Regulation of blood flow in response to changing myocardial needs occurs at the level of the coronary arterioles (Fig. 4.1). Adenosine has been suggested as a mediator that couples myocardial metabolism to coronary resistance vessel activity. When cardiac work is increased, the rate of ATP utilization by the contractile apparatus transiently exceeds the rate of resynthesis of ATP, resulting in an increase of free ADP. The cytosolic enzyme adenylate kinase can then act on two molecules of ADP to form one molecule each of ATP and AMP. AMP released by this reaction can be catabolized to adenosine which can be transported out of the myocyte into the interstitial fluid. In the interstitial fluid adenosine engages A_2A receptors on the coronary smooth muscle cell membrane to cause vasodilation [15]. Adenosine has a half-life of seconds, being rapidly reincorporated into the adenine nucleotide pool or deaminated to inosine, which has little vasodilator activity. The vasodilator effect of adenosine can be inhibited by methyl xanthines such as theophylline which act as adenosine receptor blockers. Adenosine receptor blockade does not interfere with the normal increase in myocardial blood flow that occurs during exercise or other increases of O₂ demands, implying that adenosine is not a mediator of normal metabolic vasoregulation [16]. However, adenosine production increases markedly during ischemia and does contribute to vasodilation of coronary resistance vessels in ischemic myocardial regions [16]. Other metabolic perturbations that occur during ischemia, including accumulation of hydrogen ion and lactate, also cause coronary vasodilation, but these changes are not likely to contribute to regulation of arteriolar tone during physiologic conditions. Decreases of arterial O₂ tension and increases of carbon dioxide tension exert vasodilator effects on coronary resistance vessels, with evidence for a synergistic interaction between them. Oxygen diffusion out of the coronary microvessels occurs so rapidly that O₂ tension in arterioles and even small arteries is lower than in aortic blood, suggesting a direct role for O₂ in the local regulation of blood flow [17]. There is evidence erythrocytes not only act as O₂ carriers, but also contribute to metabolic vasoregulation by releasing ATP at low O₂ tensions which causes endothelium dependent vasodilation of the coronary resistance vessels [18]. Thus, regulation of blood flow in response to changes of cardiac work and oxygen needs is dependent on multiple metabolic messengers that act on the coronary resistance vessels.

The downstream coupling of metabolic signals from the cardiac myocytes to the coronary resistance vessels involves potassium channels on the sarcolemma of the vascular smooth muscle cells [19]. Opening of these channels results in an outward flux of potassium, thereby increasing the membrane potential in the smooth muscle cell. This hyperpolarization causes voltage dependent calcium channels to close; the resultant decrease of intracellular calcium produces relaxation of the vascular smooth muscle and vasodilation [20]. Both ATP sensitive potassium channels (K_ATP) and calcium activated potassium channels (K_Ca) are abundantly expressed on coronary smooth muscle and contribute to regulation of blood flow. K_ATP channels act as metabolic sensors that open in response to decreases of intracellular ATP and/or increases of ADP. Pharmacologic blockade of K_ATP channel opening impairs coronary autoregulation, metabolic vasoregulation, and ischemic vasodilation [19]. Depletion of high energy phosphates (HEP) that occurs during ischemia would be expected to cause opening of K_ATP channels, but cannot account for coronary vasodilation during physiologic increases of myocardial O₂ demands during exercise or other stress where bulk cytosolic HEP content is unperturbed. Rather, it is likely that ATP/ADP in a subsarcolemmal microenvironment (rather than bulk changes in cellular ATP) mediate regulation of K_ATP channel activity during physiologic conditions [21]. Although the factors that regulate vascular K⁺ _ATP channel activity during physiologic conditions are not completely understood, the critical importance of this channel is demonstrated by the finding that mice with genetic deletion of coronary K_ATP channels are vulnerable to myocardial ischemia and sudden death [22]. K_Ca channels open in response to membrane depolarization and increased cytosolic Ca²⁺ concentrations, thereby providing negative feedback modulation of coronary vasoconstrictor responses [23]. K_Ca channels also respond to phosphorylation by cGMP and cAMP dependent protein kinases and are downstream effectors of vasodilators including adenosine, nitric oxide and β-adrenergic agonists. Thus, regulation of blood flow by the coronary resistance vessels involves a large number of redundant mechanisms which converge on sarcolemmal channels in the vascular smooth muscle that regulate membrane polarization and thus calcium flux and contractile activity of the smooth muscle (Table 4.2).

Myogenic automaticity refers to the intrinsic property of smooth muscle to respond to stretch with a counteracting increase in contractile force. Thus, an increase in intraluminal distending pressure causes the vascular smooth muscle to contract, while a decrease in pressure results in vasodilation. Myogenic activity is an intrinsic property of coronary arterioles and is not altered by endothelial denudation [1]. Myogenic responses are more prominent in arterioles from the subepicardium than from the subendocardium of the left ventricle, suggesting that intrinsic differences in responsiveness could contribute to the lesser ability to autoregulate in the subendocardium [24]. Although myogenic activity can be demonstrated in isolated coronary arterioles, the contribution of myogenic mechanisms to regulation of blood flow in the intact heart is likely of less importance than metabolic or endothelium-mediated responses.

Small arteries (100–300 μm in diameter) contribute up to 40 % of total coronary resistance but, unlike the arterioles, these vessels are not responsive to the metabolic state of the myocardium [25]. However, when increased cardiac work results in metabolic vasodilation of the coronary arterioles, the resultant increase of blood flow causes shear-mediated endothelium-dependent dilation of the resistance arteries. Consequently, loss of flow mediated vasodilatation of the resistance arteries in patients in whom hyperlipidemia, atherosclerosis or hypertension has resulted in endothelial dysfunction can impair vasodilator reserve even in the absence of occlusive coronary artery disease. This is demonstrated by the finding that vasodilator reserve measured with positron emission tomography is impaired in patients with hyperlipidemia but with angiographically normal coronary arteries, and that this abnormality can be corrected by lipid lowering therapy [26].

Intramyocardial arteries can be divided into two classes; class A arteries arborize soon after entering the myocardium and supply principally the outer two-thirds of the left ventricular wall, while class B arteries penetrate deep into the myocardium before arborizing to supply blood to the subendocardium (Fig. 4.2) [27]. The class B vessels are also called penetrating arteries. The potential influence of the penetrating arteries on blood flow is documented by the finding that pressure in arterioles in the subendocardium is less than in subepicardial arterioles, indicating that a significant pressure loss occurs across the penetrating arteries [28]. Furthermore, vasomotor activity of the penetrating arteries can selectively influence blood flow to the subendocardium. Vasodilation of the penetrating arteries appears to be a mechanism by which nitrates augment blood flow to the subendocardium in ischemic myocardial regions [29].

The importance of the vascular endothelium in mediating vasodilator responses was first demonstrated by Furchgott and Zawadski [30] who observed that acetylcholine caused relaxation of isolated coronary artery rings when the endothelium was intact, but produced contraction when the endothelium was removed. Subsequent studies demonstrated that a number of agonists including acetylcholine, bradykinin, histamine and thrombin cause coronary vasodilation indirectly by engaging specific receptors on the endothelium that trigger the release of one or more endothelium-derived relaxing factors (EDRF) (Fig. 4.1) [31]. The principal mediator of this vasodilation is nitric oxide (NO) which is produced when the constitutive endothelial cell enzyme nitric oxide synthase (eNOS) acts on arginine to produce citrulline with liberation of NO [32]. eNOS is a calcium-calmodulin dependent P450 enzyme; agonists that produce endothelium-dependent NO-mediated vasodilation generally act by causing increases of intracellular calcium to activate this enzyme. Alternatively, eNOS can be activated by serine phosphorylation, thereby causing sustained increases of NO production [33]. NO produced by eNOS in the endothelium can diffuse to the adjacent vascular smooth muscle and activate soluble guanylate cyclase; the resultant increase in cyclic guanosine monophosphate (cGMP) causes relaxation of the vascular smooth muscle. The shear force produced by blood flowing over the endothelial cells can also activate eNOS; in this way dilation of the epicardial arteries is coordinated with the increased flow produced by metabolic dilation of the coronary resistance vessels during exercise. eNOS is distinct from inducible nitric oxide synthase (iNOS), which is not present in normal coronary vessels, but can be induced by cytokines or inflammatory mediators, and which is not regulated by the intracellular calcium content.