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3.3. Role of metabolism and autoregulation

The ability of a vascular bed to adjust its tone, in order to maintain a constant flow during changes in perfusion pressure is termed autoregulation.21 This process is most effective in the coronary circulation when pressure is between 40 and 160 mmHg. Since the range of pressures over which autoregulation can be observed is different for the subendocardium, as compared to the subepicardium, flow will begin to decrease at pressures < 70–75 mmHg in the subendocardium, as compared to significantly lower pressures in the superficial layers of the myocardium.22 Clinically, systemic arterial hypertension affects the range over which autoregulation occurs in the subendocardium such that flow will begin to decline at even higher pressures. Such a change in subendocardial perfusion pressure in the setting of hypertrophic myocardium increases the likelihood of subendocardial ischemia.

During both autoregulation and metabolic regulation, the predominant changes in vasomotor tone occur in vessels <100 µm in diameter. The rate of oxygen consumption in the myocardium is closely related to myocardial perfusion via coronary microvascular tone. As the myocardial oxygen requirements increase, coronary flow rises in response. Mostly, this is due to the fact that the ability of the myocardium to extract additional oxygen to meet increased demand is limited since myocardial oxygen extraction is near maximum even under resting conditions.

3.4. Flow-induced dilation

Flow-induced dilation is a ubiquitous phenomenon of blood vessels in various organs and animals, including humans.2,23,24 Flow-induced dilation is considered to play important physiological roles as follows: first, to protect the vessel wall against friction-induced injury; second, to prevent the vascular steal phenomenon by dilating upstream vessels in the case of focal hyperemia; third, to reduce the heterogeneity of the coronary flow distribution; and fourth, to buffer the pressure distribution; in the face of rapid pressure changes.

Flow is sensed by endothelial cells through unidentified mechanoreceptors. In contrast to the myogenic response, the endothelium is

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of vascular smooth muscle. Due to the work of Dunker et al. as well as others, we now know that several factors work together to influence metabolic regulation and autoregulation leading to adequate regulation of coronary vascular tone despite interruption of any one particular pathway.21

3.5. Neurohumoral influence on microcirculation

The coronary arterial system is densely innervated with the sympathetic and parasympathetic nervous systems.27 Neurotransmitters released from nervous tissues and a wide variety of humoral substances significantly affect the microvascular tone. Table 1 summarizes these endogenous substances and their microvascular responses. The effect of neurohumoral factors on coronary microvascular tone, in addition to myogenic, flow-induced, and local metabolic controls all participate in determining the coronary vascular resistance necessary for oxygen and nutrition supply to the myocardium (Fig. 4).

The role of the autonomic sympathetic and parasympathetic nervous systems is important in regulation of coronary perfusion. In vivo, the vascular response to sympathetic stimulation is mediated by both α- adrenergic and β-adrenergic receptors. In the coronary circulation, the predominant receptor subtype seems to be the β-adrenergic receptor.28 For example, direct sympathetic nerve stimulation stimulates coronary vasodilation and an increase in coronary flow occurs. If β- adrenergic antagonists are administered, a transient vasoconstriction can be observed.28 When coronary microvessels are studied in vitro, α-adrenergic stimulation has minimal contractile effects. When selective α2-adrenergic stimulation is applied using pharmacological stimuli, there is rather potent vasodilation of all sized coronary microvessels, predominantly due to a release of endothelium-derived nitric oxide (NO•). β-adrenergic stimulation produces a potent relaxation of all coronary arteries, but especially small resistance vessels.28 Also, β2- adrenergic receptor subtype predominates in vessels less than 10 µm in diameter in in vitro studies, whereas a mixed β1 or β2-adrenergic receptor population controls vascular resistance in in vivo studies.28 On the other hand, larger coronary vessels are regulated by a mixed

Table 1. Heterogeneous coronary arterial microvascular responses in vivo to endogenous substances.

Arterial coronary microvessels < 100–150 µm.

†Arterial coronary microvessels > 100–150 µm. Source: Adapted from Ref. 2.

β1- and β2-adrenoceptor subtype population. Activation of cholinergic receptors by either vagal stimulation or the infusion of acetylcholine produces uniform vasodilation of coronary vessels.29 This vasodilation is predominantly mediated by endothelium-derived NO•, although release of EDHF,30 and the release of prostaglandin substances may also contribute.31 The coronary flow increase by vagal stimulation can be blunted by a metabolically-mediated flow decrease caused by a decrease in the heart rate and myocardial contractility.32