Coronary Blood Flow and Myocardial Metabolism in Angina Pectoris

It is interesting to note on this centenary celebration that we still are uncertain about the nature of anginal pain; we discuss the nitrites, we carry out experiments, yielding new data, and yet we are still really not quite sure how these agents act. I think it is desirable to review with humility some f Lauder Brunton’s ideas about the actions of these drugs. At a major national meeting in America just one year ago, the observation was made that the blood pressure rises before pain occurs in attacks of spontaneous angina pectoris. Unfortunately the speaker failed to appreciate that Sir Lauder Brunton had suggested the use of amyl nitrite for this very reason, namely high blood pressure with angina. He thought that nitrites might reduce the pain of angina pectoris by lowering the pressure. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, April 1967, Special Issue – Lauder Brunton Centenary Symposium on Angina Pectoris: 30-31 doi: 10.2218/resmedica.v5i3-4.482 CORONARY BLOOD FLOW AND MYOCARDIAL METABOLISM IN ANGINA PECTORIS (Abridged) R ich ard Gorlin Harvard Medical School, Peter Bent Brigham Hospital It is interesting to note on this centenary cele­ bration that we still are uncertain about the nature o f anginal pain; we discuss the nitrites, we carry out experiments, yielding new data, and yet we are still really not quite sure how these agents act. I think it is desirable to review with humility some o f Lauder Brunton’s ideas about the actions o f these drugs. A t a major national meeting in Am erica just one year ago, the observation was made that the blood pressure rises before pain occurs in attacks o f spontaneous angina pectoris. Unfortunately the speaker failed to appreciate that Sir Lauder Brunton had sug­ gested the use o f amyl nitrite for this very reason, namely high blood pressure with angina. He thought that nitrites might reduce the pain o f angina pectoris by lowering the pressure. I would like to discuss some aspects o f angina and myocardial ischaemia and present briefly our thoughts about the actions o f nitroglycerine on the coronary circulation and the myocardium. Anginal pain may arise not only as a function o f deficient blood supply to a particular region of the heart, but also as a function o f the distribution o f collaterals supplying the same area from other coronary arteries. The situation is further com­ plicated by the fact that the resistance blood vessels can constrict or dilate under various local influences and thereby alter the flow to a poten­ tially ischaemic zone. Another complicating factor is the bombardment o f an affected area by various efferent stimuli originating within the central nervous system. This can increase the force and speed of muscle contraction (so-called inotropic actions), and elevate the heart rate, thus increasing cardiac activity and so that energy requirements outstrip the blood supply o f a potentially ischaemic zone. Then there are motor pathways which affect the arterioles o f the coron­ ary system and m ay cause them to react with either constriction or dilation, irrespective o f the local effects o f hypoxia. Finally on the question of the pain stimulus itself we must always remember that a chemical reaction occurs in the presence o f ischaemia which may produce various peptide substances (kallikrein and plasma-kinins). These have the ability to stimulate unmyelinated nerve fibres which may or may not be present in any given zone o f the heart, depending on the degree of previous nerve damage and the patient’s inherent nerve supply. Once these receptors are stimulated the impulse goes back to the central nervous system, but there are many slips between the cup and the lip. This pain can be augmented by impulses arising in other systems of the body or dampened if there has been some change in interpretation within the cerebral cortex. So all o f these features must enter into our discussion of angina pectoris, irrespective o f the objective assessment o f myocardial ischaemia. One w ay to learn something about the nature o f myocardial ischaemia is to study cardiac metabolism. T o do so, it is necessary to place a catheter in the coronary sinus. This is a simple and safe procedure, if done under proper con­ ditions, by which blood samples can be obtained from various veins which course over the left ventricle. T he metabolic exchanges o f various substrates by the heart can then be studied by analysis o f both arterial and coronary venous samples. T he normal metabolism of the heart is essentially oxidative but when there is inadequate oxygen supply, the heart switches to glycolytic metabolism, with the result that lactic acid is generated as an end product and ultimately diffuses out into the blood stream. Thus, lactic acid concentration in the coronary sinus in excess o f levels in the arterial blood is evidence of myocardial ischaemia. In normal subjects the heart extracts lactate and uses it as a fuel both at rest and during most stresses but ischaemic hearts can do this only at rest when the oxygen supply is still adequate. In a patient who has coronary heart disease with greater than 75 per


Harvard Medical School, Peter Bent Brigham Hospital
It is interesting to note on this centenary cele bration that we still are uncertain about the nature o f anginal pain; we discuss the nitrites, we carry out experiments, yielding new data, and yet we are still really not quite sure how these agents act.I think it is desirable to review with hum ility some o f Lauder Brunton's ideas about the actions o f these drugs.A t a m ajor national m eeting in Am erica ju st one year ago, the observation was made that the blood pressure rises before pain occurs in attacks o f spontaneous angina pectoris.U nfortunately the speaker failed to appreciate that Sir Lauder Brunton had sug gested the use o f amyl nitrite for this very reason, nam ely high blood pressure with angina.He thought that nitrites m ight reduce the pain o f angina pectoris by low ering the pressure.
I would like to discuss some aspects o f angina and m yocardial ischaemia and present briefly our thoughts about the actions o f nitroglycerine on the coronary circulation and the m yocardium .
Anginal pain m ay arise not only as a function o f deficient blood supply to a particular region of the heart, but also as a function o f the distribution o f collaterals supplying the same area from other coronary arteries.T h e situation is further com plicated by the fact that the resistance blood vessels can constrict or dilate under various local influences and thereby alter the flow to a poten tially ischaemic zone.Another com plicating factor is the bom bardm ent o f an affected area by various efferent stimuli originating w ithin the central nervous system.This can increase the force and speed o f muscle contraction (so-called inotropic actions), and elevate the heart rate, thus increasing cardiac activity and so that energy requirements outstrip the blood supply o f a potentially ischaemic zone.T hen there are motor pathways which affect the arterioles o f the coron ary system and m ay cause them to react with either constriction or dilation, irrespective o f the local effects o f hypoxia.Finally -on the question o f the pain stimulus itself -we must always remember that a chem ical reaction occurs in the presence o f ischaemia which m ay produce various peptide substances (kallikrein and plasma-kinins).These have the ability to stimulate unm yelinated nerve fibres which m ay or m ay not be present in any given zone o f the heart, depending on the degree of previous nerve dam age and the patient's inherent nerve supply.O nce these receptors are stimulated the impulse goes back to the central nervous system, but there are m any slips between the cup and the lip.T his pain can be augmented by impulses arising in other systems o f the body or dampened if there has been some change in interpretation within the cerebral cortex.So all o f these features must enter into our discussion of angina pectoris, irrespective o f the objective assessment o f m yocardial ischaemia.
O ne w ay to learn something about the nature o f m yocardial ischaemia is to study cardiac metabolism.T o do so, it is necessary to place a catheter in the coronary sinus.This is a simple and safe procedure, if done under proper con ditions, by which blood samples can be obtained from various veins which course over the left ventricle.T h e m etabolic exchanges o f various substrates by the heart can then be studied by analysis o f both arterial and coronary venous samples.T h e normal metabolism o f the heart is essentially oxidative but when there is inadequate oxygen supply, the heart switches to glycolytic metabolism, with the result that lactic acid is generated as an end product and ultim ately diffuses out into the blood stream.T hus, lactic acid concentration in the coronary sinus in excess o f levels in the arterial blood is evidence of m yocardial ischaemia.In normal subjects the heart extracts lactate and uses it as a fuel both at rest and during most stresses but ischaemic hearts can do this only at rest -when the oxygen supply is still adequate.In a patient w ho has coronary heart disease with greater than 75 per cent obstructions in one or all three arteries, there is usually lactic acid extraction by the heart at rest.But, w hen cardiac activity is stim ulated, the lactate concentration rises so that coronary venous concentration becomes higher than the arterial.W hen nitroglycerine is given, it relieves anginal pain, improves oxygen supply and burns o ff lactic acid production.O n the other hand, isprenalin stresses the ischemic heart and increases lactic acid production.
In some m arginal attacks w e have recorded coronary vasoconstriction totally inappropriate to the situation.T h e first spontaneous observation o f this phenom enon showed a norm al coronary flow o f 116 cc per minute per 100 gram m es o f muscle, w hich fell to 78 cc at the tim e o f an anginal attack.Another patient had no pain, a blood pressure o f 150/78, a pulse rate o f 54, and a coronary flow o f 71 cc, when the recording began.T h e patient then becam e hypertensive (180/110) and devel oped pain; the coronary flow fe ll to 51 cc.N itro glycerine was given, the patient obtained relief of pain, the blood pressure fell to 130/73, the pulse rate dropped and the coronary flow increased to 88 cc per 100 gramm es per m inute.T his phenom enon o f a reduction in coronary flow associated w ith hypertension and coronary vasoconstriction has now been seen in three patients, each o f whom developed a spontaneous attack o f angina.Each also gave a prior history o f apparently unprovoked attacks o f anginal pain.These findings show that there is such an entity as coronary vasocon striction, and that nitroglycerine appears to be effective in attenuating such an attack b y tending to norm alize the blood pressure and b y au g m enting coronary blood flow.
Bernstein and his collaborators at the Johns Hopkins M ed ical School have attem pted to measure the effect o f nitroglycerine on coronary blood flow alone.Finding that the blood pressure tended to fall after nitroglycerine administration, they gave it d irectly into the coronary artery so that systemic circulation w ould be unaffected by its peripheral dilator actions.U n der these cir cumstances, different from how the drug is taken, they w ere able to dem onstrate that coronary flow is augm ented, that nitroglycerine is a coronary vasodilator in both norm al subjects and angina patients.But is this its most im portant action?Several workers have found evidence o f a bene ficial and som ew hat selective effect to augm ent collateral blood flow by collateral vessel dilation and w e have been able to confirm this by means o f selective coronary angiography and rad io krypton studies o f coronary flow.

Summary
It is our b elief that nitroglycerine has actions on the coronary vasculature as follows.C oronary flow is increased b y arteriolar dilation w hich is particularly im portant in the presence o f induced vasoconstriction.T h ere is also a profound effect to increase blood flow via the collateral circulation.As a result, blood is shunted towards the post obstructive and poorly perfused areas o f the m yocardium .