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

1 Department of Biomedical Sciences, College of Veterinary Medicine and 2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri Submitted 17 February 2004 ; accepted in final form 24 September 2004 Hypercholesterolemic patients display reduced coronary flow reserve in response to adenosine infusion. We previously reported that voltage-dependent K + (K v ) 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 ( 150 µm 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 + 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. K v currents were significantly reduced ( 15%) in smooth muscle cells from hypercholesterolemic compared with control animals. Furthermore, K v current sensitive to low concentrations of TEA was reduced ( 45%) 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 + current; voltage clamp Address for reprint requests and other correspondence: C. L. Heaps, E102 Veterinary Biomedical Sciences, Univ. of Missouri, Columbia, MO 65211 (E-mail: heapsc{at}missouri.edu )