In conclusion I would like to stress that these observations do not constitute direct evidence of the mechanism whereby the nitrates relieve angina pectoris. It is probable that they are capable of causing some reduction of myocardial oxygen consumption. However, there is increasing indirect evidence which suggests that the site of action of these drugs is principally on the large coronary arteries. Their administration may thus relieve coronary spasm, if this ever causes angina, and more importantly will increase collateral flow into ischemic areas of myocardium when collateral channels have become enlarged. Drugs such as dipyridamole which seem to act on the small vessels, which are the site of autoregulation, are unlikely to have this effect. Indeed, if the autoregulatory mechanism is necessary to direct a limited blood flow to the most ischemic areas of myocardium, such drugs may theoretically be harmful

McGregor, Maurice

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MCV QUARTERLY 3(2): 77·79, 19&7 Pharmacology of Anti-Anginal Agents MAURICE McGREGOR Department of Medicine, McGill University Faculty of Medicine, Montreal, Canada For me, 1967 is a double cen-tennial year; it commemorates both the year of Canadian Federation and the first use of nitrites for angina pectoris. It was in 1867 that Lauder Brunton published his paper in the Lancet on the use of "Nitrite of Amyl for Angina Pec-toris" (Brunton, 1867). It is sad to reflect that apart from this one lucky break this is really the only significant progress we have made in the medical treatment of angina pectoris in the last hundred years. The reason for this lack of progress is that we did not understand why nitrites were so beneficial and, con-sequently, we supplied explanations which were incorrect. Having done that, we subsequently have tried to produce better drugs with the same presumed action. When Brun-ton wrote his paper he deduced that the pain of angina was related to an elevation of blood pressure. He knew that nitrite of amyl could produce prostration and a thin thready pulse, and he thought it probably worked by lowering the blood pressure. For some time thereafter other drugs that were supposed to lower blood pressure were given therapeutic trial. Then, it was discovered that injection of nitrites into the coronary artery of an animal caused an increase in coronary flow. From this time on it was assumed that nitrites re-lieved angina pectoris by increas-ing coronary flow. It is for this reason that, if you want to look up anti-anginal drugs in any contem-porary textbook, you must look them up under the title of "Coro-nary Vasodilator Drugs." For the last 40 years or so man-ufacturers have continued to pro-duce more potent vasodilator drugs as judged by their ability to in-crease coronary flow in the normal heart. Unfortunately none of them has worked. The drug that drew my attention to this dilemma is one of the most potent of these preparations, dipyridamole (Per-santin). While nitroglycerin pro-duces only a small increase in coronary flow, lasting from 30 sec-onds to 1 minute, dipyridamole, given in a reasonable dose intra-venously or by mouth, may double coronary flow for 20 to 30 min-utes. It will do this without increasing myocardial oxygen con-sumption, so that the whole myo-cardium and the coronary sinus blood oxygen content increase pro-portionately. This ought to be beneficial if increasing coronary flow is going to relieve angina, and for this reason we carried out a careful clinical trial of this agent (Kinsella, Troup, and McGregor, 1962). We could find no thera-peutic effect at all. Following this experience we decided to pause and try to review the patho-physi-ology of angina and to consider in what ways it might theoretically be influenced by therapy. Pathologic Physiology of Angina Pectoris Firstly, we now know that an-gina pectoris is not just a sensation of pain and discomfort. It is a syndrome which includes not only pain, but also electrocardiographic changes, a shift to anaerobic me-77 tabolism with production of lactate and acute left ventricular failure, when the involved muscle mass is large enough. We also know that this syndrome occurs whenever there is a discrepancy between the demand for myocardial oxygen and its supply. This discrepancy may, therefore, be correctable by reducing oxygen consumption or by increasing oxygen supply. Normal oxygen supply demands fully oxygenated blood and normal hemoglobin. When the angina! pa-tient suddenly gets worse it must not necessarily be concluded that one of his coronary arteries has become occluded, though this may of course be occurring. It could well be that his hemoglobin has dropped due, e.g., to bleeding piles or a peptic ulcer. Alternatively he may have become anoxemic due to pulmonary embolism or pneu-monia; or he may have inactivated up to 20% of his hemoglobin by smoking excessively. Likewise, his coronary flow may be very de-pendent on an adequate arterial pressure. Thus angina may be pre-cipitated in the hypertensive pa-tient with coronary disease by the successful treatment of hyperten-sion. Whenever angina becomes ex-acerbated, these possibilities should be considered first. The discrepancy between oxygen supply and demand can also be influenced, of course, by changes in myocardial oxygen consump-tion. Dr. Richardson (Dr. David W., an earlier speaker at the symposium) has been telling us that the amount of tension de-veloped by the muscle fiber and the rate with which it is developed are the two critical determinants of oxygen consumption. How-ever, the tension developed is in-fluenced by two major variables. One is the amount of pressure de-veloped in the ventricular chamber, and the other is the ventricular volu.me. According to the rela-tionship between tension, pressure, and radius described by Laplace, the tension necessary for each fiber 78 ANTl-ANGINAL AGENTS to develop a certain pressure will increase with the radius of curva-ture of the ventricle. A small ven-tricle can thus produce the same pressure with a smaller wall ten-sion. It is more efficient. All other things being equal then, one might expect angina to be exacerbated by ventricular enlargement and im-proved by reduction in ventricular size. Fear or emotion causing in-creased sympatho-adrenal activity will increase both the force of contraction, the rate of develop-ment of tension, and the heart rate. These are good reasons why the blocking agent Propranolol, re-ferred to earlier in this symposium, ought to raise the angina! thres-hold. The disappointing thing is how relatively poorly is does work, and I think, used at random in an angina! population, this drug is probably going to have more dan-gers than benefits. There are people, however, such as the thy-rotoxic and the patient who gets pain associated with emotion, in whom I suspect this drug will prove to be extremely beneficial. Mechanism of Action of Nitrites Let us now consider the possible mechanism of action of the nitrite drugs, because these are the only really useful group of drugs avail-able to us. First of all , it is clear that they do not just act by re-lieving pain. They are capable of lowering ventricular end-diastolic pressure, of abolishing the lactate production in the myocardium, and of abolishing the electrocardio-graphic changes of angina. The question is how they achieve this effect. Theoretically, they might either decrease myocardial oxygen consumption, or increase oxygen supply, or do both at once. The prime effect of the nitrites is on vascular smooth muscle, and they cause an increase in large vessel diameter with veno-dilata-tion. When administered to a rest-ing subject or to an anesthetized animal there is a fall in venous pressure, venous return to the heart, ventricular volume, cardiac output, and blood pressure. As we have seen, these effects should re-duce myocardial oxygen consump-tion and may well explain the re-lief obtained by this drug in the resting subject. However, nitroglyc-erin will also produce relief in the exercising subject, and it is un-likely that the same mechanisms operate. For example, we have found that when patients are cy-cling on an ergometer a nitroglyc-erin tablet may actually increase the cardiac output, and the hypo-tensive effect of the drug is almost completely abolished (Hoeschen et al., 1966). Thus we have turned again to the possibility that nitrites may indeed exert their effect by changing coronary flow. Now I would like to distinguish carefully between increasing coro-nary flow in a normal heart and re-distributing flow to the most ischemic areas of a chronically diseased heart. On consideration it would seem that the very last drug that you would choose to relieve angina pectoris is one which in-creases coronary flow in the normal heart. There is already present an extraordinarily effective mechanism which will increase or reduce coro-nary flow according to the local metabolic need, and as far as we can see it is geared very closely to oxygen tension. Any substance which increases coronary flow in the normal heart must do so by interfering with this autoregulatory mechanism, and it has been shown that this mechanism is completely paralyzed following a dose of a potent vasodilator drug such as dipyridamole (Fam and McGregor, 1967). This cannot be beneficial if local hypoxia is already causing maximum flow to the most ische-mic areas of heart muscle. Indeed, in the presence of coronary nar-rowing it might even have an ad-verse effect by increasing flow to non-ischemic areas of heart muscle. In atherosclerotic coronary dis-ease it is the large coronary vessels which are narrowed. Studies which Dr. W. Fam and I are carrying out at present indicate that these ves-sels take no part in autoregulation. Thus to increase flow through them it is necessary to use a vaso-d i lator substance which will act at this site in the coronary tree. It may well be that the diseased ves-sels themselves are incapable of vasodilatation, but as you well know the ischemic areas of muscle may be partly or wholly supplied by collateral vessels ansmg from healthy neighbouring coronary ar-teries. A drug which acts on these arteries may be expected to in-crease flow into the ischemic areas of the heart through collateral channels. It is probably significant that this is precisely the site of action of nitroglycerin. Angiographic observation tells us that a nitroglycerin tablet will in-crease the size of all the larger coronary arteries for several min-utes, and we have found that the effect of nitroglycerin is almost completely confined to the larger vessels (McGregor and Fam, 1966). Furthermore, when a coro-nary branch of a dog is gradually narrowed, thus creating obstruc-tion, nitroglycerin can be shown to augment the collateral flow into the ischemic area. Dipyridamole, which acts principally on the small coro-nary vessels does not have this effect (Fam and McGregor, 1964). Conclusion In conclusion I would like to stress that these observations do not constitute direct evidence of the mechanism whereby the nitrites relieve angina pectoris. It is prob-able that they are capable of caus-ing some reduction of myocardial oxygen consumption. However, there is increasing indirect evi-dence which suggests that the site of action of these drugs is princi-pally on the large coronary arter-ies. Their administration may thus relieve coronary spasm, if this ever causes angina, and more impor-M. McGREGOR tantly will increase collateral flow into ischemic areas of myocardium when collateral channels have be-come enlarged. Drugs such as di-pyridamole which seem to act on the small vessels, which are the site of autoregulation, are unlikely to have this effect. Indeed, if the au-toregulatory mechanism is neces-sary to direct a limited blood flow to the most ischemic areas of my-ocardium, such drugs may theo-retically be harmful. References BRUNTON, T. L. Use of nitrite of amyl in angina pectoris. Lancet 2: 97-98, 1867. FAM, W. M., AND M. McGREGOR. Effect of coronary vasodilator drugs on retrograde flow in areas of chronic myocardial ischemia. Gire. R es. I 5: 355-365, 1964. FAM, W. M., AND M. McGREGOR. The role of collateral circulation in evaluation of anti-angina] drugs. In Problems in Laboratory Evalua-tion of Anti-Anginal A gents. M. J. Winbury (ed.) Amsterdam: North-Holland, 1967, p. 17. HOESCHEN, R. J., G. A. BousvAROS, G. A. KLASSEN, W. M. FAM, AND M. McGREGOR. Haemodynamic ef-fects of nitroglycerine in normal and angina! subjects: Haemody-namic consequences of angina pec-toris. Brit. Heart J. 28: 221- 230, 1966. KINSELLA, D., W. TROUP, AND M. McGREGOR. Studies with a new coronary vasodilator drug: Persan-tin. Am. Heart J. 63: 146- 151, 1962. McGREGOR, M. AND W. M. FAM. Regulation of coronary blood flow. Bull. N. Y. A cad. Med. 42: 940-950, 1966. 79' 

Pharmacology of Anti-Anginal Agents

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Pharmacology of Anti-Anginal Agents

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