Coronary microcirculation

Abstract

Coronary microvessels play a pivotal role in determining the supply of oxygen and nutrients to the myocardium by regulating the coronary flow conductance and substance transport. Direct approaches analyzing the coronary microvessels have provided a large body of knowledge concerning the physiological and pharmacological characteristics of the coronary circulation, as has the rapid accumulation of biochemical findings about the substances that mediate vascular functions. Myogenic and flow-induced intrinsic vascular controls that determine basal tone have been observed in coronary microvessels in vitro. Coronary microvascular responses during metabolic stimulation, autoregulation, and reactive hyperemia have been analyzed in vivo, and are known to be largely mediated by metabolic factors, although the involvement of other factors should also be taken into account. The importance of ATP-sensitive K⁺ channels in the metabolic control has been increasingly recognized. Furthermore, many neurohumoral mediators significantly affect coronary microvascular control in endothelium-dependent and -independent manners. The striking size-dependent heterogeneity of microvascular responses to all of these intrinsic, metabolic, and neurohumoral factors is orchestrated for optimal perfusion of the myocardium by synergistic and competitive interactions. The regulation of coronary microvascular permeability is another important factor for the nutrient supply and for edema formation. Analyses of collateral microvessels and subendocardial microvessels are important for understanding the pathophysiology of ischemic hearts and hypertrophied hearts. Studies of the microvascular responses to drugs and of the impairment of coronary microvessels in diseased conditions provide useful information for treating microvascular dysfunctions. In this article, the endogenous regulatory system and pharmacological responses of the coronary circulation are reviewed from the microvascular point of view.

Introduction

The heart, because of its continuous beating, requires large amounts of oxygen and metabolic substrates. As the resting coronary arteriovenous oxygen difference is near maximal (60–70%), and it does not appreciably increase when the heart requires more oxygen, the oxygen supply is dependent on coronary flow. Also, the dynamic changes of the metabolic state of the heart require a rapid and elaborate regulatory system of the coronary flow for balancing the supply with the demand of oxygen and nutrients Feigl 1983, Marcus 1983. Since most of the coronary vascular resistance resides in arterial microvessels (Chilian et al., 1986), coronary arterioles and small arteries are responsible for this matching and for determining the flow conductance by changing their tone from moment to moment.

Coronary flow conductance is determined by several factors: factors intrinsic to the vascular wall (myogenic control and flow-induced diameter changes), local metabolic factors, and neurohumoral factors. In classical physiological approaches, the coronary vascular bed is considered to consist of three components (conduit vessels, resistance vessels, and exchange vessels), and the coronary flow control is investigated by measuring coronary flow and perfusion pressure. In such analyses, the vascular segments that determine the coronary conductance are dealt with as a lump component, the resistance vessels. However, direct observations of coronary microvessels in vivo and in vitro have clearly shown that each factor regulating the coronary flow acts on specific sites in the microvascular level, and that the responses of the microvessels are too heterogeneous and complicated to be dealt with as a lump component (Marcus et al., 1990). This size-dependent heterogeneity of the microvascular responses makes it possible for each factor to efficiently and finely adjust the flow conductance and distribution.

Direct evaluations of the coronary microcirculation in vivo and in vitro enable us to more profoundly investigate the intracellular pathways for the regulatory system. Thus, research on the coronary physiology and pharmacology from the viewpoint of the microcirculation has provided us with valuable knowledge for understanding the mechanism of coronary regulation.

The development of reliable techniques for the direct observation of epicardial coronary microvessels in vivo was achieved in the 1980s by overcoming the problems caused by the beating of the heart (Nellis et al. 1981, Tillmanns et al. 1981, Ashikawa et al. 1984, 1996; Chilian et al., 1986). On the other hand, the techniques for investigating isolated coronary microvessels were established in the late 1980s Kuo et al. 1988, Nakayama et al. 1988, Myers et al. 1989, and the intrinsic nature, as well as the agonist-induced responses, of coronary microvessels have been intensely investigated. In vitro studies have elucidated not only the regulation of vascular tone, but also that of microvascular permeability Yuan et al. 1992, Yuan et al. 1993a, which plays important physiological roles in supplying nutrients to parenchymal cells. Furthermore, the transmural heterogeneity of the microvascular responsiveness has also been elucidated by observing subendocardial microvessels in vivo (Yada et al., 1993) and in vitro Kuo et al. 1988, Quillen & Harrison 1992. These in vivo and in vitro studies complement each other towards the accumulation of physiological findings.

The biochemical identification and recognition of molecular mechanisms, such as nitric oxide (NO), ATP-sensitive K⁺ channel (K_ATP channel), and endothelium-derived hyperpolarizing factors (EDHFs), which are important for the regulation of vascular functions, have advanced over the past 15 years, and their importance in vascular physiology has been recognized. Progress in techniques for studying the coronary microcirculation has greatly assisted our understanding of the significance of these molecules in terms of where and how they are involved in the coronary flow regulation. In this review, we discuss the recent research on the coronary microcirculation and provide an overview of how the coronary microvessels are regulated in normal conditions and how they are impaired in diseased conditions.