- Email: [email protected]
Adrenergic receptors in the coronary circulation
Annotations
Preserving
a medical
document
‘l‘he s-ray film may be regarded as a medical document containing anatomic data relex-ant to the time at which it was obtained. It is frequently of diagnostic importance for the phq-sick to have objective information in regard to the medical background of a patient. The x-ray film provides such information. For example, it may inform the cardiologist whether his patient’s heart was enlarged 5 or 10 years previously or whether an abdominal aortic aneurysm is of recent origin. Yet it is the practice of most hospitals to discard s-ray films after 3 to 5 years. This has been necessary because of the vast number of s-ray films taken each year. ‘1‘0 store s-ray lilms for an indefinite period of time is beyond the capacity of most institutions. Howe\-er,‘it seems to us that, if physicians could arrange for hospitals to give patients their s-ray films, these documents could be preserved for the lifetime of the patient with no difficulty. The patient could be instructed to place the s-ray films on a shelf in the linen closet, where the)- could he forgotten until
Adrenergic
receptors
the physician requested them. E‘urthermore, if the patient moves, the ph>xician in the new community would be spared the trouble of writing for the old s-ray films, and hospital personnel would be spared the inconvenience of searching for and mailing them. However, more important, the patient’s new doctor is guaranteed that the old s-ray films are available to him. Although written reports of s-ray findings are of some benefit, they are no substitute for the s-ray lihn itself when a recent x-ray film is to be compared with one taken years previously. Ry the simple expedient of giving patients their x-ray films for safekeeping this most vital of medical documents may be preserved and nvaillble to an) physician for the lifetime of the patient. George E. Hwch, X.11.
in the coronary
Ilespite the fact that almost nothing is knoxvn about their physical structure, the concept of speciiic cellular sites (receptors) which interact aith chemical substances to produce definite pharmacologic effects has proved to be a most useful one. r\n attractix-e hypothesis, proposed by .\hlquist,’ explains the cardiox-ascuk actions of adrenaline and noradrenaline in terms of t\vo different types of “adrenotropic.” receptors situated on the blood vessel wall. Combination of these substances with a-receptors mediates vasoconstriction, and with P-receptors, \ asodilatation. In general, combination with 01- and p-adrenergic receptors mediates excitatory and iw hibitory responses, respectively; an important exception. howe\-er, is the stimulant action of adrenaline and noradrenaline on the myocnrdium, which is mediated through interaction with J% receptors.‘Jg Until quite recently, little was known about the
137
circulation
existence of adrenergic -‘receptors in the coronar)vascular bed, although a clarification of this problem is important in view of the widespread clinical use of fi-adrenergic blocking drugs. It is a pecnliarlg difficult problem to elucidate because, although most workers in this field are agreed that the net effect of adrenaline and noradrenaline in viva is to produce an increase in coronary blood flow, the precise action on the vessels themselves has been the subject of considerable controversy. This stems from the fact that, besides a direct action on the smooth muscle of the blood vessel wall, the sympathomimetic amines alter systemic arterial blood pressure, heart rate, and myocardial contractile force (and, hence, extravascular support and cardiac oxygen consumption), and each of these factors can profoundly modify coronarv flow. These factors could mask the direct a&n of adrenaline and noradrenaline on the vessels themselves.
138
Annotcltions
A considerable amount of evidence has accumulated recently for the existence of both types of adrenergic receptors in the coronary vascular bed.fi~7J~44 By measuring phasic flow in the cannulated left coronary artery of dogs, perfused under constant pressure, and estimating vasomotor activity within the coronary bed by recording end-diastolic flow, Doutheil and his colleagues7 found that both isoprenaline and noradrenaline caused vasodilatation when infused into the coronary artery, and that these effects were profoundly altered by @-adrenergic blockade with pronethalol. A point of particular interest was that the vasodilator effect of noradrcnaline was in fact reversed after fi-adrenergic blockade to a vasoronstrictor action; this was interpreted as being due to stimulation of cr-adrenergic receptors. Similar conclusions were reached by Parratt,31 who measured myocardial (as opposed to coronary) blood flow in dogs and monkeys, using a thermoelectric method. Intravenous infusions of adrenaline in doses which had no effect on blood pressure or heart rate usually lowered myocardial vascular resistance ; after a-receptor blockade, adrenaline always increased myocardial vascular resistance. Noradrenaline was usually slightly vasoconstrictor before p-blockade and very markedly constrictor after it. These results were again interpreted as indicating the presence of both LYand fl-adrenergic receptors in the myocardial vascular bed. A rather different interpretation of the reversal of adrenaline and noradrenaline vasodilatation by p-blockade has been proposed by Hashimoto and his colleagues.i7 Their suggestion was that “sympathetic amines induce coronaryvasodilatation through stimulation of myocardial metabolism,” and that reversal by dichloroisoprenaline is due solely to blockade of these metabolic effects. In v-iew of more recent evidence, however,n~lsJO their conclusion that “the presence of pure sympathetic vasodilator receptors in the coronary vascular bed is improbable” cannot be upheld. Thus, HircheL8 has found that the infusi’on of very small amounts of adrenaline into the left coronary artery increased coronary sinus outflow and PO? without infhrencing heart rate, systemic pressure, or cardiac contractile force, and similar effects have been observed in the isolated potassium-arrested heart, in which decreases in coronary vascular resistance due to metabolic effects R’Ue eliminated.?F The conclusion that both types of adrenergic receptors exist and function in the coronary vasculature has also been reached by Gregg and his colleaguesi Intracoronary injections of catecholamines is unanesthetized dogs caused large increases in coronary flow before any change in my-ocardial function and contractility occurred. In some very interesting experiments with isolated smooth muscle strips from coronary arteries of different sizes, Zuberbuhler and BohF have come to the conclusion that both types of receptors are present in the larger arteries, but that B-receptors predominate in the smooth muscle of the vessels of smaller diameter. This variation in the distribution of the two types of receptors in different parts of the vascular tree, the probability that the level of the coronary vascular tree which makes the
major contribution to resistance to flow may vary with the species and with the physiologic state of the animal, alid the possibility that different experimental approaches may favor either CY- or P-receptor stimulation, could explain the many conflicting reports concerning the action of adrenaline on the coronary vessels.3~*4 Other factors which may also be involved are the different dose-dependent actions of catecholamines on resistance and cap:rcitanre vessels and on the muscle sphincters,8J2 and the fact that with infusions of catecholamines different receptors are affected at different times,i3J1 depending on the rate at which the substances combine with and leave the receptor, and on their rate of destruction. A very closely related problem with important clinical implications is whether adrenergic vasodilator fibers exist to the coronary vascular bed. If we are correct in the conclusion that /3-adrenergic receptors predominate in the smaller coronary arteries, we would expect that the release of adrenergic transmitters from the rich sympathetic innervation to these vessels would result in a decrease in vascular resistance and an increase in coronary flow. Sympathetic vasodilator fibers to the coronary vessels in the cat and dog have been described by Szentivanyi and Juhas,-Nagy2’~“i; the pregangliomc fibers are believ-ed to synapse in ganglia within the heart muscle. Since acetylcholine can be detected in the blood leaving the heart after stimulation of these fibers,g and since the resulting vasodilstation is said to be blocked by atropine,4* it has been suggested that these sympathetic postgangbonic vasodilator fibers may be cholinergicPa situation rather analogous to that in skeletal muscle.43 There is evidence, however, that acetylrholinc can release adrenaline from cardiac tissue by a nicotine-like action on postganglionic adrenergic terminals,5f’9 and the finding that the f3-adrenergic blocking drugs pronethalol and propranolol markedly increase myocardial vascular resistance3’J3 suggests that the end transmitter released is in fact adrenaline. It is conceivable that the actual vasodilator fibers are cholinergic, and that we have here another example of the “double transmission” concept proposed by Burn and Kand.s It has been suggested that these vasodilator fibers are activated when there is a fall in perfusion pressure in the coronary vascular bed.‘” The normal relationship between perfusion pressure and flow in the coronary v-ascular bed is such that very little change in flow occurs when the perfusion pressure is reduced from about 120 to 10 mm. Hg.30 This “autoregulation” is abolished or modified by- the injection of procaine around the stellate ganglia,‘* by B-receptor blockade of the rnyocardial vascular bed,33 by depleting the cardiac tissue of catecholamines, and by preventing their release from cardiac sympathetic nerves with adrenergic neurone blocking agents.32 These findings suggest that the “autoregulation” in the coronary vascular bed is mediated through adrenergic vasodilator fibers. These fibers are also probably activated during excitemenP and after stimulation of the brain stem.42 Substances that block &adrenergic receptors decrease my-ocardial blood flow in the dog and
monkey.31-33 This could be the result of a reduction either in sympathetic vasodilator tone or in the oxidative requirements of the myocardium resulting from the reduction in contractile force.23*28 As has been previously pointed out,34 it is impossible to state categorically which of these two factors is primarily responsible, but the existence of &receptors in the coronary vascular bed, the very marked decrease in flow observed, and the fact that coronary sinus ~02 decreases after /3-blockade,37 all suggest a predominant effect on the vessels themselves. Propranolol and pronethalol have been used in the treatment of angina pectoris but the initial claims of effectiveness2~‘2~1~~*~ have not been contirmed in other studies.4*20.*7.43 A particular problem associated with the use of these drugs is apparent from the conclusion that (Y- as well as fl-adrenergic receptors are present in the coronary vascular bed. Patients with angina may be quite happy with propranolol, but any procedure that would lead to the release of adrenaline and noradrenaline, from cardiac nerves or from the adrenal medulla, could result in coronary vasoconstriction by an effect on the coronary a-adrenergic receptors.33.34 It is just conceivable that this may be a factor in the few cases of cardiac failure which have been reported after the administration of P-adrenergic blocking drugs,35*38,39 particularly since there is some rather disturbing evidence that these substances can also reduce the vasodilator effects of myocardial hypoxia.‘0 J. R. Pauratt, B.Pharm., M.Sc., Ph.D. Department of Physiology Lrniversity of Ibadan Ibadan, Nigeria
9.
10.
11.
12.
13.
14.
15.
16.
17. REFERENCES 1. Ahlquist, R. P.: A study of adrenotropic receptors, Am. J. Physiol. 153:586, 1948. 2. Alleyne, G. A. O., Dickinson, C. J., Dornhorst, A. C., Fulton, R. M., Green, K. G., Hill, I. D., Hurst, P., Laurence, D. R., Pilkington, T., Prichard, B. N. C., Robinson, B., and Rosenheim, M. L.: Effect of pronethalol in angina pectoris, Brit. M. J. 2:1226, 1963. 3. Berne, R. M.: Regulation of coronary blood flow, Physiol. Rev. 44:1, 1964. 4. Besterman, E. M. M., and Friedlander, D. H.: Clinical experiences with propranolol, Postgrad. M. J. 41:526, 1965. 5. Burn, J. H., and Rand, M. J.: Sympathetic postganglionic cholinergic fibres, Brit. J. Pharmacol. 15:56, 1960. 6. Doutheil, U.: \Virkung van Brenzcatechinaminen auf die Coronardurchblutung an asystolischen Hundeherzen, I’fliigers Arch. ges. Physiol. 287:111, 1966. 7. Doutheil, U., ten Bruggencate, H. G., and Kramer, Ii.: Coronarvasomotorik unter I-Norund Isopropylnoradrenalin nach adrenalin Blockierung der adrenergischen o-Receptoren durch Nethalide, Pfliigers Arch. ges. Physiol. 281:181, 1946. 8. Folkow, B.: Effects of catechol amines on con-
18.
19.
20.
21.
22.
23.
secutive vascular sections, in Adrenergic mechanisms (Ciba Foundation), Boston, 1961, Little, Brown & Co., and London, J. & A. Churchill Ltd., pp. 190-198. Folkow, B., Frost, J., Haeger, K., and Uvniis, B.: Cholinergic fibres in the sympathetic outflow to the heart in the dog and cat, Acta Physiol. Scandinav. 15:421, 1918. Folle, I,. E., and .;lviado, D. M. : Cardio Jascular effects of anoxia and the influence of a new beta adrenergic receptor blocking drug, J. Phnrmncol. & Exper. Therap. 149:79, 1965. Gaal, I’. G., Kattus, A. A., Kolin, A., and Ross, G.: Effects of adrenaline and noradrenaline on coronary blood flow before and after betnadrenergic blockade, Brit. J. Pharmacol. 26:713, 1966. Gillam, P. M. S., and Prichard, B. N. C.: I-he of propranolol in angina pectoris, Brit. M. J. 2:337, 1965. Ginsburg, J., and Cobbold, A. F.: Effects of adrenaline, noradrenaline and isopropylnoradrenaline in man. Adrenergic mechantsms,* pp. 173-189. Grayson, J., and Parratt, J. R.: A species comparison of the effects of changing perfusion pressure on blood flow and metabolic heat production in the myocardium, J. Physiol. In press. Pitt, B., Elliot, E. C., and Gregg, D. E.: Hemodynamic effects of catecholamines on the coronary circulatiolt in the unanesthetized dog, Fed. Proc. 25:401, 1966. Hamer, J., Grandjean, T., hlelendez, I,., and Sowton, G. E.: Effect of propranolol (InderaIl in angina pectoris: Preliminary report, Brit. M. J. 2:720, 1961. Hashimoto, K., Shigei, T., lmai, S., Saito, Y., Yago, N., Uci, I., and Clark, R. E.: Oxygen consumption and coronary vascular tone in the isolated fibrillating dog heart, A\m. J. Physiol. 198:965, 1960. Hirche, Hj.: Die \X’irkung van Tsoproterenol, Adrenalin, Noradrenalin und Adenosin auf die Durchblutung und den 02-Verbrauch des Herzmuskels vor und nach der Blockierung der fi-Receptoren, PAtigers Arch. ges. Physiol. 288:185, 1966. Hoffmann, F., Hoffmann, E. J., Middleton, S., and Talesnik, J.: Stimulating effect of acetl lcholine on mammalian heart and liberation of epinephrine-like substance by isolated heart, Am. J. Physiol. 144:189, 1945. Joss, E., Balmer, P., and Gubler, R.: Klinische Erfahrungen mit einem nellen herzwirksnmen Sympatholyticum (Nethalide), Cardiologia 44:144, 196-1. Juh&sz-Nagy, ,4., and Szentiv!myi, 31.: Separation of cardioaccelerator and coronary vasomotor tibres in the dog, .\m. J. Ph!.siol. 200:125, 1961. Kaiser, G. ,\., Ross, J., and Braunwald, E.: Alpha and beta adrenergic receptor mechanisms in the systemic venous bed, J. Pharmacol. & Exper. Therap. 144:156, 1964. Kako, K., Krayenbiihl, H. P., Liithy, E., and Hegglin, R.: Cardiovascular effects of catechol-
140
24. 25.
26.
27.
Annotations
amines in dogs before and after beta-adrenergic blockade, Naun)n Schmiedeberg Arch. Exp. Path. 246:297, 1964. Kaverina, N. V.: Pharmacology of the coronar)~ circulation, Oxford, 1965, Pergamon Press. Keelan, P.: Double-blind trial of propranolol (Inderal) in angina pectoris, Brit. M. J. 1:897, 1965. Klocke, F. J., Kaiser, G. A., Ross, J., and Braunwald, E.: An intrinsic adrenergic vasodilator mechanism in the coronary vascular bed of the dog, Circulation Res. 16:376, 1965. MacAlpin, R. N., Kattus, A. A., and \\iinfield, M. E.: The effect of a ,f+adrenergic-blocking agent (Nethalide) and nitroglq-cerin on exercise tolerance in angina pectoris, Circulation 31:869,
34. Parratt, 35. 36.
37. 38. 39.
1965. 28. Mendel,
40.
29.
41.
30.
D.: %lyocardial vascular renctivit!,, Lancet 1:597, 1966. Moran, ?J. C., and Perkins, M. IX.: Xdrenergic blockade of the mammalian heart by a dichloro analogue of isoproterenol, J. I’harmacol. K: Exper. Therap. 124:223, 1958. Mosher, I’., Ross, J., McFate, I’. A., and Shaw, R. I;.: Control of coronary blood flow by an autoregulatory mechanism, Circulation Res.
1959. 42. I leda, H., Shimomum,
14:250, 1964. 31. Parratt, J. R.: Blockade 32.
33.
of sympathetic fi-receptars in the mJ.ocardial circulation, Brit. J. Pharmacol. 24:601, 1965. Parratt, J. R.: Studies on the mechanism of autoregulation of myocardial blood fow. In preparation. Parratt, J. R., and Gral-son, J.: 311 ocardinl vascular reactivity after beta-adrener$ic blockade, Izxet 1:338, 1966.
Beta-adrenergic hypertrophic
blockade obstructive
The specific beta-adrenergic receptor antagonist propranolol selectively inhibits both the inotropic and chronotropic effects of adrenaline on the heart. Since there is now abundant evidence that the heart in hypertrophic obstructive cardiomyopathy is chronically under the influence of a pathologically increased sympathetic drive,‘.Z the use of propranolo1 for long-term therapy of patients with hypertrophic obstructive cardiomyopathy has a firm rational basis. The hemodynamic abnormality in hypertrophic obstructive cardiomyopathy is estremely labile and readily modified both by physiologic maneuvers and by drugs. Although acute beta-adrenergic blockade usually has little effect
J. R., and Grayson, J.: n3yocardial vascular reactivity, Lancet 1:819, 1966. I’richard, B. N. C., and Gillam, P. M. S.: The ttse of propranolol in the treatment of hypertension, Brit. M. J. 2:725, 1964. Ra>,ford, C. Ii., Khouri, E. WI., and Gregg, T>. E.: Effect of excitement on coronary and systemic energetics in unanesthetized dogs, Am. .J. I’h>siol. 209&O, 1965. Redding, V. J., and Rees, J. I~.: Myocardial vascular reactivitv, T.ancet 1:548, 1966. Snow, P. J. I).: Effect of propranolol in myorardial infarction, I.nncet 2:551, 1965. Stock, J. P. t’., and Dale, N.: Beta-adrenergic receptor blockage iI1 cardiac arrhqthmins, Rrit. 91. J. 2:1230, 1963. Strait, G. B., and Bruce, R. X.: Nonspecific and beta-adrenergic blocking effects of Alderlin in angina pectori5, :\,\I. HEART J. iO:lSO, 1965. Szelltiv~in>.i, lI., and Juh&-?\[ng>-, A.: .\ new aspect of the nervous control of the coronar\ blood vessel>, Qu;trt. J. Esper. l’hysiol. 44:6?,
43. 44.
K., Goto, H., Yahuda, II., Ito, K., Kata!xma, S., liuroiwa, *I., and Sugimoto, ‘I‘. : Changes in coronary blood How lrh- stimulation of central nervous system, Jnp. lieart J. 5:3X, 1964. I:vniis, B. : Sympathetic vasodilator system nrld blood tlow, Ph?.5iol. Rev. 40:69, 1960. Zuberbuhler, R. C., and Bohr, D. P. : Responses of coronar! smooth muscle to catecholamines, Circlllation Res. 16:431, 1965.
in patients
with
cardiomyopathy
on the hemodynamics of the tranquil patient on the catheterization table, it has been shown to oppose the exacerbation in gradient induced by exercise or by infused adrenaline or isoprenaline. It was thought, therefore, that the long-term use of propranolol might protect patients with hypertrophic obstructive cardiomyopathy from the risk of sudden death by opposing surges of sympathetic stimulation after emotional stress or sudden exertion. Since unopposed vagal influence on the heart in hypertrophic obstructive cardiomyopathy could be almost as undesirable, a chemical autonomic denervation of the heart was attempted by the combined USC of propranolol and propanthcline.
Preserving
a medical
document
‘l‘he s-ray film may be regarded as a medical document containing anatomic data relex-ant to the time at which it was obtained. It is frequently of diagnostic importance for the phq-sick to have objective information in regard to the medical background of a patient. The x-ray film provides such information. For example, it may inform the cardiologist whether his patient’s heart was enlarged 5 or 10 years previously or whether an abdominal aortic aneurysm is of recent origin. Yet it is the practice of most hospitals to discard s-ray films after 3 to 5 years. This has been necessary because of the vast number of s-ray films taken each year. ‘1‘0 store s-ray lilms for an indefinite period of time is beyond the capacity of most institutions. Howe\-er,‘it seems to us that, if physicians could arrange for hospitals to give patients their s-ray films, these documents could be preserved for the lifetime of the patient with no difficulty. The patient could be instructed to place the s-ray films on a shelf in the linen closet, where the)- could he forgotten until
Adrenergic
receptors
the physician requested them. E‘urthermore, if the patient moves, the ph>xician in the new community would be spared the trouble of writing for the old s-ray films, and hospital personnel would be spared the inconvenience of searching for and mailing them. However, more important, the patient’s new doctor is guaranteed that the old s-ray films are available to him. Although written reports of s-ray findings are of some benefit, they are no substitute for the s-ray lihn itself when a recent x-ray film is to be compared with one taken years previously. Ry the simple expedient of giving patients their x-ray films for safekeeping this most vital of medical documents may be preserved and nvaillble to an) physician for the lifetime of the patient. George E. Hwch, X.11.
in the coronary
Ilespite the fact that almost nothing is knoxvn about their physical structure, the concept of speciiic cellular sites (receptors) which interact aith chemical substances to produce definite pharmacologic effects has proved to be a most useful one. r\n attractix-e hypothesis, proposed by .\hlquist,’ explains the cardiox-ascuk actions of adrenaline and noradrenaline in terms of t\vo different types of “adrenotropic.” receptors situated on the blood vessel wall. Combination of these substances with a-receptors mediates vasoconstriction, and with P-receptors, \ asodilatation. In general, combination with 01- and p-adrenergic receptors mediates excitatory and iw hibitory responses, respectively; an important exception. howe\-er, is the stimulant action of adrenaline and noradrenaline on the myocnrdium, which is mediated through interaction with J% receptors.‘Jg Until quite recently, little was known about the
137
circulation
existence of adrenergic -‘receptors in the coronar)vascular bed, although a clarification of this problem is important in view of the widespread clinical use of fi-adrenergic blocking drugs. It is a pecnliarlg difficult problem to elucidate because, although most workers in this field are agreed that the net effect of adrenaline and noradrenaline in viva is to produce an increase in coronary blood flow, the precise action on the vessels themselves has been the subject of considerable controversy. This stems from the fact that, besides a direct action on the smooth muscle of the blood vessel wall, the sympathomimetic amines alter systemic arterial blood pressure, heart rate, and myocardial contractile force (and, hence, extravascular support and cardiac oxygen consumption), and each of these factors can profoundly modify coronarv flow. These factors could mask the direct a&n of adrenaline and noradrenaline on the vessels themselves.
138
Annotcltions
A considerable amount of evidence has accumulated recently for the existence of both types of adrenergic receptors in the coronary vascular bed.fi~7J~44 By measuring phasic flow in the cannulated left coronary artery of dogs, perfused under constant pressure, and estimating vasomotor activity within the coronary bed by recording end-diastolic flow, Doutheil and his colleagues7 found that both isoprenaline and noradrenaline caused vasodilatation when infused into the coronary artery, and that these effects were profoundly altered by @-adrenergic blockade with pronethalol. A point of particular interest was that the vasodilator effect of noradrcnaline was in fact reversed after fi-adrenergic blockade to a vasoronstrictor action; this was interpreted as being due to stimulation of cr-adrenergic receptors. Similar conclusions were reached by Parratt,31 who measured myocardial (as opposed to coronary) blood flow in dogs and monkeys, using a thermoelectric method. Intravenous infusions of adrenaline in doses which had no effect on blood pressure or heart rate usually lowered myocardial vascular resistance ; after a-receptor blockade, adrenaline always increased myocardial vascular resistance. Noradrenaline was usually slightly vasoconstrictor before p-blockade and very markedly constrictor after it. These results were again interpreted as indicating the presence of both LYand fl-adrenergic receptors in the myocardial vascular bed. A rather different interpretation of the reversal of adrenaline and noradrenaline vasodilatation by p-blockade has been proposed by Hashimoto and his colleagues.i7 Their suggestion was that “sympathetic amines induce coronaryvasodilatation through stimulation of myocardial metabolism,” and that reversal by dichloroisoprenaline is due solely to blockade of these metabolic effects. In v-iew of more recent evidence, however,n~lsJO their conclusion that “the presence of pure sympathetic vasodilator receptors in the coronary vascular bed is improbable” cannot be upheld. Thus, HircheL8 has found that the infusi’on of very small amounts of adrenaline into the left coronary artery increased coronary sinus outflow and PO? without infhrencing heart rate, systemic pressure, or cardiac contractile force, and similar effects have been observed in the isolated potassium-arrested heart, in which decreases in coronary vascular resistance due to metabolic effects R’Ue eliminated.?F The conclusion that both types of adrenergic receptors exist and function in the coronary vasculature has also been reached by Gregg and his colleaguesi Intracoronary injections of catecholamines is unanesthetized dogs caused large increases in coronary flow before any change in my-ocardial function and contractility occurred. In some very interesting experiments with isolated smooth muscle strips from coronary arteries of different sizes, Zuberbuhler and BohF have come to the conclusion that both types of receptors are present in the larger arteries, but that B-receptors predominate in the smooth muscle of the vessels of smaller diameter. This variation in the distribution of the two types of receptors in different parts of the vascular tree, the probability that the level of the coronary vascular tree which makes the
major contribution to resistance to flow may vary with the species and with the physiologic state of the animal, alid the possibility that different experimental approaches may favor either CY- or P-receptor stimulation, could explain the many conflicting reports concerning the action of adrenaline on the coronary vessels.3~*4 Other factors which may also be involved are the different dose-dependent actions of catecholamines on resistance and cap:rcitanre vessels and on the muscle sphincters,8J2 and the fact that with infusions of catecholamines different receptors are affected at different times,i3J1 depending on the rate at which the substances combine with and leave the receptor, and on their rate of destruction. A very closely related problem with important clinical implications is whether adrenergic vasodilator fibers exist to the coronary vascular bed. If we are correct in the conclusion that /3-adrenergic receptors predominate in the smaller coronary arteries, we would expect that the release of adrenergic transmitters from the rich sympathetic innervation to these vessels would result in a decrease in vascular resistance and an increase in coronary flow. Sympathetic vasodilator fibers to the coronary vessels in the cat and dog have been described by Szentivanyi and Juhas,-Nagy2’~“i; the pregangliomc fibers are believ-ed to synapse in ganglia within the heart muscle. Since acetylcholine can be detected in the blood leaving the heart after stimulation of these fibers,g and since the resulting vasodilstation is said to be blocked by atropine,4* it has been suggested that these sympathetic postgangbonic vasodilator fibers may be cholinergicPa situation rather analogous to that in skeletal muscle.43 There is evidence, however, that acetylrholinc can release adrenaline from cardiac tissue by a nicotine-like action on postganglionic adrenergic terminals,5f’9 and the finding that the f3-adrenergic blocking drugs pronethalol and propranolol markedly increase myocardial vascular resistance3’J3 suggests that the end transmitter released is in fact adrenaline. It is conceivable that the actual vasodilator fibers are cholinergic, and that we have here another example of the “double transmission” concept proposed by Burn and Kand.s It has been suggested that these vasodilator fibers are activated when there is a fall in perfusion pressure in the coronary vascular bed.‘” The normal relationship between perfusion pressure and flow in the coronary v-ascular bed is such that very little change in flow occurs when the perfusion pressure is reduced from about 120 to 10 mm. Hg.30 This “autoregulation” is abolished or modified by- the injection of procaine around the stellate ganglia,‘* by B-receptor blockade of the rnyocardial vascular bed,33 by depleting the cardiac tissue of catecholamines, and by preventing their release from cardiac sympathetic nerves with adrenergic neurone blocking agents.32 These findings suggest that the “autoregulation” in the coronary vascular bed is mediated through adrenergic vasodilator fibers. These fibers are also probably activated during excitemenP and after stimulation of the brain stem.42 Substances that block &adrenergic receptors decrease my-ocardial blood flow in the dog and
monkey.31-33 This could be the result of a reduction either in sympathetic vasodilator tone or in the oxidative requirements of the myocardium resulting from the reduction in contractile force.23*28 As has been previously pointed out,34 it is impossible to state categorically which of these two factors is primarily responsible, but the existence of &receptors in the coronary vascular bed, the very marked decrease in flow observed, and the fact that coronary sinus ~02 decreases after /3-blockade,37 all suggest a predominant effect on the vessels themselves. Propranolol and pronethalol have been used in the treatment of angina pectoris but the initial claims of effectiveness2~‘2~1~~*~ have not been contirmed in other studies.4*20.*7.43 A particular problem associated with the use of these drugs is apparent from the conclusion that (Y- as well as fl-adrenergic receptors are present in the coronary vascular bed. Patients with angina may be quite happy with propranolol, but any procedure that would lead to the release of adrenaline and noradrenaline, from cardiac nerves or from the adrenal medulla, could result in coronary vasoconstriction by an effect on the coronary a-adrenergic receptors.33.34 It is just conceivable that this may be a factor in the few cases of cardiac failure which have been reported after the administration of P-adrenergic blocking drugs,35*38,39 particularly since there is some rather disturbing evidence that these substances can also reduce the vasodilator effects of myocardial hypoxia.‘0 J. R. Pauratt, B.Pharm., M.Sc., Ph.D. Department of Physiology Lrniversity of Ibadan Ibadan, Nigeria
9.
10.
11.
12.
13.
14.
15.
16.
17. REFERENCES 1. Ahlquist, R. P.: A study of adrenotropic receptors, Am. J. Physiol. 153:586, 1948. 2. Alleyne, G. A. O., Dickinson, C. J., Dornhorst, A. C., Fulton, R. M., Green, K. G., Hill, I. D., Hurst, P., Laurence, D. R., Pilkington, T., Prichard, B. N. C., Robinson, B., and Rosenheim, M. L.: Effect of pronethalol in angina pectoris, Brit. M. J. 2:1226, 1963. 3. Berne, R. M.: Regulation of coronary blood flow, Physiol. Rev. 44:1, 1964. 4. Besterman, E. M. M., and Friedlander, D. H.: Clinical experiences with propranolol, Postgrad. M. J. 41:526, 1965. 5. Burn, J. H., and Rand, M. J.: Sympathetic postganglionic cholinergic fibres, Brit. J. Pharmacol. 15:56, 1960. 6. Doutheil, U.: \Virkung van Brenzcatechinaminen auf die Coronardurchblutung an asystolischen Hundeherzen, I’fliigers Arch. ges. Physiol. 287:111, 1966. 7. Doutheil, U., ten Bruggencate, H. G., and Kramer, Ii.: Coronarvasomotorik unter I-Norund Isopropylnoradrenalin nach adrenalin Blockierung der adrenergischen o-Receptoren durch Nethalide, Pfliigers Arch. ges. Physiol. 281:181, 1946. 8. Folkow, B.: Effects of catechol amines on con-
18.
19.
20.
21.
22.
23.
secutive vascular sections, in Adrenergic mechanisms (Ciba Foundation), Boston, 1961, Little, Brown & Co., and London, J. & A. Churchill Ltd., pp. 190-198. Folkow, B., Frost, J., Haeger, K., and Uvniis, B.: Cholinergic fibres in the sympathetic outflow to the heart in the dog and cat, Acta Physiol. Scandinav. 15:421, 1918. Folle, I,. E., and .;lviado, D. M. : Cardio Jascular effects of anoxia and the influence of a new beta adrenergic receptor blocking drug, J. Phnrmncol. & Exper. Therap. 149:79, 1965. Gaal, I’. G., Kattus, A. A., Kolin, A., and Ross, G.: Effects of adrenaline and noradrenaline on coronary blood flow before and after betnadrenergic blockade, Brit. J. Pharmacol. 26:713, 1966. Gillam, P. M. S., and Prichard, B. N. C.: I-he of propranolol in angina pectoris, Brit. M. J. 2:337, 1965. Ginsburg, J., and Cobbold, A. F.: Effects of adrenaline, noradrenaline and isopropylnoradrenaline in man. Adrenergic mechantsms,* pp. 173-189. Grayson, J., and Parratt, J. R.: A species comparison of the effects of changing perfusion pressure on blood flow and metabolic heat production in the myocardium, J. Physiol. In press. Pitt, B., Elliot, E. C., and Gregg, D. E.: Hemodynamic effects of catecholamines on the coronary circulatiolt in the unanesthetized dog, Fed. Proc. 25:401, 1966. Hamer, J., Grandjean, T., hlelendez, I,., and Sowton, G. E.: Effect of propranolol (InderaIl in angina pectoris: Preliminary report, Brit. M. J. 2:720, 1961. Hashimoto, K., Shigei, T., lmai, S., Saito, Y., Yago, N., Uci, I., and Clark, R. E.: Oxygen consumption and coronary vascular tone in the isolated fibrillating dog heart, A\m. J. Physiol. 198:965, 1960. Hirche, Hj.: Die \X’irkung van Tsoproterenol, Adrenalin, Noradrenalin und Adenosin auf die Durchblutung und den 02-Verbrauch des Herzmuskels vor und nach der Blockierung der fi-Receptoren, PAtigers Arch. ges. Physiol. 288:185, 1966. Hoffmann, F., Hoffmann, E. J., Middleton, S., and Talesnik, J.: Stimulating effect of acetl lcholine on mammalian heart and liberation of epinephrine-like substance by isolated heart, Am. J. Physiol. 144:189, 1945. Joss, E., Balmer, P., and Gubler, R.: Klinische Erfahrungen mit einem nellen herzwirksnmen Sympatholyticum (Nethalide), Cardiologia 44:144, 196-1. Juh&sz-Nagy, ,4., and Szentiv!myi, 31.: Separation of cardioaccelerator and coronary vasomotor tibres in the dog, .\m. J. Ph!.siol. 200:125, 1961. Kaiser, G. ,\., Ross, J., and Braunwald, E.: Alpha and beta adrenergic receptor mechanisms in the systemic venous bed, J. Pharmacol. & Exper. Therap. 144:156, 1964. Kako, K., Krayenbiihl, H. P., Liithy, E., and Hegglin, R.: Cardiovascular effects of catechol-
140
24. 25.
26.
27.
Annotations
amines in dogs before and after beta-adrenergic blockade, Naun)n Schmiedeberg Arch. Exp. Path. 246:297, 1964. Kaverina, N. V.: Pharmacology of the coronar)~ circulation, Oxford, 1965, Pergamon Press. Keelan, P.: Double-blind trial of propranolol (Inderal) in angina pectoris, Brit. M. J. 1:897, 1965. Klocke, F. J., Kaiser, G. A., Ross, J., and Braunwald, E.: An intrinsic adrenergic vasodilator mechanism in the coronary vascular bed of the dog, Circulation Res. 16:376, 1965. MacAlpin, R. N., Kattus, A. A., and \\iinfield, M. E.: The effect of a ,f+adrenergic-blocking agent (Nethalide) and nitroglq-cerin on exercise tolerance in angina pectoris, Circulation 31:869,
34. Parratt, 35. 36.
37. 38. 39.
1965. 28. Mendel,
40.
29.
41.
30.
D.: %lyocardial vascular renctivit!,, Lancet 1:597, 1966. Moran, ?J. C., and Perkins, M. IX.: Xdrenergic blockade of the mammalian heart by a dichloro analogue of isoproterenol, J. I’harmacol. K: Exper. Therap. 124:223, 1958. Mosher, I’., Ross, J., McFate, I’. A., and Shaw, R. I;.: Control of coronary blood flow by an autoregulatory mechanism, Circulation Res.
1959. 42. I leda, H., Shimomum,
14:250, 1964. 31. Parratt, J. R.: Blockade 32.
33.
of sympathetic fi-receptars in the mJ.ocardial circulation, Brit. J. Pharmacol. 24:601, 1965. Parratt, J. R.: Studies on the mechanism of autoregulation of myocardial blood fow. In preparation. Parratt, J. R., and Gral-son, J.: 311 ocardinl vascular reactivity after beta-adrener$ic blockade, Izxet 1:338, 1966.
Beta-adrenergic hypertrophic
blockade obstructive
The specific beta-adrenergic receptor antagonist propranolol selectively inhibits both the inotropic and chronotropic effects of adrenaline on the heart. Since there is now abundant evidence that the heart in hypertrophic obstructive cardiomyopathy is chronically under the influence of a pathologically increased sympathetic drive,‘.Z the use of propranolo1 for long-term therapy of patients with hypertrophic obstructive cardiomyopathy has a firm rational basis. The hemodynamic abnormality in hypertrophic obstructive cardiomyopathy is estremely labile and readily modified both by physiologic maneuvers and by drugs. Although acute beta-adrenergic blockade usually has little effect
J. R., and Grayson, J.: n3yocardial vascular reactivity, Lancet 1:819, 1966. I’richard, B. N. C., and Gillam, P. M. S.: The ttse of propranolol in the treatment of hypertension, Brit. M. J. 2:725, 1964. Ra>,ford, C. Ii., Khouri, E. WI., and Gregg, T>. E.: Effect of excitement on coronary and systemic energetics in unanesthetized dogs, Am. .J. I’h>siol. 209&O, 1965. Redding, V. J., and Rees, J. I~.: Myocardial vascular reactivitv, T.ancet 1:548, 1966. Snow, P. J. I).: Effect of propranolol in myorardial infarction, I.nncet 2:551, 1965. Stock, J. P. t’., and Dale, N.: Beta-adrenergic receptor blockage iI1 cardiac arrhqthmins, Rrit. 91. J. 2:1230, 1963. Strait, G. B., and Bruce, R. X.: Nonspecific and beta-adrenergic blocking effects of Alderlin in angina pectori5, :\,\I. HEART J. iO:lSO, 1965. Szelltiv~in>.i, lI., and Juh&-?\[ng>-, A.: .\ new aspect of the nervous control of the coronar\ blood vessel>, Qu;trt. J. Esper. l’hysiol. 44:6?,
43. 44.
K., Goto, H., Yahuda, II., Ito, K., Kata!xma, S., liuroiwa, *I., and Sugimoto, ‘I‘. : Changes in coronary blood How lrh- stimulation of central nervous system, Jnp. lieart J. 5:3X, 1964. I:vniis, B. : Sympathetic vasodilator system nrld blood tlow, Ph?.5iol. Rev. 40:69, 1960. Zuberbuhler, R. C., and Bohr, D. P. : Responses of coronar! smooth muscle to catecholamines, Circlllation Res. 16:431, 1965.
in patients
with
cardiomyopathy
on the hemodynamics of the tranquil patient on the catheterization table, it has been shown to oppose the exacerbation in gradient induced by exercise or by infused adrenaline or isoprenaline. It was thought, therefore, that the long-term use of propranolol might protect patients with hypertrophic obstructive cardiomyopathy from the risk of sudden death by opposing surges of sympathetic stimulation after emotional stress or sudden exertion. Since unopposed vagal influence on the heart in hypertrophic obstructive cardiomyopathy could be almost as undesirable, a chemical autonomic denervation of the heart was attempted by the combined USC of propranolol and propanthcline.