Pharmacology of the coronary circulation.

Until recently, the medical management of coronary artery disease consisted of depressing the heart's requirements for oxygen. Little thought was directed towards improving coronary blood flow as it was believed that atherosclerotic lesions were fixed, unchangeable obstructions. Attempts at pharmacological coronary dilatation were, therefore, considered futile. Within the last few years, these concepts have undergone radical revision.t-3 It is now recognized that coronary stenoses are not fixed but are capable of both dilatation and constriction and these changes can have dramatic effects on blood supply to the heart. Drugs that either dilate or prevent constriction of atherosclerotic coronary articles arc, therefore, of value in patients with coronary artery disease. 4,5 However, paradoxically, drugs that dilate distal intramyocardial coronary arterioles may have the opposite effect. Coronary arteriolar dilatation, in the presence of epicardial atherosclerosis, may exacerbate maldistribution of cornnary blood flow and lead to ischaemia. 2'3'6 This confusing picture is best understood by considering the composition of the coronary vascular system. The coronary circulation consists of large proximal coronary arteries that branch and ultimately form an intramyocardial network of small arteries and arterioles. 2-4"7 The arterioles become smaller metarterioles and they eventually form the capillary bed. Blood returns via the coronary venous system. There are major functional differences between the large proximal coronary arteries and the smaller downstream arterioles. The proximal coronary arteries are large bore, relatively thin-walled vessels that lie predominantly on the epieardial surface of the heart. The:so vessels serve to conduct blood from the aorta to the intramyocardial network of arterioles. They are transport vessels 2-'t,7 and contribute little to the overall vascular resistance of the coronary system. They possess considerable reserve capacity and even when blood flow is maximal, such as during extreme exertion, they continue to conduct the much increased flow of blood without imposing resistance. It is these vessels which are visualized during coronary angiography, undergo coronary atheroselerosis and are bypassed during coronary artery_ surgery. Distal, downstream to the epicardial coronary arteries is a system of smaller arteries, arterioles and metarterioles that end in precapillary sphincters. T M These vessels penetrate throughout the myocardium and are responsible for delivery of blood to the cardiac tissue and for appropriate distribution of blood flow within the myocardlum. They are relatively thick-walled, having a thick smooth muscle coat. At rest, in normal man, blood flow to the left ventricle is about 60 to 80 ml/100 g myocardium/minute. 7 When myocardial oxygen requirements increase, the resistance vessels dilate and permit myocardial flow to increase in proportion to demand. When oxygen requirements decrease, arterioles constrict and limit flow. For example, the subendocardium has a high metabolic rate yet coronary flow is restricted during systole because of a "throttling" effect of myocardial contraction on intramyocardial vessels, s However, during diastole, subendocardial resistance vessels dilate and blood flow to this region is enhanced and transmural flow is distributed equitably. In this way, intramyocardial vascular tone modulates a tight coupling between oxygen requirements and oxygen supply. Factors responsible for regulating arteriolar tone are not known, but adenosine and other products of metabolism such as potassium ions have ready access to the intramyocardial vessels and are thought to have a regulator role. 9'~~ Epicardial coronary arteries, in contrast, do not participate to any marked extent in flow autoregulation. Even at maximum blood flow rates (mammalian hearts are capable of a six-fold increase in coronary flow), the vessels are of sufficient calibre to permit flow without imposing significant resistance. However, it does appear that some variation in tone occurs and regulatory mechanisms exist. Coronary adrenergic alpha receptors ~* and beta I and beta2 receptors .2 have been identified and serotinergic and neuropeptidergic nerve fibres have been found in mammalian epicardial vessels.t3'*4 Also, high bloodflow states are thought to promote the release of vasodilators from the epicardial vascular endothelium, t s,*s In addition, epicardial arteries are passively dilated when arterial pressure is elevated by manoeuvres such as exercise. Atheroselerosis impairs the function of this perfusion system. Atherosclerosis involves only the epicardial vessels, not downstream resistance arterioles, t7 Now the previously low-resistance epieardial transport arteries take