Number 22, 2004
Endothelial Dysfunction

Regulation of coronary perfusion

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Susannah J. Fraser, David E. Newby, Neal G. Uren
Department of Cardiology, Royal Infirmary of Edinburgh, Edinburgh, UK
Correspondence: Dr S Fraser, Department of Cardiology, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK.
Tel: +441312421781, fax: +441312421880, e-mail: susannah099@hotmail.com

Introduction
The coronary circulation supplies the myocardium with oxygen and substrates, and removes metabolic waste products. Cardiac contractile function requires aerobic metabolism and, as basal oxygen extraction is about 60%, an adequate increase in coronary blood flow is required to meet increased oxygen consumption. Coronary perfusion is regulated by a complex interplay of several factors that allows coronary blood flow to increase about 5-fold during strenuous exercise.
Changes in coronary vascular tone are essential for the adaptation of coronary blood flow to varying hemodynamic and metabolic demands [1]. Blood flow depends on both the aortic driving pressure and the resistance offered by the coronary bed. Several different control mechanisms regulate coronary vascular resistance; they include metabolic, endothelial, humoral, autoregulatory, myogenic, extravascular compressive, and neural factors. There is a heterogeneity in the response to the last two of these throughout the coronary circulation [1, 2], and it is worth considering the differing coronary vessels and compartments separately.

Coronary vasculature
The large epicardial coronary arteries are conductive vessels which do not contribute significantly to vascular resistance. Myogenic autoregulation of the vascular lumen occurs in these vessels, in response to alterations in aortic pressure. Modulation of coronary tone also occurs here, in response to flow-mediated endothelium-dependent vasodilatation, circulating vasoactive substances, and neural stimuli.
Myocardial oxygen extraction is virtually constant over a wide range of cardiac work and perfusion pressures. The resistive vessels match myocardial blood flow to variable myocardial energy requirements, and to myocardial demand when the coronary perfusion pressure varies. Coronary resistance is influenced both by extrinsic factors such as myocardial compression and by intrinsic factors such as tissue metabolism and neural and humoral mediators. Different mechanisms may account for the heterogeneity of the response of resistive vessels, such as different populations and subtypes of receptors for vasoactive substances [3] or variable metabolic pathways [4]. The resistive vessels have been separated into two general groups: prearteriolar and arteriolar [5, 6]. The arterioles (<100m) respond to local tissue metabolism and maintain the extracellular environment within optimal biochemical limits for myocardial contractile function, modulated primarily by tissue oxygen tension. Prearteriolar vessels (100350m) are influenced by coronary perfusion pressure and flow, myogenic tone, and neurogenic factors [6].
Figure 1 summarizes the factors influencing the regulation of coronary perfusion [7].

Quail et al [2] classified the regulatory factors into those acting from the adventitial aspect of coronary smooth muscle (eg, phasic myogenic compressive forces and autonomic neurotransmitters), and those acting from the luminal aspect (eg, endothelium-dependent or -independent vasodilator or constrictor substances), plus the myogenic properties of the vascular smooth muscle itself, responsible for autoregulation [2].

Metabolic control
Arterioles are directly exposed to the effects of the myocardial metabolites, which diffuse into the interstitial space. The vasodilator metabolites cause smooth muscle cell relaxation and vasodilatation, and thus increased flow. Adenosine is believed to be the major substance that influences metabolically induced coronary vasodilatation [8]; it has also been investigated most extensively. It is formed by 52nucleotidase from adenosine monophosphate (AMP), which itself arises from adenosine triphosphate (ATP). It diffuses into the interstitial space, where it can induce arteriolar dilation and re-enter the myocardial cell. It is either phosphorylated to AMP by adenosine kinase, or deaminated to inosine monophosphate by adenosine deaminase, or it can enter the capillaries and leave the tissue.
Nitric oxide also is implicated in metabolic control. There are two known stimuli for release of nitric oxide, namely hypoxia and flow-mediated dilatation. It is believed that hypoxia initiates hyperaemia, and flow-mediated dilatation sustains and amplifies it.
Oxygen tension, acidbase balance, potassium, osmotic pressure, and ATP-sensitive potassium channels also contribute to the metabolic regulation of flow.

Endothelium-mediated regulation
The arterial endothelium comprises cells resting on a basement membrane, which have autocrine, paracrine, and endocrine functions [9]. This monolayer of endothelial cells has a crucial role in the regulation of coronary vasomotor tone through the elaboration of potent endothelium-derived vasoactive factors formed locally [10]. The endothelial cells also regulate inflammation, thrombosis, fibrinolysis, and cellcell interactions [11]. Endothelial cells produce and release both vasodilator and vasoconstrictor factors. One of the factors modulating vasodilatation is nitric oxide [12], produced from L-arginine by nitric oxide synthetase [13] (Figure 2).

Nitric oxide may be released in response to a variety of different stimuli: flow (shear stress), platelet-derived products (ADP, thrombin, serotonin), and vasoactive agents (bradykinin, histamine, norepinephrine, substance P, vasopressin). Vasoconstrictor substances such as endothelin may override the normal vasomotor tone associated with endothelium-dependent vasodilatation in both pathological and physiological states [14]. In the human coronary circulation, infusion of an inhibitor of nitric oxide production causes a small reduction in blood flow in normal arteries [15], indicating a basal release of nitric oxide to maintain resting flow. Studies in the peripheral circulation in an animal model showed that nitric oxide activity is greatest in vessels larger than 100m in diameter [16], which are under the most shear stress, the major determinant of nitric oxide release. Studies confirm the importance of nitric oxide in modulating microvascular flow by dilating the prearterioles by between 100 and 300m, thus preserving the vasodilator potential of the arterioles smaller than 100m [17]. In atherosclerosis, a loss of this endothelium-dependent mechanism for microcirculatory regulation could account for changes in vasomotor tone at the prearteriolar level, upstream from the potent metabolic vasodilator stimuli of hydrogen ions and low tissue oxygen tension.
Increased release of nitric oxide is seen as a result of stimuli such as an increase in blood pressure or a decrease in the partial pressure of oxygen, or also secondary to the action of acetylcholine, ADP, ATP, bradykinin, or histamine [18].

Autoregulation
There is a broad range of arterial pressures over which coronary autoregulation can occur, permitting sustained and constant coronary blood flow. However, this autoregulation may fail at extremes of arterial pressure change [19]. There are upper and lower limits to the autoregulatory range, but they are not reached in physiological conditions.
There are two proposed mechanisms of autoregulation. First, nitric oxide is believed to be involved through the ability of the endothelium to sense changes in perfusion pressure through pressure-sensitive ion channels. Inhibition increases the lower autoregulatory threshold by about 15mm Hg. Myogenic control plays a small part in autoregulation, as the smooth muscle in the artery wall contracts in response to increased intraluminal pressure.

Neural control
The autonomic nervous system acts to modulate coronary blood flow through direct neuronal stimulation (vessels >100m) or by the release of catecholamine [20]. It has been demonstrated previously that selective ₂-adrenergic activation may induce endothelium-dependent vasodilatation in isolated canine epicardial arteries [21]. In the open-chest dog model, ₁- and ₂-adrenergic activation constricted prearterioles and arterioles, respectively. Inhibition of nitric oxide synthesis unmasked additional vasoconstriction by ₁-adrenergic activation in arterioles and ₂-adrenergic activation in the prearterioles [22]. This implies that the release of nitric oxide, induced by the shear stress of increased coronary flow, opposes -adrenergic vasoconstriction, thus limiting the potential reduction in myocardial perfusion during augmented sympathoadrenal drive. In pathological states, endothelial dysfunction may lead to unopposed -adrenergic vasoconstriction and subsequent prearteriolar resistive vessel dysfunction.

Conclusion
It is clear that the regulation of coronary perfusion is a complex process, and relies on the integration of the factors that are described in this article. It is likely that further research into these factors could improve our treatment strategies in patients with coronary artery disease in the future.

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REFERENCES

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