The many faces of myocardial ischaemia and angina

Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.

Muscle blood flow, hypoxia, and hypoperfusion

Blood flow increases to exercising skeletal muscle, and this increase is driven primarily by vasodilation in the contracting muscles. When oxygen delivery to the contracting muscles is altered by changes in arterial oxygen content, the magnitude of the vasodilator response to exercise changes. It is augmented during hypoxia and blunted during hyperoxia. Because the magnitude of the increased vasodilation during hypoxic exercise tends to keep oxygen delivery to the contracting muscles constant, we have termed this phenomenon “compensatory vasodilation.” In a series of studies, we have explored metabolic, endothelial, and neural mechanisms that might contribute to compensatory vasodilation. These include the contribution of vasodilating substances like nitric oxide (NO) and adenosine, along with altered interactions between sympathetic vasoconstriction and metabolic vasodilation. We have also compared the compensatory vasodilator responses to hypoxic exercise with those seen when oxygen delivery to contracting muscles is altered by acute reductions in perfusion pressure. A synthesis of our findings indicate that NO contributes to the compensatory dilator responses during both hypoxia and hypoperfusion, while adenosine appears to contribute only during hypoperfusion. During hypoxia, the NO-mediated component is linked to a β-adrenergic receptor mechanism during lower intensity exercise, while another source of NO is engaged at higher exercise intensities. There are also subtle interactions between α-adrenergic vasoconstriction and metabolic vasodilation that influence the responses to hypoxia, hyperoxia, and hypoperfusion. Together our findings emphasize both the tight linkage of oxygen demand and supply during exercise and the redundant nature of the vasomotor responses to contraction.

Interaction between prostanoids and nitric oxide in regulation of systemic, pulmonary, and coronary vascular tone in exercising swine

Prostacyclin and nitric oxide (NO) are produced by the endothelium in response to physical forces such as shear stress. Consequently, both NO and prostacyclin may increase during exercise and contribute to metabolic vasodilation. Conversely, NO has been hypothesized to inhibit prostacyclin production. We therefore investigated the effect of cyclooxygenase (COX) inhibition on exercise-induced vasodilation of the porcine systemic, pulmonary, and coronary beds before and after inhibition of NO production. Swine were studied at rest and during treadmill exercise at 1–5 km/h, before and after COX inhibition with indomethacin (10 mg/kg iv), and in the absence and presence of NO synthase inhibition with Nω-nitro-l-arginine (l-NNA; 20 mg/kg iv). COX inhibition produced systemic vasoconstriction at rest, which waned during exercise. The systemic vasoconstriction by COX inhibition was enhanced after l-NNA, particularly at rest. In the coronary circulation, COX inhibition also resulted in vasoconstriction at rest and during exercise. However, vasoconstriction was not modified by pretreatment with l-NNA. In contrast, COX inhibition had no effect on the pulmonary circulation, either at rest or during exercise. Moreover, a prostanoid influence in the pulmonary circulation could not be detected after l-NNA. In conclusion, endogenous prostanoids contribute importantly to systemic and coronary tone in awake swine at rest but are not mandatory for exercise-induced vasodilation in these beds. Endogenous prostanoids are not mandatory for the regulation of pulmonary resistance vessel tone. Finally, NO blunts the contribution of prostanoids to vascular tone regulation in the systemic but not in the coronary and pulmonary beds.

Metabolic Control of Muscle Blood Flow During Exercise in Humans

During muscle contraction, several mechanisms regulate blood flow to ensure a close coupling between muscle oxygen delivery and metabolic demand. No single factor has been identified to constitute the primary metabolic regulator, yet there are signal transduction pathways between skeletal muscle and the vasculature that induce vasodilation. A link between muscle metabolic events and microvascular control of blood flow is illustrated by local dilation of terminal arterioles during contraction of muscle fibers and conduction of vasodilation upstream. Endothelial-derived vasodilator mechanisms are known to exert control of muscle vasodilation. Adenosine, nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarization factor (EDHF) are possible mediators of muscle vasodilation during exercise. In humans, adenosine has been shown to contribute to functional hyperemia as blood flow is reduced under nonselective adenosine-receptor blockade. No clear role has been demonstrated for either NO or PGI2, based on studies employing selective inhibition of these substances individually, suggesting a redundancy of vasodilator mechanisms. This is supported by recent work demonstrating that combined blockade of NOS and PGI2, and NOS and cytochrome P450, both attenuate exercise-induced hyperemia in humans. Combined vasodilator blockade studies offer the potential to uncover important interactions and compensatory vasodilator responses. The signaling pathways that link metabolic events evoked by muscle contraction to vasodilatory signals in the local vascular bed remains an important area of study. Key words: metabolic vasodilation, endothelium

Coronary blood flow regulation in exercising swine involves parallel rather than redundant vasodilator pathways

In dogs, only combined blockade of vasodilator pathways [via adenosine receptors, nitric oxide synthase (NOS) and ATP-sensitive K+ (KATP) channels] results in impairment of metabolic vasodilation, which suggests a redundancy design of coronary flow regulation. Conversely, in swine and humans, blocking KATP channels, adenosine receptors, or NOS each impairs coronary blood flow (CBF) at rest and during exercise. Consequently, we hypothesized that these vasodilators act in parallel rather than in redundancy to regulate CBF in swine. Swine exercised on a treadmill (0–5 km/h), during control and after blockade of KATP channels (with glibenclamide), adenosine receptors [with 8-phenyltheophylline (8-PT)], and/or NOS [with Nω-nitro-l-arginine (l-NNA)]. l-NNA, 8-PT, and glibenclamide each reduced myocardial O2 delivery and coronary venous O2 tension. These effects of l-NNA, 8-PT, and glibenclamide were not modified by simultaneous blockade of the other vasodilators. Combined blockade of KATP channels and adenosine receptors with or without NOS inhibition was associated with increased H+ production and impaired myocardial function. However, despite an increase in O2 extraction to >90% during administration of l-NNA + 8-PT + glibenclamide, vasodilator reserve could still be recruited during exercise. Thus in awake swine, loss of KATP channels, adenosine, or NO is not compensated for by increased participation of the other two vasodilator mechanisms. These findings suggest a parallel rather than a redundancy design of CBF regulation in the porcine circulation.