Altered effects of potassium channel modulation in the coronary circulation in experimental hypercholesterolemia

Abstract

Objective: To evaluate the role of potassium channels in the regulation of coronary hemodynamics in experimental hypercholesterolemia. Background: Potassium (K +) channels play an important role in coronary vasoregulation. It has previously been demonstrated that experimental hypercholesterolemia is associated with altered coronary vasomotion; however, the role of K + channels in modulating coronary blood flow in this pathophysiologic state has not been evaluated. Methods and results: Pinacidil (group 1, n=5) at 2 μg/kg per min, glibenclamide (group 2, n=5), or N-monomethyl- l-arginine (LNMMA) (group 3, n=4) at 50 μg/kg per min were infused into the left anterior descending artery of pigs prior to and following 10 weeks of 2% cholesterol diet. After 10 weeks of cholesterol feeding, intracoronary pinacidil resulted in a significant increase in coronary blood flow (CBF) and coronary artery diameter (CAD) compared to the normolipidemic state (111±10 versus 59±12%, and 6±1.1 versus 2.7±1.0%, respectively, P<0.05 for both comparisons), whereas intracoronary glibenclamide resulted in a significant decrease in CBF and CAD compared to the normolipidemic state (−17±5 versus 5±6%, and −0.8±1.4 versus 3.6±1.6%, respectively, P<0.05 for both comparisons). The effect of intracoronary LNMMA on CBF and CAD was significantly attenuated after 10 weeks of cholesterol feeding as compared to the normolipidemic state (−47±5.4 versus −0.8±6.8%, and −19.4±5.7 versus −2.3±3.3%, respectively, P<0.05 for both comparisons). Furthermore, pretreatment with intracoronary LNMMA did not alter the CBF response to pinacidil in normal pigs (group 4, n=4) (57.4±19 versus 59±12%, P=NS). Conclusions: The current study demonstrates an enhanced effect of coronary K + channel modulation and confirms the attenuated basal NO activity previously reported in experimental hypercholesterolemia. Acute withdrawal of basal NO activity alone, however, does not explain the enhanced effect of coronary K + channel modulation. These findings underscore the importance of the K + channel pathway in the regulation of coronary vasomotor tone in pathophysiologic states.