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

Objective: To evaluate the role of potassium channels in the regulation of coronary hemodynamics in experimental hypercholesterolemia. Background: Pot assium (Ki) 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+ channe ls in modulating coronary blood flow in this pathophysiologic state has not been evaluated. Methods and results: Pinacidil (group 1, n = 5) at 2 mug/k g per min, glibenclamide (group 2, n = 5), or N-monomethyl-L-arginine (LNMM A) (group 3, n = 4) at 50 mug/kg per min were infused into the left anterio r descending artery of pigs prior to and following 10 weeks of 2% cholester ol diet. After 10 weeks of cholesterol feeding, intracoronary pinacidil res ulted in a significant increase in coronary blood flow (CBF) and coronary a rtery diameter (CAD) compared to the normolipidemic state (111 +/- 10 versu s 59 +/- 12%. and 6 +/- 1.1 versus 2.7 +/- 1.0%, respectively. P < 0.05 for both comparisons), whereas intracoronary glibenclamide resulted in a signi ficant 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 c ompared 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 compari sons). Furthermore, pretreatment with intracoronary LNMMA did not alter the CBF response to pinacidil in normal pigs (group 4, n = 4) (57.4 +/- 19 ver sus 59 +/- 12%, P = NS). Conclusions: The current study demonstrates an enh anced 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 undersco re the importance of the K+ channel pathway in the regulation of coronary v asomotor tone in pathophysiologic states. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.