Review article
Regulation of coronary vasomotor tone under normal conditions and during acute myocardial hypoperfusion

https://doi.org/10.1016/S0163-7258(99)00074-1Get rights and content

Abstract

Ischemia generally has been assumed to cause maximal vasodilation of the coronary resistance vessels. However, recent observations have demonstrated that during ischemia, the coronary microvessels can retain some degree of vasodilator reserve and remain responsive to vasoconstrictor stimuli. Traditional understanding of coronary blood flow regulation envisioned an array of resistance vessels that respond homogeneously to local myocardial metabolic needs. Although coronary arterioles (<100 μm) do respond to myocardial metabolic activity, recent studies have demonstrated that up to 40% of total coronary resistance resides in small arteries 100–400 μm in diameter. Vasoconstriction of these small arteries is capable of decreasing blood flow, but they are minimally responsive to the metabolic effects of the resultant flow reduction. The lack of metabolic vasoregulation of the resistance arteries explains, at least in part, the observation that myocardial ischemia does not predictably cause maximal resistance vessel dilation. In addition, vasoconstrictor influences can compete with metabolic vasodilator activity in coronary arterioles. These findings suggest that pharmacologic vasodilators acting at the microvascular level might be therapeutically useful in patients with ischemic heart disease. Unfortunately, when myocardial ischemia results from a flow-limiting coronary stenosis, nonselective pharmacologic vasodilation of the resistance vessels can worsen subendocardial ischemia by decreasing intravascular pressure to produce coronary steal and by worsening of stenosis severity. Selective dilation of small arteries in ischemic regions might have potential for enhancing blood flow. A critical property of an effective agent is that it not interfere with metabolic vasoregulation at the arteriole level, so that dilation of small arteries in adequately perfused regions would be countered by compensatory vasoconstriction of the arterioles to prevent coronary steal.

Introduction

Ischemia generally has been assumed to cause maximal vasodilation of the coronary microvasculature and to render these vessels unresponsive to vasoconstrictor stimuli Khouri et al. 1968, Hoffman 1978, Gallagher et al. 1980, Gewirtz et al. 1983. However, recent studies have demonstrated that even during ischemia, the coronary resistance vessels often retain some degree of vasomotor tone and can respond to vasoconstrictor stimuli (Gorman & Sparks, 1982). This unexpected finding has required reassessment of the location and function of the principal sites for resistance to blood flow in the coronary circulation. The coronary arterial vasculature traditionally has been divided into two discrete segments: arteries, which offer little resistance to blood flow and which do not participate in regulation of perfusion, and intramural microvessels, which represent the major locus of resistance to flow Marcus et al. 1990, Jones et al. 1995a. The resistance vessels generally have been treated as a homogeneous array of vessels that act principally in response to local myocardial needs, but that can also respond weakly to systemic vasomotor influences. However, the development of methods to directly visualize the coronary microvessels has demonstrated that the concept of a functionally homogeneous coronary microvascular circulation is an oversimplification Marcus et al. 1990, Jones et al. 1995a. Direct measurements of microvascular pressures in beating hearts have demonstrated that during basal conditions, up to 40% of total coronary resistance resides in small arteries between 100 and 400 μm in diameter, and that during vasodilation, these vessels contribute an even greater fraction of total coronary resistance Chilian et al. 1986, Chilian et al. 1989b. The importance of this finding is that although these small arteries contribute a substantial fraction of total coronary resistance and are capable of active vasomotion, they do not appear to be under local metabolic control (Kanatsuka et al., 1989). The finding that a substantial fraction of resistance resides at the level of the small arteries may explain in part the finding that myocardial ischemia does not predictably cause maximal vasodilation of the coronary resistance vessels. Persistence of vasomotor tone in the coronary resistance vessels during myocardial ischemia can be ascribed (at least in part) to vasoconstrictor tone in these small arteries, which are not under metabolic control. In addition, recent studies have provided evidence that even in coronary arterioles that are under metabolic control (<100 μm in diameter), vasoconstrictor influences can compete with metabolic vasodilator activity (Chilian & Layne, 1990).

Section snippets

Functional delineation of coronary arterial segments

The finding that vessels previously not considered to contribute to regulation of blood flow actually represent a substantial and variable locus of resistance indicates that the coronary arterial tree cannot simply be divided into conduit and resistance vessels. Furthermore, the assumption that the resistance vessels respond as a homogeneous unit is an oversimplification. A more utilitarian approach is to separate the coronary arterial bed into three segments on the basis of functional as well

Normal arterial inflow

Adenosine predominantly dilates arterioles <100 μm in diameter. Vessels of this size correspond to the site at which coronary metabolic regulation (Kanatsuka et al., 1989) and autoregulation (Kanatsuka et al., 1990) occur. Adenosine has characteristics that suggest that it could be a messenger by which the coronary resistance vessels are regulated in response to changing myocardial metabolic needs Berne & Rubio 1974, Engler 1991. There are two pathways for adenosine production in the heart.

Is coronary vasodilation maximal in hypoperfused myocardium?

Systolic wall stress and thus, oxygen requirements are greatest in the innermost layers of the LV wall. The need for greater blood flow in the subendocardium requires a transmural gradient of vasomotor tone, with vascular resistance being lower in the inner than in the outer layers. Since extravascular compressive forces are highest in the deeper layers, as perfusion pressure falls, vasodilator reserve is exhausted first in the subendocardium Flameng et al. 1974, Hoffman 1987. Consequently,

α-Adrenoceptors

Blockade of α-adrenoceptors can influence CBF through two separate mechanisms. First, blockade of prejunctional α2-adrenoceptors interrupts the negative feedback control of norepinephrine release Langer 1977, Heyndrickx et al. 1984. The resultant increase in norepinephrine stimulates myocardial β-adrenoceptors and increases CBF secondary to an increase in myocardial oxygen consumption. Second, α-adrenergic blockade can increase CBF by interrupting postjunctional vasoconstriction of coronary

Clinical implications and future perspectives

Ischemia generally has been assumed to cause maximal vasodilation of the coronary microvasculature and to render these vessels unresponsive to vasoconstrictor stimuli. However, both experimental studies and recent clinical observations (Zeiher et al., 1995) have demonstrated that during exercise-induced ischemia, vasodilator reserve exists in the distal coronary vasculature, which can be recruited by administration of adenosine or nitrovasodilators. TXA2 and 5-HT can aggravate myocardial

Acknowledgements

This study was supported by U.S. Public Health Service Grants HL20598, HL32427, and HL21872 from the National Heart, Blood and Lung Institute. D.J.D. is supported by a Fellowship of the Royal Netherlands Academy of Arts and Sciences.

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