypertension. For example, the black circle of mitral stenosis if shifted downward will represent those case6 where mechanical obstruction of the mitral If it is shifted upward and to the left, the other form flow is the main cause of pulmonary hypertension. of the disease is shown in which arteriolar resistance is the major obstacle to blood flo~.~’
From these observations it appears that even anatomic findings are to some extent suggestive of a superimposed functional factor in pulmonary hypertension. The importance of this issue is by no means merely academic. It should be remembered that static factors are either irreparable or are the surgeon’s concern; the physician can only hope to treat the functional components of the disease. The functional components of pulmonary hypertension may be chemical Only the latter will be dealt with in this paper. or neurogenic in nature. Recent reviews in several languages3J1J4~27*4s have given a detailed account of our present knowledge concerning the nervous regulation of the normal pulmonary circulation. A fair number of nerve endings are known to exist in the walls of the lung vessels supplied by afferent and efferent nerve fibers. Sym-
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pathetic discharges were found to have a constricting effect on these vesse1s.l’ Interruption of the efferent pathway (vagotomy) had no effect on pulmonary In addition to this direct action, nervous induced changes in hemodynamics.30 heart rate, cardiac output, bronchomotor tone, and intrathoracic blood volume are capable of affecting indirectly the pulmonary circulation. There is a further aspect of the neurogenic regulation of the lesser circulation which should not be allowed to remain unmentioned here. The concept of “neurogenic lung edema” was often emphasized in the earlier literature, which implied a specific role of the nervous system in inducing lung edema. It has been demonstrated in recent years that some types of this “neurogenic lung edema” are mediated by the indirect action of the nervous system on lung circulation, for example, by an excessive increase in systemic arterial pressure or by excessive bradycardia. The mechanism of other types of “neurogenic lung edema” (e.g., vagotomy30) is not yet well understood. It should be emphasized, however, that no evidence has hitherto been presented in support of any specific action of the nervous system on the permeability of the lung capillaries. This topic is considered elsewhere in this symposium (Aviado and Schmidt, p. 495). Students of the neurogenic aspects of pulmonary hypertension use the technique of right heart catheterization. Cardiac output (a), pulmonary arterial pressure (b), and pulmonary arterial “wedge” pressure (c) are usually determined before and after the administration of a ganglionic or adrenergic blocking agent. These variables are substituted into Poiseuille’s formula47 in order to calculate resistance to flow in the pulmonary circuit. Two types of resistances are usually calculated : total pulmonary resistance (TPR), and pulmonary vascular resistance (PVR). According to this approach, cardiac output, arteriolar diameter, and height of “wedge” pressure are the main factors which determine the level of pulmonary artery pressure. A change in the pressure in the pulmonary artery might therefore be the result of a change in any of the aforementioned variables. Resistance equals pressure drop across the circuit divided by flow; a change in its value can (if flow and “wedge” pressure remain constant) be attributed to a change in the diameter of vessels. For calculating total pulmonary resistance (TPR), pulk . Left ventricular di0 astolic pressure in this calculation is assumed to be zero and the pressure drop across the circuit is hypothetically regarded to be equal to the pulmonary arterial pressure. The height of the pulmonary artery pressure is influenced, however, by the level of the pulmonary arterial “wedge” pressure. A decrease in the latter will involve in most of the cases an equivalent decrease in the former. A normal “wedge” pressure is unlikely to decrease significantly. In precapillary pulmonary hypertension (e.g., car pulmonale, Eisenmenger syndrome, and others) a decrease In postcapillary in TPR will most probably be due to arteriolar dilatation. pulmonary hypertension (e.g., left ventricular failure, mitral stenosis, and others) most of the neuroplegic substances will decrease “wedge” pressure. In these cases, therefore, a decrease in TPR will not necessarily reflect pulmonary arteriolar dilatation.
monary
artery
pressure is divided
by cardiac
output
528
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J. Chron. Dis. May, 1959
Pulmonary vascular resistance (PVR) is obtained by dividing the pressure gradient between the pulmonary artery and the “wedge” by cardiac output b-c -. Values obtained in this way are commonly used as reflections of ( a > changes in the lumina of the pulmonary arterioles. This is the scheme generally used in interpreting changes in pulmonary hemodynamics following the use of blocking agents. The lively criticism to which this scheme has recently been subjected should induce us to look into it It should be found out how far the shortcomings of this interpremore closely. tation undermine the results and conclusions to be reviewed here. The expression “wedge” pressure has been frequently used but not explained in this review. Pulmonary arterial “wedge” pressure has been found by the majority of investigators to be a close estimate of left atria1 pressure, both in the normal man and animal. There is a minority who believe that “wedge” pressure is identical with pulmonary capillary pressure. The difference between pulmonary capillary and left atria1 pressures is very slight under normal conditions and is unlikely to influence our calculations for clinical purposes. There is one point, however, which does not seem to have received sufficient attention: the role of the pulmonary veins. A muscle layer has been unequivocally demonstrated by many histologists in the pulmonary veins. Some pharmacologic evidence has been accumulated in the animal showing that the pulmonary veins are capable of constriction. In this stage, “wedge” pressure would certainly not correspond any more to left atria1 pressure but rather to pulmonary capillary pressure. Blocking agents in this stage would probably partly, or totally, abolish this venoconstriction resulting in a “wedge” pressure which again would reflect left atria1 pressure. One would, therefore, at the moment prefer to adhere to the rather vague term “wedge” pressure. The looseness of this term will certainly challenge some investigators to study more closely the simultaneous behavior of “wedge” and left atria1 pressures under different conditions. The main attack of criticism is directed against the use of the concept “resistance.” Poiseuille’s law4’ was originally meant to describe pressure-flow relationships in rigid tubes filled by a Newtonian fluid, exhibiting a constant flow. One can hardly help wondering if this formula is still valid in a system of elastic tubes, filled by a non-Newtonian fluid, exhibiting an intermittent flow. To discard the concept completely appears to some of us unwise. A primitive compromise has been adopted as a temporary expedient. This compromise presupposes that, while small numerical differences in resistance might be misleading, a constant trend of changes could be indicative of the direction of changes. Tables in this review will therefore not show absolute values; only trends of changes are shown. The many sources of error inherent in right heart catheterization cannot be described here in detail. One point, however, does not seem to have received sufficient attention in the past. P. Fleming and Brotmacherzl have demonstrated recently that spontaneous fluctuations in the pulmonary arterial pressure of
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32 patients suffering from pulmonary hypertension were considerable and, in one case, amounted to 28 mm. Hg. In patients with normal pulmonary artery pressures (11 cases) the fluctuations never exceeded 7 mm. Hg. MITRAL
STENOSIS
Most of the work on the neurogenic aspects of pulmonary hypertension has been carried out in this disease. All available data are summarized in Table I. TABLE I. THE EFFECT OF NEUROPLEGICSUBSTANCESON THE PULMONARYCIRCULATIONIN MITRAL STENOSIS
____
SUBSTANCE Dihydroergotamine Hydergin Hydergin Hydergin Dibenamine Priscoline Priscoline Regitine Tetraethylammonium Tetraethylammonium Hexamethonium Hexamethonium Hexamethonium Hexamethonium Hexamethonium Hexamethonium Reserpine Reserpine Reserpine Acetylcholine Acetylcholine Morphine Sleep
I-
OF CASES
IVO.
i 4 : 4 :6” : 10 1;
1.5 14 32 12 19 z 24 21 3
MEASUREMENT
TPR TPR TPR TPR TPR TPR PAP TPR PVR TPR PVR TPR PVR PVR PVR PVR PVR PVR TPR PVR PAP PVR TPR
KESULTS Increase No change Inconsistent Decrease Decrease Inconsistent Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease No change Inconsistent Decrease Decrease Decrease Decrease Decrease Increase Decrease
REMARKS
Mean change: slight increase PVR decreased in 1 case Inverse response in 1 case Drop in PWP primary? Therapeutic implications Therapeutic implications Direct + indirect mechanism Drop, no change, increase No effect in 1 case Transient effect Transient effect No detailed data published
Explnnalion of s?/mboZst PVR-pulmonary vascular resistance. TPR-total PAP-pulmonary artery pressure (no flow measurement). PWP-pulmonary
pulmonary resistance. “wedge” pressure.
Adrenergic blocking agents failed to exhibit any uniformity in their action. This effect TPR increased following the administration of dihydroergotamine.32 appeared to be unrelated to the sympatholytic property of the substance; the administration of Hydergin resulted either in a slight decrease40 or no change32s37 The administration of Dibenamine,31 Priscoline,6z37 and Regitine54 in TPR. in a rather small series of patients resulted in a decrease in TPR; PVR was not determined. More investigations have been carried out with ganglionic blocking agents. Tetraethylammonium has lowered PVRS1 and TPR.31 A decrease in PVR was observed after hexamethonium in most cases4,57s61;no change55 or inconsistent resultsF5were observed in others. The cause of these different results is not clear. There were apparently no major differences in the composition of the series; the dosage, the period of observation, and experimental techniques were more
530
HALMAGYI
or less similar. It seems not unlikely that the neurogenic component of pulmonary hypertension differs from case to case. Reserpine was found to decrease PVR significantly in practically all the cases investigated.2~2g~3g Its mode of action is not yet well understood. A 20minute interval was observed between the administration of the drug through the catheter and the decrease in PVR. The pulmonary hypotensive effect lasted for several hours and the systemic circulation remained practically unaffected. Acetylcholine also decreases pulmonary arterial pressure and resistance33s60; the effect is, however, drastic and transient. A significant increase in PVR was reported following the administration of morphine.rg The only paper on this subject unfortunately fails to give any detailed data on this highly interesting finding. A significant reduction of TPR was observed during sleep.31 Since PVR, due to obvious technical difficulties, could not be determined, the mechanism of this pressure fall cannot be properly interpreted. An increase in PVR has been regarded as instrumental in protecting the lung capillaries from the high pulmonary arterial pressure by decreasing right If one accepts that this increase ventricular output (Dexter and associatesr3). in PVR is due partly to neurogenic vasoconstriction one wonders what could be gained by abolishing this protective mechanism. Nonetheless the use of hypotensive drugs might be advantageous in two forms or stages of mitral stenosis. In the first group of cases, PVR is unduly elevated, approaching, or even surpassing, systemic resistance; in these instances a long-term treatment with a hypotensive drug might be worth a trial. The drug of choice appears to be reserpine since other substances which have been tested require a dose which first affects the systemic circulation. This form of treatment has still to be explored. Good results have been reported in the second group in imminent or manifest lung edema due to mitral stenosis. This seems to be a contradiction to what was said before about the protective vasospasm of the lung arterioles. In this use of hypotensive agents, however, not their pulmonary vasodilator activities are exploited but rather their indirect effect on lung circulation. These drugs, by decreasing systemic resistance, apparently allow part of the intrathoracic blood This redistribution of circulating blood volume volume to shift to the periphery. decreases pulmonary capillary pressure and prevents or reverts lung edema. This effect is best achieved by a quick-acting substance with a predominantly systemic action, such as hexamethonium or tetraethylammonium. LEFT VENTRICULAR
FAILURE
Only a few investigations have been carried out in this form of pulmonary hypertension (Table I I). Blocking agents invariably caused a reduction in pulmonary artery pressure. PVR was investigated by a single author only22; it was found to decrease. Blocking agents have an excellent therapeutic effect in paroxysmal nocturnal dyspnea and acute lung edema due to left ventricular failure. The mechanism of this action is presumably identical with that described in mitral stenosis.
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TABLE II. THE EFFECT OF NEUROPLEGIC SUBSTANCES ON THE PULMONARY CIRCULATION IN LEFT VENTRICULAR FAILURE
NUMBER OF CASES _
SUBSTANCE
HEART
DISEASE
III.
THE
PULMONARY
EFFECT OF NEUROPLECIC
HEART
NUMBEROF CASES
SUBSTANCE
I
MEASUREMENT
i :,
/
13
SUBSTANCES ON THE PULMONARY
DISEASE WITH
PULMONARY
-1 PVR E
IN
REMARKS
RESULT Decrease No change Decrease No change
CIRCULATION
HYPERTENSION
/ TPR
Reserpinez9 Acetylcholine33
HYPERTENSION
small number of patients have been investigated in this A decrease in resistance was observed only occasionally.
CONGENITAL
Hydergin3* Priscoline4*
WITH
Decrease Decrease Decrease Decrease
TPR TPR TPR
:
A comparatively group (Table III). TABLE
RESULTS
PVH
Tetraethylammonium~ TetraethyIammonium3’ Dibenamine” Sleep3i
CONGENITAL
MEASUREMENT _______
l---
_____ Decrease
in 2 cases
Some decrease
in 2 cases
In these diseases, a wide communication exists between the left and the right side of the circulation. Since blood will always flow toward the lesser resistance, an increase in pulmonary vascular resistance is a vital condition in The increase in PVR is occasionally maintaining the balance of circulation. The much exaggerated ; it may become higher than the systemic resistance. If PVR in these cases could result will be a right-to-left shunt with cyanosis. be reduced pharmacologically to a more reasonable level, cyanosis would disappear. Although only a minority of cases can be expected to respond, the trial appears to be a useful undertaking. For many reasons, reserpine seems to be the most suitable substance. CHRONIC
COR PULMONALE
Very little work has been done to assess the neurogenic contribution to the genesis of pulmonary hypertension in this group of diseases (Table IV). A slight decrease in resistance was observed following the administration of Regitine,38 tetraethylammonium,22 and hexamethonium,3g~50~5g the effect of the latter being rather inconsistent. the narrowed Blood flow in mitral stenosis has to overcome two obstacles: In pulmonary heart disease pulmonary arteries and the tightened mitral valve. it is only the former obstacle which impedes blood flow. It appears therefore
J. Chron.Dis.
HALMAGYI
TABLE IV.
May, 1959
THE EFFECT OF NEUROPLECIC SUBSTANCESON THE PULMONARY CIRCULATION IN CHRONICPULMONARYHEART DISEASE T.x
NUM. BER CIF CASE S
SUBSTANCE
MEASUREMENT
RESULT
REMARKS
--
Hydergin, dihydroergotamine3z Priscoline37 Regitinea* Tetraethylammoniumn Hexamethoniums9 Hexamethonium5’J Hexamethonium3* Acetylcholine33 HeptaminoP6 A&opine, Banthinei
2 1
TPR TPR TPR PVR TPR TPR TPR PAP PAP (syst. .) PAP
: 4 ! 1; 18
Increase No change Decrease Decrease Decrease No change Decrease Inconsistent Decrease Inconsistent
Unconvincing data Initial PAP not very high Decrease in flow Unconvincing data Transient decrease in 2 cases Unconvincing data Interpretation controversial
that pharmacologic dilatation of the pulmonary bed would be particularily advantageous. Recent observations 28 have shown, however, that any improvement in the perfusion of the lung, if unaccompanied by an equivalent increase in alveolar ventilation, will decrease arterial oxygen tension and saturation. This is due to a decrease in the ventilation-perfusion ratio of the lung and is in accord with the original suggestion by von Euler and Liljestrandl* that pulmonary vasoconstriction may serve as a useful adaptation which prevents overperfusion of underventilated alveoli. IDIOPATHIC
PULMONARY
HYPERTENSION
It is generally agreed that this group consists of several pathogenetically different diseases. It is by no means unusual, 52 however, to find cases with little or no anatomic damage of the lung vessels, despite pre-existing hypertension of extreme degree. This is one of the reasons why this disease has been considered When Priscoline was first reported to be due to pulmonary vasoconstriction.
TABLE V.
-__
THE EFFECT OF NEUROPLEGICSUBSTANCESAND INTERVENTIONSON THE PULMONARY CIRCULATIONIN IDIOPATHIC PULMONARY HYPERTENSION
NUMBEROF CASES
SUBSTANCE ___
Priscoline16~10 Priscoline46 Priscolineso Priscolinez6 PriscoIine@ HexamethoniumsG HexamethoniumG* AcetyIchoIine33 Chlorpromazine’3 Ggl. stellatum bIockade*6 Ggl. stellatum bIockadeK8 Sympathectomy (T2-Te)r6
MEASUREMENT
PVR TPR
PVR PVR
I
TPR
PVR
TPR PAP
! i
I
l
I
None PVR PVR TPR
RESULT
Decrease No change No change No change Decrease No change Decrease Inconsistent No clinical benefit Increase No change No change
REMARKS
Due to pain
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to decrease pulmonary arterial pressure in this clinical entity,15J6 the general belief was that the vasoconstriction was neurogenic in origin. Further investigators have, however, mostly failed to confirm this effect of Priscoline26,46.56 and only YULE was able to reproduce Priscoline-induced hypotension in one of his patients. This difference in results might perhaps be the reflection of the difference in the etiology of individual cases. Many other substances have since been tried (Table V). Their effect was nearly always disappointing. H. A. Fleming20 has recently given reserpine to one of his patients suffering from idiopathic pulmonary hypertension. No response was observed. Similar negative findings have led Wade and Ba1156 to suggest that pulmonary vasoconstriction in this disease (although apparently present26) is non-neurogenic in origin. A search for an unknown pressor-agent should perhaps be attempted. SUMMARY
The extent of neurogenic contribution to the genesis of chronic pulmonary hypertension appears to depend on the particular form of the underlying disease. It seems considerable in mitral stenosis and may be totally absent in idiopathic pulmonary hypertension. The other forms of the syndrome lie between these two extremes. Neurogenic pulmonary vasoconstriction in some cases seems to contribute to the maintenance of circulatory homeostasis in the lungs. In other cases its extent appears unreasonably high and attempts should be made to relieve it. Neuroplegic drugs are not only beneficial in relieving this vasoconstriction, but also by being capable of inducing a rapid decrease in pulmonary capillary pressure. This renders their use advisable in cases of imminent or manifest lung edema due to engorgement of the lungs. REFERENCES
1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11.
Abbott! 0. E., Van Fliet, W. E., Roberto, A. E., and Salomone, F. P.: Studies on the Functron of the Human Vagus Nerve in Various Types of Intrathoracic Diseases, J. Thoracic Surg. 30:564, 195.5. Angelino, P. F., and Levi, V.: Sulle modificazione dell’emodinamica dell’ piccolo circolo indotta alla reserpina nei mitralici, Minerva cardioangiol. 4:165, 1956. Bad Oeyenhausener Gspraeche ueber den Lungenkreislauf, Berlin, 1957. Springer Verlag. Balhoum, 0. J., Gensini, G. G., BIount, S: G.,, Jr.: The Effect of Hexamethonium Upon ;hg;7Pulmonary Vascular Resrstance m Mrtral Stenosis, J. Lab. & Clin. Med. 50:186, Bloomfield; R. A., Lauson, H. D., Cournand, A., Breed,, E. S., and Richards, D. W., Jr.: Recording of Right Heart Pressures in Normal Sublects and in Patients With Chronic Pulmonary Disease and Various Types of Cardiocirculatory Disease, J. Clin. Invest. 25:39, 1946. Braun! K., Izak, G., and Rosenberg, Z. S.: Pulmonary Artery Pressure After Priscoline m Mitral Stenosis, Brit. Heart J. 19:279, 1957. Brenner, 0.: Pathology of the Vessels of the Pulmonary Circulation. I-V. Arch. Int. Med. 56:211;457; 724;976;1189, 1935. Burton, A. C.: Laws of Physics and Flow in Blood Vessels, Ciba Symposium on Visceral Circulation (edited by G. E. W. Wolstenholm), London, 1953, J. & A. Churchill, Ltd. Curti, P. C:, Cohen, H., Castleman, P., Scannell, F. G,., Friedlich, A:L. x, and Myers, G. S.: Respuatory and Clinical Studies in Patients Wrth Mitral Stenosis, Circulation 8:893, 1953. Daley, R.: The Autonomus Nervous System in its Relations to Some Forms of Heart and Lung Disease, Brit. M. J. 2:173, 1957. Daly, I. de Burgh: Intrinsic Mechanisms of the Lungs, Quart. J. Exper. Physiol. 43:2, 1958.
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Davies, L. G., Goodwin, J. F., and van Leuven, B. D.: The Nature of Pulmonary Hypertension in Mitral Stenosis, Brit. Heart J. 16:440, 1954. Dexter, L., Dow, J. W., Haynes, F. W., Whittenberger, J. L., Ferris, B. G., Goodale, W. T., and Hellems, H. K.: Studies on the Pulmonary Circulation in Man at Rest. Normal Variations and the Interrelation Between Increased Pulmonary Arterial Pressure and Hieh Pulmonarv Caoillarv Pressure. I. Clin. Invest. 29:602. 1950. Donnet, “v., and Ardisson- ) 5. i.: Don&s” recentes sur la circulation pulmonaire, J. de Physiol. (Paris) 50:68 , 1958. Dresdale, D. T., Michtom, J. R., and Schultz, M.: Primary Pulmonary Hypertension, Bull. New York Acad. Med. 30:195, 1954. Dresdale, D. T., Schultz, M., and Michtom, J. R.: Primary Pulmonary Hypertension, Am. J. Med. 11:686, 1951. Edwards, J. E.: Functional Pathology of the Pulmonary Vascular Tree in Congenital Cardiac Disease, Circulation 15:164, 1957. Von Euler. U. S.. and Liliestrand. G.: Observations on the Pulmonarv Arterial Blood Pressure in’the Cat, Acta physiol. scandinav. 12:301, 1946. ’ Fejfar, Z., Bergmann, K., Fejfarova, M., and Valach, A.: The Effect of Morphine on Pulmonary Haemodynamics in Mitral Stenosis, Cardiologia 31:461, 1957. Fleming, H. f Personal communication. Fleming. P.. and Brotmacher. L.: The Reliabilitv of Observations at Cardiac Catheterizat&t, Guy’s Hosp. Rep.‘107:233, 1958. . Fowler, N. O., Westcott, R. N., Hauenstein, V. D., Scott, R. C., and McGuire, J.: Observations on Autonomic Participation in Pulmonary Arteriolar Resistance in Man, J. Clin. Invest. 29:1387, 1950. Gardiner, J. M.: The Effect of Priscol in Pulmonary Hypertension, Australasian Ann. Med. 3:59, 1954. Goodale, F., Jr., Sanchez, G., Friedlich, A. L., Scannell, F. G., and Myers, G. S.: Correlation of Pulmonary Arteriolar Resistance With Pulmonary Vascular Changes in Patients With Mitral Stenosis Before and After Valvulotomy, New England J. Med. 252:979. 1955. Goodwin, J. F., Hollman, A., and O’Donnell, T. V.: Ganglionic Blocking Agents in Mitral Valve Disease, 2:1251, 1958. Gorlin, R., Glare, F. B., and Zuska, J. J.: Evidence of Pulmonary Vasoconstriction in Man, Brit. Heart J. 20:346, 1958. Halmagyi, D. F. J.: Die klinische Physiologie des kleinen Kreislaufs, Jena, 1957, Fischer Verlag. Halmagyi, D. F. J., and Cotes, J. E.: Reduction in Systemic Blood Oxygen as a Result of Procedures Affecting the Pulmonary Circulation in Patients With Chronic Pulmonary Disease, Clin. SC. In press. Z.. and Kovacs. G.: The Effect of Seroasil in PulHalmaevi. D. F. T.. Felkai. B.. CZiDOtt. Gonary Hypertension, I&it. Heart J: 19:37.5, 1957. Halmagyi, D. F. J., Felkai, B., Ivanyi, J., Zsoter, T., Sziics, Z., and Pint&, I.: The Effect of Vagotomy in Pulmonary Oedema Produced by Massive Intravascular Infusions in Dogs, Acta Med. Hung. 8:261, 195.5. Halmagyi, D. F. J,, Felkai, B., Ivlnyi, J., ZsotCr, T., Tenyi, M., and Sztics, Z.: The Role of the Nervous System in the Maintenance of Pulmonary Hypertension in Heart Failure, Brit. Heart J. 15:15, 1953. Halmagyi, D. F. J., Ivanyi, J., Felkai, B., ZsotCr, T., Tenyi, M., and Sziics, Z.: The Effect of Dihydroergotamine and Hydergin on Pulmonary Arterial Pressure in Man, Scandinav. J. Clin. Lab. Invest. 5:85, 1953. Harris, P. : Influence of Acetylcholine on the Pulmonary Arterial Pressure, Brit. Heart J. 19:272, 1957. Merkmale der Vasoconstriction beim Menschen; Hirsch, S. : Ueber die morphologische zugleich ein Beitrag zum Problem der Funktion der glatten Muskulatur, Acta med. scandinav. 152:379, 1955. Langeron, L., Giard, N., and Routier, G.: Action de I’amino-2-methyl-6-heptanol-6sur la pression des cavites chez l’homme. Etudes par le catheterisation intracardiaque, Presse med. 65:1287,. 1957. Lilienthal, J. L., Jr., and Riley, R. L.: Diseases of the Respiratory System, Ann. Rev. Med. 5:237, 1954. Mackinnon, J., Vickers, C. F. H., and Wade, A. G.: The Effects of Adrenergic Blocking Agents on the Pulmonary Circulation m Man, Brit. Heart J. 18:442, 1956. Malamos, B., Moulopoulos, S., Dimakis, D., Primikiris, D., and Kyriapoulos, A.: Ueber die Wirkung der Ganglienblocker und Aminophyllm auf den kleinen Kreislauf, Ztschr. f. Kreislauff. 46:681, 1957. Marx, H. H.: Die Behandlung der chronischen Cor pulmonale, Deutsch. med. Wchnschr., 83:1269, 1958. Meriel, P., Bollinelli, R., Calazel, P., and Cassagneau, J.: Epreuve a l’hydergine et pressions pulmonaires, Arch. mal. coeur 46:329, 1953.
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Merkel, H.: Zur Histologie der Lungengefaesse, Beitr. path. Anat. 105:176, 1940-41. und die Druck-Umfang BezieMeyer, W. W., and Schollmayer, P.: Die Volumdehnbarkeit hungen der Lungenschlagader-Windkessels in Abhaengigkeit vom Alter und pulmonalem Hochdruck, Klin. Wchnschr. 35:1070, 1957. O’Neal, R. M., Ahlvin,, R. C., Bauer, W. C., and Thomas, W. A.: Development of Fetal Pulmonary Arterioles, Arch. Path. 63:309, 1957. O’Neal, R. M., and Thomas, W. A.: The Role of Pulmonary Hypertension and Thromboembolism in the Production of Pulmonary Atherosclerosis, Circulation 12:370, 1955. O’Neal, R. M., Thomas, W. A., and Hartroft, P. M.: The Media of Small Muscular Pulmonary Arteries in Mitral Stenosis, Arch. Path. 60:267, 195.5. Panuccio, P., and Caini, B.: Ulteriore contribute allo studio dell’ipertensione polmonare primitiva: prove farmacodimaniche con Priscol, Minerva Cardioangiol. 5:226, 1957. Poiseuille, J. L. M.: Recherches experimentales sur le mouvement des liquides dans les tubes trespetits diametres, Compt. rend. Acad. Roy. 11, 1841. Rudolph, A. M., Paul, M. H., Sommer, L. S., and Nadas, A. S.: Effects of TolazolidineHydrocholoride (Priscol) on Circulatory Dynamics of Patients With Pulmonary Hypertension, Am. Heart J. 55:424! 1958. Sales Luis, A.: Fisiopatologia de cuculacao pulmonar, Gaz. med. port. 8:285, 195.5. Sancetta, S. M.: Acute Hemodynamic Effects of Hexamethonium in Patients With Emphysematous Pulmonary Hypertension, Am. Heart J. 49:501, 195.5. Scott, R. C., Kaplan! S., and Stiles, W. J.: Observations on the Effect of Tetraethylammonium Chloride on the Pulmonary Vascular Resistance in Mitral Stenosis, Am. Heart J. 50:720, 1955. Soothill, J. F.: A Case of Primary Pulmonary Hypertension With Paralysed Left Vocal Cord, Guy’s Hosp. Rep. 100:232, 1951. Soulie, P., DiMatteo, J., Vernant, P., and Caldier, L.: Considerations sur la physiopathologie et le diagnostic de I’ hypertension arterielle pulmonaire primitive, Bull. et. m&m. Sot. med. HBp. Paris 71:187, 1955. Storstein, O., Elgvin, T., Helle, I., and Sebelien, J.: The Effect of Phentholamine (Regitine) on the Pulmonary Circulation, Scandinav. J. Clin. Lab. Invest. 9:150, 1957. Storstein, O., and Tveten, H.: The Effect of Hexamethonium Bromide on the Pulmonary Circulation, Scandinav. J. Clin. Lab. Invest. 6:169, 1954. Wade,If;,A., and Ball, J.: Unexplained Pulmonary Hypertension, Quart. J. Med. 26:83, Wade. G. A.. Mackinnon. T.. and Vickers. C. F. H.: The Nature of the Increased Pulmonarv , ‘Vascular Resistance-in-Mitral Stenosis, Brit. Heart J. 18:458, 1956. Werko, L., and Eliasch, H.: Circulatory Studies in a Case of Primary Pulmonary Hypertension, Cardiologia 21:403, 1952. Wilson, V. H,., and Keeley, K. J.: The Haemodynamic Effects of Hexamethonium Bromide in Patients With Pulmonary Hypertension and Heart Failure, South African J. M. SC. 18:125, 1953. Wood, P., Besterman, E. M., Towers, M. K., and McIlroy, M. B.: The Effect of Acetylcholine on Pulmonary Vascular Resistance and Left Auricular Pressure in Mitral Stenosis, Brit. Heart J. 19:279, 1957. Yu, P. N., Nye, Jr., R. E., Lovejoy, J. F. W., Schreiner, B. F., and Yim, B. J. B.: Studies on Pulmonary Hypertension. IX. The Effect of Intravenous Hexamethonium on the Pulmonary Circulation in Patients With Mitral Stenosis, J. Clin. Invest. 37:194, 1958. Yu, P. N.: Primary Pulmonary Hypertension: Report of 6 Cases and Review of Literature, A~II. Int. Med. 49:1138, 1958.
From the Department Sydney
SYDNEY, AUSTRALIA
of Medicine,
lTniversity
of
(Received for publication Feb. 9, 1959)
AST new territories of cardiology were opened up by Bloomfield and assoV ciates5 when they first pushed a catheter intentionally into the human pulmonary artery. Not only was one of nature’s closely guarded secrets revealed but the pulmonary bed became one of the most easily accessible segments of the human circulation. It was soon learned that pulmonary hypertension is a frequent and important feature in many types of heart disease and that different pathogenetic types of pulmonary hypertension exist (Fig. 1). The role of the nervous system is one of the main controversial points in the genesis of pulmonary hypertension. The roots and causes of this controversy have been described by Lilienthal and Riley36 with an admirable clarity: There is in historical perspective a recurrent pattern in the development of concepts concerning special circulations. In the earlier stages of investigation the experimental technics available for isolation and measurement of the circuit under study are relatively crude and unwitting damage is done to the controlling mechanisms. During this period the conclusion is oftimes drawn that the special circulation mirrors in a passive way the pressures and flows imposed on it by the systemic circulation. With progressive refinement of experimental technics there begin to appear observations which suggest that active vasomotion does occur in response to a host of neural and chemical stimuli. The growth of our knowledge concerning the cerebral and hepatic circulations are examples of this pattern. For many years this same question has confronted students of the pulmonary circulation and to this day the dilemma has not been resolved with any finality.s6 The importance of static factors in the genesis of pulmonary hypertension is generally accepted. A stenosed mitral valve or a large interventricular septal defect can obviously be the main cause of pulmonary hypertension. Microscopic changes in the lung vessels, consisting of intimal proliferation and atherosclerotic deposits, and thromboembolic obliteration of several branches, are of equal importance. These changes not only decrease the capacity of the pulmonary vascular bed but also severely impair its biophysical characteristics.8,42 This is why anatomic changes appeared amply sufficient to explain the increase in pulmonary arterial pressure to some observers.iO It is not very difficult, however, *Adolph
Basser
Senior Research
Fellow
of the Royal 525
Australasian
College of Physicians.
J. Chron. Dis. May, 1959
HALMAGYI
to find anatomic observations which fail to support this view. In some cases of idiopathic pulmonary hypertension with an extremely high pressure, no microscopic anomalies were detected in the lung vessels.52 A poor correlation was found between microscopic changes in the pulmonary arterioles and the increase in arteriolar resistance in mitral stenosis.s~24 The thickening of the medial musculature of the pulmonary arterioles, hitherto regarded as real muscular hypertrophy, has been revealed as the consequence of pre-existing vasoconstriction 17,34.43,44,45
OBSTRUCTED
Fig. l.-Pathogenesis of pulmonary hypertension. White circles represent the three possible general causes of pulmonary hypertension while the resulting diseases are shown as black circles. By shifting the black circles in different directions one can illustrate the varying extent to which one of the three mechanisms participates in the genesis of pulmonary hypertension. For example, the black circle of mitral stenosis if shifted downward will represent those case6 where mechanical obstruction of the mitral If it is shifted upward and to the left, the other form flow is the main cause of pulmonary hypertension. of the disease is shown in which arteriolar resistance is the major obstacle to blood flo~.~’
From these observations it appears that even anatomic findings are to some extent suggestive of a superimposed functional factor in pulmonary hypertension. The importance of this issue is by no means merely academic. It should be remembered that static factors are either irreparable or are the surgeon’s concern; the physician can only hope to treat the functional components of the disease. The functional components of pulmonary hypertension may be chemical Only the latter will be dealt with in this paper. or neurogenic in nature. Recent reviews in several languages3J1J4~27*4s have given a detailed account of our present knowledge concerning the nervous regulation of the normal pulmonary circulation. A fair number of nerve endings are known to exist in the walls of the lung vessels supplied by afferent and efferent nerve fibers. Sym-
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pathetic discharges were found to have a constricting effect on these vesse1s.l’ Interruption of the efferent pathway (vagotomy) had no effect on pulmonary In addition to this direct action, nervous induced changes in hemodynamics.30 heart rate, cardiac output, bronchomotor tone, and intrathoracic blood volume are capable of affecting indirectly the pulmonary circulation. There is a further aspect of the neurogenic regulation of the lesser circulation which should not be allowed to remain unmentioned here. The concept of “neurogenic lung edema” was often emphasized in the earlier literature, which implied a specific role of the nervous system in inducing lung edema. It has been demonstrated in recent years that some types of this “neurogenic lung edema” are mediated by the indirect action of the nervous system on lung circulation, for example, by an excessive increase in systemic arterial pressure or by excessive bradycardia. The mechanism of other types of “neurogenic lung edema” (e.g., vagotomy30) is not yet well understood. It should be emphasized, however, that no evidence has hitherto been presented in support of any specific action of the nervous system on the permeability of the lung capillaries. This topic is considered elsewhere in this symposium (Aviado and Schmidt, p. 495). Students of the neurogenic aspects of pulmonary hypertension use the technique of right heart catheterization. Cardiac output (a), pulmonary arterial pressure (b), and pulmonary arterial “wedge” pressure (c) are usually determined before and after the administration of a ganglionic or adrenergic blocking agent. These variables are substituted into Poiseuille’s formula47 in order to calculate resistance to flow in the pulmonary circuit. Two types of resistances are usually calculated : total pulmonary resistance (TPR), and pulmonary vascular resistance (PVR). According to this approach, cardiac output, arteriolar diameter, and height of “wedge” pressure are the main factors which determine the level of pulmonary artery pressure. A change in the pressure in the pulmonary artery might therefore be the result of a change in any of the aforementioned variables. Resistance equals pressure drop across the circuit divided by flow; a change in its value can (if flow and “wedge” pressure remain constant) be attributed to a change in the diameter of vessels. For calculating total pulmonary resistance (TPR), pulk . Left ventricular di0 astolic pressure in this calculation is assumed to be zero and the pressure drop across the circuit is hypothetically regarded to be equal to the pulmonary arterial pressure. The height of the pulmonary artery pressure is influenced, however, by the level of the pulmonary arterial “wedge” pressure. A decrease in the latter will involve in most of the cases an equivalent decrease in the former. A normal “wedge” pressure is unlikely to decrease significantly. In precapillary pulmonary hypertension (e.g., car pulmonale, Eisenmenger syndrome, and others) a decrease In postcapillary in TPR will most probably be due to arteriolar dilatation. pulmonary hypertension (e.g., left ventricular failure, mitral stenosis, and others) most of the neuroplegic substances will decrease “wedge” pressure. In these cases, therefore, a decrease in TPR will not necessarily reflect pulmonary arteriolar dilatation.
monary
artery
pressure is divided
by cardiac
output
528
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J. Chron. Dis. May, 1959
Pulmonary vascular resistance (PVR) is obtained by dividing the pressure gradient between the pulmonary artery and the “wedge” by cardiac output b-c -. Values obtained in this way are commonly used as reflections of ( a > changes in the lumina of the pulmonary arterioles. This is the scheme generally used in interpreting changes in pulmonary hemodynamics following the use of blocking agents. The lively criticism to which this scheme has recently been subjected should induce us to look into it It should be found out how far the shortcomings of this interpremore closely. tation undermine the results and conclusions to be reviewed here. The expression “wedge” pressure has been frequently used but not explained in this review. Pulmonary arterial “wedge” pressure has been found by the majority of investigators to be a close estimate of left atria1 pressure, both in the normal man and animal. There is a minority who believe that “wedge” pressure is identical with pulmonary capillary pressure. The difference between pulmonary capillary and left atria1 pressures is very slight under normal conditions and is unlikely to influence our calculations for clinical purposes. There is one point, however, which does not seem to have received sufficient attention: the role of the pulmonary veins. A muscle layer has been unequivocally demonstrated by many histologists in the pulmonary veins. Some pharmacologic evidence has been accumulated in the animal showing that the pulmonary veins are capable of constriction. In this stage, “wedge” pressure would certainly not correspond any more to left atria1 pressure but rather to pulmonary capillary pressure. Blocking agents in this stage would probably partly, or totally, abolish this venoconstriction resulting in a “wedge” pressure which again would reflect left atria1 pressure. One would, therefore, at the moment prefer to adhere to the rather vague term “wedge” pressure. The looseness of this term will certainly challenge some investigators to study more closely the simultaneous behavior of “wedge” and left atria1 pressures under different conditions. The main attack of criticism is directed against the use of the concept “resistance.” Poiseuille’s law4’ was originally meant to describe pressure-flow relationships in rigid tubes filled by a Newtonian fluid, exhibiting a constant flow. One can hardly help wondering if this formula is still valid in a system of elastic tubes, filled by a non-Newtonian fluid, exhibiting an intermittent flow. To discard the concept completely appears to some of us unwise. A primitive compromise has been adopted as a temporary expedient. This compromise presupposes that, while small numerical differences in resistance might be misleading, a constant trend of changes could be indicative of the direction of changes. Tables in this review will therefore not show absolute values; only trends of changes are shown. The many sources of error inherent in right heart catheterization cannot be described here in detail. One point, however, does not seem to have received sufficient attention in the past. P. Fleming and Brotmacherzl have demonstrated recently that spontaneous fluctuations in the pulmonary arterial pressure of
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32 patients suffering from pulmonary hypertension were considerable and, in one case, amounted to 28 mm. Hg. In patients with normal pulmonary artery pressures (11 cases) the fluctuations never exceeded 7 mm. Hg. MITRAL
STENOSIS
Most of the work on the neurogenic aspects of pulmonary hypertension has been carried out in this disease. All available data are summarized in Table I. TABLE I. THE EFFECT OF NEUROPLEGICSUBSTANCESON THE PULMONARYCIRCULATIONIN MITRAL STENOSIS
____
SUBSTANCE Dihydroergotamine Hydergin Hydergin Hydergin Dibenamine Priscoline Priscoline Regitine Tetraethylammonium Tetraethylammonium Hexamethonium Hexamethonium Hexamethonium Hexamethonium Hexamethonium Hexamethonium Reserpine Reserpine Reserpine Acetylcholine Acetylcholine Morphine Sleep
I-
OF CASES
IVO.
i 4 : 4 :6” : 10 1;
1.5 14 32 12 19 z 24 21 3
MEASUREMENT
TPR TPR TPR TPR TPR TPR PAP TPR PVR TPR PVR TPR PVR PVR PVR PVR PVR PVR TPR PVR PAP PVR TPR
KESULTS Increase No change Inconsistent Decrease Decrease Inconsistent Decrease Decrease Decrease Decrease Decrease Decrease Decrease Decrease No change Inconsistent Decrease Decrease Decrease Decrease Decrease Increase Decrease
REMARKS
Mean change: slight increase PVR decreased in 1 case Inverse response in 1 case Drop in PWP primary? Therapeutic implications Therapeutic implications Direct + indirect mechanism Drop, no change, increase No effect in 1 case Transient effect Transient effect No detailed data published
Explnnalion of s?/mboZst PVR-pulmonary vascular resistance. TPR-total PAP-pulmonary artery pressure (no flow measurement). PWP-pulmonary
pulmonary resistance. “wedge” pressure.
Adrenergic blocking agents failed to exhibit any uniformity in their action. This effect TPR increased following the administration of dihydroergotamine.32 appeared to be unrelated to the sympatholytic property of the substance; the administration of Hydergin resulted either in a slight decrease40 or no change32s37 The administration of Dibenamine,31 Priscoline,6z37 and Regitine54 in TPR. in a rather small series of patients resulted in a decrease in TPR; PVR was not determined. More investigations have been carried out with ganglionic blocking agents. Tetraethylammonium has lowered PVRS1 and TPR.31 A decrease in PVR was observed after hexamethonium in most cases4,57s61;no change55 or inconsistent resultsF5were observed in others. The cause of these different results is not clear. There were apparently no major differences in the composition of the series; the dosage, the period of observation, and experimental techniques were more
530
HALMAGYI
or less similar. It seems not unlikely that the neurogenic component of pulmonary hypertension differs from case to case. Reserpine was found to decrease PVR significantly in practically all the cases investigated.2~2g~3g Its mode of action is not yet well understood. A 20minute interval was observed between the administration of the drug through the catheter and the decrease in PVR. The pulmonary hypotensive effect lasted for several hours and the systemic circulation remained practically unaffected. Acetylcholine also decreases pulmonary arterial pressure and resistance33s60; the effect is, however, drastic and transient. A significant increase in PVR was reported following the administration of morphine.rg The only paper on this subject unfortunately fails to give any detailed data on this highly interesting finding. A significant reduction of TPR was observed during sleep.31 Since PVR, due to obvious technical difficulties, could not be determined, the mechanism of this pressure fall cannot be properly interpreted. An increase in PVR has been regarded as instrumental in protecting the lung capillaries from the high pulmonary arterial pressure by decreasing right If one accepts that this increase ventricular output (Dexter and associatesr3). in PVR is due partly to neurogenic vasoconstriction one wonders what could be gained by abolishing this protective mechanism. Nonetheless the use of hypotensive drugs might be advantageous in two forms or stages of mitral stenosis. In the first group of cases, PVR is unduly elevated, approaching, or even surpassing, systemic resistance; in these instances a long-term treatment with a hypotensive drug might be worth a trial. The drug of choice appears to be reserpine since other substances which have been tested require a dose which first affects the systemic circulation. This form of treatment has still to be explored. Good results have been reported in the second group in imminent or manifest lung edema due to mitral stenosis. This seems to be a contradiction to what was said before about the protective vasospasm of the lung arterioles. In this use of hypotensive agents, however, not their pulmonary vasodilator activities are exploited but rather their indirect effect on lung circulation. These drugs, by decreasing systemic resistance, apparently allow part of the intrathoracic blood This redistribution of circulating blood volume volume to shift to the periphery. decreases pulmonary capillary pressure and prevents or reverts lung edema. This effect is best achieved by a quick-acting substance with a predominantly systemic action, such as hexamethonium or tetraethylammonium. LEFT VENTRICULAR
FAILURE
Only a few investigations have been carried out in this form of pulmonary hypertension (Table I I). Blocking agents invariably caused a reduction in pulmonary artery pressure. PVR was investigated by a single author only22; it was found to decrease. Blocking agents have an excellent therapeutic effect in paroxysmal nocturnal dyspnea and acute lung edema due to left ventricular failure. The mechanism of this action is presumably identical with that described in mitral stenosis.
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TABLE II. THE EFFECT OF NEUROPLEGIC SUBSTANCES ON THE PULMONARY CIRCULATION IN LEFT VENTRICULAR FAILURE
NUMBER OF CASES _
SUBSTANCE
HEART
DISEASE
III.
THE
PULMONARY
EFFECT OF NEUROPLECIC
HEART
NUMBEROF CASES
SUBSTANCE
I
MEASUREMENT
i :,
/
13
SUBSTANCES ON THE PULMONARY
DISEASE WITH
PULMONARY
-1 PVR E
IN
REMARKS
RESULT Decrease No change Decrease No change
CIRCULATION
HYPERTENSION
/ TPR
Reserpinez9 Acetylcholine33
HYPERTENSION
small number of patients have been investigated in this A decrease in resistance was observed only occasionally.
CONGENITAL
Hydergin3* Priscoline4*
WITH
Decrease Decrease Decrease Decrease
TPR TPR TPR
:
A comparatively group (Table III). TABLE
RESULTS
PVH
Tetraethylammonium~ TetraethyIammonium3’ Dibenamine” Sleep3i
CONGENITAL
MEASUREMENT _______
l---
_____ Decrease
in 2 cases
Some decrease
in 2 cases
In these diseases, a wide communication exists between the left and the right side of the circulation. Since blood will always flow toward the lesser resistance, an increase in pulmonary vascular resistance is a vital condition in The increase in PVR is occasionally maintaining the balance of circulation. The much exaggerated ; it may become higher than the systemic resistance. If PVR in these cases could result will be a right-to-left shunt with cyanosis. be reduced pharmacologically to a more reasonable level, cyanosis would disappear. Although only a minority of cases can be expected to respond, the trial appears to be a useful undertaking. For many reasons, reserpine seems to be the most suitable substance. CHRONIC
COR PULMONALE
Very little work has been done to assess the neurogenic contribution to the genesis of pulmonary hypertension in this group of diseases (Table IV). A slight decrease in resistance was observed following the administration of Regitine,38 tetraethylammonium,22 and hexamethonium,3g~50~5g the effect of the latter being rather inconsistent. the narrowed Blood flow in mitral stenosis has to overcome two obstacles: In pulmonary heart disease pulmonary arteries and the tightened mitral valve. it is only the former obstacle which impedes blood flow. It appears therefore
J. Chron.Dis.
HALMAGYI
TABLE IV.
May, 1959
THE EFFECT OF NEUROPLECIC SUBSTANCESON THE PULMONARY CIRCULATION IN CHRONICPULMONARYHEART DISEASE T.x
NUM. BER CIF CASE S
SUBSTANCE
MEASUREMENT
RESULT
REMARKS
--
Hydergin, dihydroergotamine3z Priscoline37 Regitinea* Tetraethylammoniumn Hexamethoniums9 Hexamethonium5’J Hexamethonium3* Acetylcholine33 HeptaminoP6 A&opine, Banthinei
2 1
TPR TPR TPR PVR TPR TPR TPR PAP PAP (syst. .) PAP
: 4 ! 1; 18
Increase No change Decrease Decrease Decrease No change Decrease Inconsistent Decrease Inconsistent
Unconvincing data Initial PAP not very high Decrease in flow Unconvincing data Transient decrease in 2 cases Unconvincing data Interpretation controversial
that pharmacologic dilatation of the pulmonary bed would be particularily advantageous. Recent observations 28 have shown, however, that any improvement in the perfusion of the lung, if unaccompanied by an equivalent increase in alveolar ventilation, will decrease arterial oxygen tension and saturation. This is due to a decrease in the ventilation-perfusion ratio of the lung and is in accord with the original suggestion by von Euler and Liljestrandl* that pulmonary vasoconstriction may serve as a useful adaptation which prevents overperfusion of underventilated alveoli. IDIOPATHIC
PULMONARY
HYPERTENSION
It is generally agreed that this group consists of several pathogenetically different diseases. It is by no means unusual, 52 however, to find cases with little or no anatomic damage of the lung vessels, despite pre-existing hypertension of extreme degree. This is one of the reasons why this disease has been considered When Priscoline was first reported to be due to pulmonary vasoconstriction.
TABLE V.
-__
THE EFFECT OF NEUROPLEGICSUBSTANCESAND INTERVENTIONSON THE PULMONARY CIRCULATIONIN IDIOPATHIC PULMONARY HYPERTENSION
NUMBEROF CASES
SUBSTANCE ___
Priscoline16~10 Priscoline46 Priscolineso Priscolinez6 PriscoIine@ HexamethoniumsG HexamethoniumG* AcetyIchoIine33 Chlorpromazine’3 Ggl. stellatum bIockade*6 Ggl. stellatum bIockadeK8 Sympathectomy (T2-Te)r6
MEASUREMENT
PVR TPR
PVR PVR
I
TPR
PVR
TPR PAP
! i
I
l
I
None PVR PVR TPR
RESULT
Decrease No change No change No change Decrease No change Decrease Inconsistent No clinical benefit Increase No change No change
REMARKS
Due to pain
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to decrease pulmonary arterial pressure in this clinical entity,15J6 the general belief was that the vasoconstriction was neurogenic in origin. Further investigators have, however, mostly failed to confirm this effect of Priscoline26,46.56 and only YULE was able to reproduce Priscoline-induced hypotension in one of his patients. This difference in results might perhaps be the reflection of the difference in the etiology of individual cases. Many other substances have since been tried (Table V). Their effect was nearly always disappointing. H. A. Fleming20 has recently given reserpine to one of his patients suffering from idiopathic pulmonary hypertension. No response was observed. Similar negative findings have led Wade and Ba1156 to suggest that pulmonary vasoconstriction in this disease (although apparently present26) is non-neurogenic in origin. A search for an unknown pressor-agent should perhaps be attempted. SUMMARY
The extent of neurogenic contribution to the genesis of chronic pulmonary hypertension appears to depend on the particular form of the underlying disease. It seems considerable in mitral stenosis and may be totally absent in idiopathic pulmonary hypertension. The other forms of the syndrome lie between these two extremes. Neurogenic pulmonary vasoconstriction in some cases seems to contribute to the maintenance of circulatory homeostasis in the lungs. In other cases its extent appears unreasonably high and attempts should be made to relieve it. Neuroplegic drugs are not only beneficial in relieving this vasoconstriction, but also by being capable of inducing a rapid decrease in pulmonary capillary pressure. This renders their use advisable in cases of imminent or manifest lung edema due to engorgement of the lungs. REFERENCES
1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11.
Abbott! 0. E., Van Fliet, W. E., Roberto, A. E., and Salomone, F. P.: Studies on the Functron of the Human Vagus Nerve in Various Types of Intrathoracic Diseases, J. Thoracic Surg. 30:564, 195.5. Angelino, P. F., and Levi, V.: Sulle modificazione dell’emodinamica dell’ piccolo circolo indotta alla reserpina nei mitralici, Minerva cardioangiol. 4:165, 1956. Bad Oeyenhausener Gspraeche ueber den Lungenkreislauf, Berlin, 1957. Springer Verlag. Balhoum, 0. J., Gensini, G. G., BIount, S: G.,, Jr.: The Effect of Hexamethonium Upon ;hg;7Pulmonary Vascular Resrstance m Mrtral Stenosis, J. Lab. & Clin. Med. 50:186, Bloomfield; R. A., Lauson, H. D., Cournand, A., Breed,, E. S., and Richards, D. W., Jr.: Recording of Right Heart Pressures in Normal Sublects and in Patients With Chronic Pulmonary Disease and Various Types of Cardiocirculatory Disease, J. Clin. Invest. 25:39, 1946. Braun! K., Izak, G., and Rosenberg, Z. S.: Pulmonary Artery Pressure After Priscoline m Mitral Stenosis, Brit. Heart J. 19:279, 1957. Brenner, 0.: Pathology of the Vessels of the Pulmonary Circulation. I-V. Arch. Int. Med. 56:211;457; 724;976;1189, 1935. Burton, A. C.: Laws of Physics and Flow in Blood Vessels, Ciba Symposium on Visceral Circulation (edited by G. E. W. Wolstenholm), London, 1953, J. & A. Churchill, Ltd. Curti, P. C:, Cohen, H., Castleman, P., Scannell, F. G,., Friedlich, A:L. x, and Myers, G. S.: Respuatory and Clinical Studies in Patients Wrth Mitral Stenosis, Circulation 8:893, 1953. Daley, R.: The Autonomus Nervous System in its Relations to Some Forms of Heart and Lung Disease, Brit. M. J. 2:173, 1957. Daly, I. de Burgh: Intrinsic Mechanisms of the Lungs, Quart. J. Exper. Physiol. 43:2, 1958.
534 12. 13.
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 3.5. 36. 37. 38. 39. 40.
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