Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-flow autoregulation.

The mechanisms responsible for coronary pressure-flow autoregulation, a critical physiologic phenomenon that maintains coronary blood flow relatively constant in the presence of changes in perfusion pressure, remain poorly understood. This investigation tested the hypothesis that voltage-sensitive K(+) (K(V)) and Ca(2+) (Ca(V)1.2) channels play a critical role in coronary pressure-flow autoregulation in vivo. Experiments were performed in open-chest, anesthetized Ossabaw swine during step changes in coronary perfusion pressure (CPP) from 40 to 140 mmHg before and during inhibition of K(V) channels with 4-aminopyridine (4AP, 0.3 mM, ic) or Ca(V)1.2 channels with diltiazem (10 µg/min, ic). 4AP significantly decreased vasodilatory responses to H(2)O(2) (0.3-10 µM, ic) and coronary flow at CPPs = 60-140 mmHg. This decrease in coronary flow was associated with diminished ventricular contractile function (dP/dT) and myocardial oxygen consumption. However, the overall sensitivity to changes in CPP from 60 to 100 mmHg (i.e. autoregulatory gain; Gc) was unaltered by 4-AP administration (Gc = 0.46 ± 0.11 control vs. 0.46 ± 0.06 4-AP). In contrast, inhibition of Ca(V)1.2 channels progressively increased coronary blood flow at CPPs > 80 mmHg and substantially diminished coronary Gc to -0.20 ± 0.11 (P < 0.01), with no effect on contractile function or oxygen consumption. Taken together, these findings demonstrate that (1) K(V) channels tonically contribute to the control of microvascular resistance over a wide range of CPPs, but do not contribute to coronary responses to changes in pressure; (2) progressive activation of Ca(V)1.2 channels with increases in CPP represents a critical mechanism of coronary pressure-flow autoregulation.

Intracoronary glucagon-like peptide 1 preferentially augments glucose uptake in ischemic myocardium independent of changes in coronary flow.

We examined the acute dose-dependent effects of intracoronary glucagon-like peptide (GLP)-1 (7-36) on coronary vascular tone, cardiac contractile function and metabolism in normal and ischemic myocardium. Experiments were conducted in open chest, anesthetized dogs at coronary perfusion pressures (CPP) of 100 and 40 mmHg before and during intracoronary GLP-1 (7-36) infusion (10 pmol/L to 1 nmol/L). Isometric tension studies were also conducted in isolated coronary arteries. Cardiac and coronary expression of GLP-1 receptors (GLP-1R) was assessed by Western blot and immunohistochemical analysis. GLP-1R was present in the myocardium and the coronary vasculature. The tension of intact and endothelium-denuded coronary artery rings was unaffected by GLP-1. At normal perfusion pressure (100 mmHg), intracoronary GLP-1 (7-36) (targeting plasma concentration 10 pmol/L to 1 nmol/L) did not affect blood pressure, coronary blood flow or myocardial oxygen consumption (MVO(2)); however, there were modest reductions in cardiac output and stroke volume. In untreated control hearts, reducing CPP to 40 mmHg produced marked reductions in coronary blood flow (0.50 ± 0.10 to 0.17 ± 0.03 mL/min/g; P < 0.001) and MVO(2) (27 ± 2.3 to 15 ± 2.7 µL O(2)/min/g; P < 0.001). At CPP = 40 mmHg, GLP-1 had no effect on coronary blood flow, MVO(2) or regional shortening, but dose-dependently increased myocardial glucose uptake from 0.11 ± 0.02 µmol/min/g at baseline to 0.17 ± 0.04 µmol/min/g at 1 nmol/L GLP-1 (P < 0.001). These data indicate that acute, intracoronary administration of GLP-1 (7-36) preferentially augments glucose metabolism in ischemic myocardium, independent of effects on cardiac contractile function or coronary blood flow.

Contribution of voltage-dependent K⁺ channels to metabolic control of coronary blood flow.

The purpose of this investigation was to test the hypothesis that K(V) channels contribute to metabolic control of coronary blood flow and that decreases in K(V) channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of K(V) channels with 4-aminopyridine (4-AP, 0.3mg/kg, iv). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of K(V) channels also increased aortic pressure (P<0.01) while reducing coronary venous PO(2) (P<0.01) at a given level of myocardial oxygen consumption (MVO(2)). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous PO(2) in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary K(V) current (P<0.01) and decreased expression of K(V)1.5 channels in coronary arteries (P<0.01). Together, these data demonstrate that K(V) channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVO(2). Our findings also indicate that decreases in K(V) channel current and expression contribute to impaired control of coronary blood flow in the MetS. This article is part of a Special Issue entitled "Coronary Blood Flow".

Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease.

UNLABELLED: Adipose tissue is an active endocrine and paracrine organ that may influence the development of atherosclerosis and vascular disease. In the setting of obesity, adipose tissue produces a variety of inflammatory cytokines (or adipokines) that are known to modulate key mechanisms of atherogenesis. In particular, adipose tissue located on the surface of the heart surrounding large coronary arteries (i.e. epicardial perivascular adipose tissue) has been implicated in the pathogenesis of coronary artery disease. The present review outlines our current understanding of the cellular and molecular links between perivascular adipose tissue and atherosclerosis with a focus on potential mechanisms by which epicardial perivascular adipose tissue contributes to obesity-related coronary disease. The pathophysiology of perivascular adipose tissue in obesity and its influence on oxidative stress, inflammation, endothelial dysfunction and vascular reactivity is addressed. In addition, the contribution of specific epicardial perivascular adipose-derived adipokines (e.g. leptin, adiponectin) to the initiation and expansion of coronary disease is also highlighted. Finally, future investigative goals are discussed with an emphasis on indentifying novel therapeutic targets and disease markers within perivascular adipose tissue. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.