Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

1 Department of Exercise Physiology, Center for Interdisciplinary Research in Cardiovascular Sciences, West Virginia University School of Medicine, Morgantown, West Virginia; 2 Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; 3 Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and 4 Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana Submitted 1 November 2007 ; accepted in final form 27 March 2008 We previously demonstrated a role for voltage-dependent K + (K V ) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H 2 O 2 , as responses were attenuated by the K V channel blocker 4-aminopyridine (4-AP). Here we tested the hypothesis that K V channels participate in coronary reactive hyperemia and examined the role of K V channels in responses to nitric oxide (NO) and adenosine, two putative mediators. Reactive hyperemia (30-s occlusion) was measured in open-chest dogs before and during 4-AP treatment [intracoronary (ic), plasma concentration 0.3 mM]. 4-AP reduced baseline flow 34 ± 5% and inhibited hyperemic volume 32 ± 5%. Administration of 8-phenyltheophylline (8-PT; 0.3 mM ic or 5 mg/kg iv) or N G -nitro- L -arginine methyl ester ( L -NAME; 1 mg/min ic) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hyperemia in the presence of 8-PT or L -NAME. Adenosine-induced blood flow responses were attenuated by 4-AP (52 ± 6% block at 9 µg/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 µM correolide, a selective K V 1 antagonist (76 ± 7% and 47 ± 2% block, respectively, at 1 µM). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 ± 6% block at 10 µg/min) and by correolide in vitro (29 ± 4% block at 1 µM). K V current in smooth muscle cells was inhibited by 4-AP (IC 50 1.1 ± 0.1 mM) and virtually eliminated by correolide. Expression of mRNA for K V 1 family members was detected in coronary arteries. Our data indicate that K V channels play an important role in regulating resting coronary blood flow, determining duration of reactive hyperemia, and mediating adenosine- and NO-induced vasodilation. ischemic vasodilation; adenosine; 4-aminopyridine; delayed rectifier potassium channel; vascular smooth muscle Address for reprint requests and other correspondence: J. D. Tun