Hypercholesterolemia abolishes voltage-dependent K⁺ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles

Abstract

. Hypercholesterolemia abolishes voltage-dependent K ϩ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles. Am J Physiol Heart Circ Physiol 288: H568 -H576, 2005. First published September 30, 2004; doi:10.1152/ajpheart.00157.2004.-Hypercholesterolemic patients display reduced coronary flow reserve in response to adenosine infusion. We previously reported that voltagedependent K ϩ (Kv) channels contribute to adenosine-mediated relaxation of coronary arterioles isolated from male miniature swine. For this study, we hypothesized that hypercholesterolemia attenuates K v channel contribution to adenosine-induced vasodilatation. Pigs were randomly assigned to a control or high fat/high cholesterol diet for 20 -24 wk, and then killed. After completion of the experimental treatment, arterioles (ϳ150 m luminal diameter) were isolated from the left-ventricular free wall near the apical region of the heart, cannulated, and pressurized at 40 mmHg. Adenosine-mediated relaxation was significantly attenuated in both endothelium-intact and -denuded arterioles from hypercholesterolemic compared with control animals. The classic K v channel blocker, 4-aminopyridine (1 mM), significantly attenuated adenosine-mediated relaxation in arterioles isolated from control but not hypercholesterolemic animals. Furthermore, the nonselective K ϩ channel blocker, tetraethylammonium (TEA; 1 mM) significantly attenuated adenosine-mediated relaxation in arterioles from control but not hypercholesterolemic animals. In additional experiments, coronary arteriolar smooth muscle cells were isolated, and whole cell K v currents were measured. Kv currents were significantly reduced (ϳ15%) in smooth muscle cells from hypercholesterolemic compared with control animals. Furthermore, K v current sensitive to low concentrations of TEA was reduced (ϳ45%) in smooth muscle cells from hypercholesterolemic compared with control animals. Our data indicate that hypercholesterolemia abolishes K v channel contribution to adenosine-mediated relaxation in coronary arterioles, which may be attributable to a reduced contribution of TEA-sensitive K v channels in smooth muscle of hypercholesterolemic animals. microcirculation; smooth muscle; K ϩ current; voltage clamp HYPERCHOLESTEROLEMIA IS RECOGNIZED as a primary independent risk factor for coronary artery disease (3, 31) and is associated with altered vascular reactivity and ion channel function of the coronary microcirculation (20,21,27). Both hypercholesterolemic patients and animal models display impaired vasodilatory responses of the coronary microcirculation, which are generally attributed to endothelium dysfunction (16,20,27). However, numerous studies (11,12,24,32) have documented reduced coronary flow reserve in hypercholesterolemic patients in response to intravenous infusion of adenosine or dipyridamole, which also act directly on smooth muscle. These reports indicate that changes in vascular reactivity of the coronary microcirculation in response to hypercholesterolemia may a...

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