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

We previously demonstrated a role for voltage-dependent K+ (K-V) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H2O2, 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 mu g/min). Dilation of arterioles to adenosine was attenuated by 0.3 mM 4-AP and 1 mu M correolide, a selective K(V)1 antagonist (76 +/- 7% and 47 +/- 2% block, respectively, at 1 mu M). Dilation in response to sodium nitroprusside, an NO donor, was attenuated by 4-AP in vivo (41 +/- 6% block at 10 mu g/min) and by correolide in vitro (29 +/- 4% block at 1 mu M). K-V current in smooth muscle cells was inhibited by 4-AP (IC50 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.