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1 Exercise Physiology, West Virginia University School of Medicine, West Virginia, United States
2 Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States
3 Dept. of Pediatrics, Baylor College of Medicine, Houston, Texas, United States
4 Physiology, LSUHSC-NO, New Orleans, Louisiana, United States
* To whom correspondence should be addressed. E-mail: jtune{at}iupui.edu.
We demonstrated previously a role for voltage-dependent K+ (KV) channels in coronary vasodilation elicited by myocardial metabolism and exogenous H2O2, as responses were attenuated by the KV channel blocker 4-aminopyridine (4-AP). The present study tested the hypothesis that KV channels participate in coronary reactive hyperemia. Further, we examined the role of KV channels in responses to NO and adenosine, two putative mediators. Reactive hyperemia (30 second occlusion) was measured in open-chest dogs before and during treatment with 4-AP (intracoronary, i.c., 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 i.c. or 5 mg/kg i.v.) or L-NG-nitroarginine methyl ester (L-NAME; 1 mg/min i.c.) inhibited early and late portions of hyperemic flow, supporting roles for adenosine and NO. 4-AP further inhibited hypermia 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 KV1 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 correolide in vitro (29 ± 4% block at 1 µM). KV current in smooth muscle cells was inhibited by 4-AP with an IC50 of 1.1 ± 0.1 mM and virtually eliminated by correolide. Expression of mRNA for KV1 family members was detected in coronary arteries. Our data indicate that KV channels play an important role in regulating resting coronary blood flow, determining the duration of reactive hyperemia, and mediating adenosine- and NO-induced vasodilation.
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