Myogenic Tone Coronary Circulation

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Chapter 3: NORMAL PHYSIOLOGY OF THE CARDIOVASCULAR SYSTEM THE CORONARY CIRCULATION Anatomic and Mechanical Considerations

The right and left main coronary arteries (CAs) arise at the root of the aorta and provide the blood supply to the myocardium. The right CA normally supplies the inferior surface of the LV, the RV and RA, whereas the left CA divides into circumflex and anterior descending branches that perfuse the rest of the LV and the LA. In about 10 percent of cases the left circumflex branch rather than the right CA supplies the inferior LV. Branches from the main CAs ramify and penetrate the myocardium, forming dense capillary beds. Most venous blood returns to the RA via the coronary sinus; there is also communication between the cardiac chambers and myocardium via arteriosinusoidal channels. Delivery of blood to the myocardium is complicated by compression of intramyocardial vessels during systole, which induces retrograde flow in epicardial CAs.195-201 As a consequence, the bulk of coronary flow occurs during diastole, and the upstream perfusion pressure is the Ao diastolic pressure. The subendocardial layer of the myocardium is more susceptible to hypoperfusion because ventricular diastolic pressure opposes the driving pressure for flow. Moreover, compression of microvessels during systole is more prominent in the subendocardium. There has been some uncertainty about the actual driving pressure for nutrient flow, in particular whether the downstream pressure should be considered RA/coronary sinus pressure or a higher value related to tissue forces that cause collapse of the microcirculation (i.e., a critical closing pressure).

Modulation of Coronary Vasomotor Tone and Flow

The distribution of coronary vascular resistance is complex and dependent on type of vessel, region, and specific vasomotor stimuli.198,200 Arterioles clearly comprise the main component of resistance, but small arteries and venules also contribute in a coordinated fashion to control flow to specific regions. Some vasodilators and contrictors preferentially dilate small arteries rather than arterioles. Resistance in subendocardial microvessels appears to be significantly lower than in the subepicardium. Modulation of coronary vascular resistance is exceedingly complex, and only a brief discussion will be undertaken here (see ref. 200 and Chap. 37 for additional details). As the heart varies its mechanical performance over a wide range of physiologic demands, the coronary circulation must keep pace. For example, nutritive coronary flow increases by as much as 400 percent during exercise. Since upstream Ao diastolic pressure does not change markedly during exercise (or even decreases), this requires an ability to markedly dilate coronary resistance vessels. The most potent mechanism of modulation of coronary resistance and flow is endogenous autoregulation. As discussed earlier, this is the ability of the coronary circulation to maintain flow constant over a wide range of perfusion pressures and/or alter flow in response to increased metabolic demands by changing its resistance.198,200 Autoregulation occurs at the level of small arteries, arterioles, and venules and appears to be due to both myogenic and metabolically mediated responses.198,200,201 As discussed earlier, a myogenic response is the ability of vessels to alter tone as a direct response to changes in pressure and/or flow. This is most prominent in arterioles and results in constriction when perfusion pressure is increased and dilatation when pressure is reduced. Although myogenic responses play a role in autoregulation, the most important factors are those related to changes in the washout of metabolites. (Of course, changes in perfusion pressure and flow themselves alter metabolite concentration.) The actual metabolites and effector mechanisms responsible for autoregulation are incompletely defined, but the effects are most prominent in small arterioles. There is much evidence that local release of adenosine (a potent coronary dilator) under conditions of increased metabolic demand is a key mediator of autoregulation.198,200,202,203 However, other endogenous vasoactive mechanisms also contribute. For example, local release of K and activation of ATP-sensitive K channels in small arteries and arterioles also may have a role.204 Moreover, adenosine release itself may activate ATP-sensitive K channels. NO appears to have a significant role in autoregulation as well (see below).

Neurohumorally mediated responses also play a role in modulation of coronary vascular resistance.198'200 Their importance under normal physiologic conditions is uncertain. 0(-Adrenergic responses are well documented in the coronary circulation. ^-Adrenergic agonists constrict large epicardial and small coronary arteries/arterioles (>100 Mm in diameter) and dilate smaller arterioles. At physiologic perfusion pressure, the main effect appears to be constriction of small arteries. While there is evidence of d-adrenergic activity under physiologic conditions, endogenous mechanisms mask and/or counteract this vasoconstrictive influence. Thus endothelial release of NO occurs concomitant with d-adrenergic activity. Adrenergic receptors are present in coronary vessels and cause dilation of large arteries and resistance vessels. However, this influence is difficult to distinguish from and likely of minor importance compared with autoregulation.

Constrictive and dilatory substances produced by the endothelium play a key role in many, if not all, of the changes in coronary tone occurring in response to a variety of physiologic stimuli, including autoregulation in general and adenosine, serotonin, acetylcholine, and adrenergic stimulation.198,200,205,206 These endothelial-derived substances include prostaglandins, ET-1, endothelium-derived hyperpolarizing factor,207 and NO.198,200,204-209 At present, there is considerable information about the physiologic role of NO, but relatively little is known about the others. Although NO is a coronary vasodilator, it produces somewhat heterogeneous effects and may have quantitatively different influences on large arteries versus resistance vessels. NO appears to be the key effector of autoregulatory responses to normal physiologic stimuli, including tachycardia and vasodilation during exercise,208-210 and is intimately connected to responses to the endothelial-derived substances mentioned earlier, as well as a variety of vasoactive drugs.

The response of the coronary circulation to changes in demand requires the coordination of the multiple modulatory mechanisms discussed earlier. The integrated response consists of heterogeneous effects that depend on the type of vessel and the region of the myocardium, which together increase nutritive flow. A scheme illustrating the complex interactions involved in the response to an increase in demand is shown in Fig. 3-26.

Myogenic Response

Figure 3-26: Schematic diagram of integrated response of metabolic, myogenic and flow-mediated regulation of coronary vascular resistance and flow during increase in metabolic demand. Plus sign indicates vasodilatory feed-forward steps in response to initial increase in demand. Minus sign indicates negative-feedback processes that limit vasodilation. Events marked by lines ("Production of Metabolites") occur as a reaction to metabolic or vascular changes. Bolded items are metabolic or vasoactive adjustments. (From Muller et al.200 Reprinted with permission of the publisher.)

Figure 3-26: Schematic diagram of integrated response of metabolic, myogenic and flow-mediated regulation of coronary vascular resistance and flow during increase in metabolic demand. Plus sign indicates vasodilatory feed-forward steps in response to initial increase in demand. Minus sign indicates negative-feedback processes that limit vasodilation. Events marked by lines ("Production of Metabolites") occur as a reaction to metabolic or vascular changes. Bolded items are metabolic or vasoactive adjustments. (From Muller et al.200 Reprinted with permission of the publisher.)

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