© 1999 American Heart Association, Inc.
Integrative Physiology |
cAMP-Independent Dilation of Coronary Arterioles to Adenosine
Role of Nitric Oxide, G Proteins, and KATP Channels
From the Department of Medical Physiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, College Station, Tex.
Correspondence to Lih Kuo, PhD, Department of Medical Physiology, Cardiovascular Research Institute, Texas A&M University System Health Science Center, College Station, TX 77843-1114. E-mail lkuo{at}tamu.edu
Abstract—Adenosine is known to play an important role in the regulation of coronary blood flow during metabolic stress. However, there is sparse information on the mechanism of adenosine-induced dilation at the microcirculatory levels. In the present study, we examined the role of endothelial nitric oxide (NO), G proteins, cyclic nucleotides, and potassium channels in coronary arteriolar dilation to adenosine. Pig subepicardial coronary arterioles (50 to 100 µm in diameter) were isolated, cannulated, and pressurized to 60 cm H2O without flow for in vitro study. The arterioles developed basal tone and dilated dose dependently to adenosine. Disruption of endothelium, blocking of endothelial ATP-sensitive potassium (KATP) channels by glibenclamide, and inhibition of NO synthase by NG-nitro-L-arginine methyl ester and of soluble guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one produced identical attenuation of vasodilation to adenosine. Combined administration of these inhibitors did not further attenuate the vasodilatory response. Production of NO from coronary arterioles was significantly increased by adenosine. Pertussis toxin, but not cholera toxin, significantly inhibited vasodilation to adenosine, and this inhibitory effect was only evident in vessels with an intact endothelium. Tetraethylammonium, glibenclamide, and a high concentration of extraluminal KCl abolished vasodilation of denuded vessels to adenosine; however, inhibition of calcium-activated potassium channels by iberiotoxin had no effect on this dilation. Rp-8-Br-cAMPS, a cAMP antagonist, inhibited vasodilation to cAMP analog 8-Br-cAMP but failed to block adenosine-induced dilation. Furthermore, vasodilations to 8-Br-cAMP and sodium nitroprusside were not inhibited by glibenclamide, indicating that cAMP- and cGMP-induced dilations are not mediated by the activation of KATP channels. These results suggest that adenosine activates both endothelial and smooth muscle pathways to exert its vasodilatory function. On one hand, adenosine opens endothelial KATP channels through activation of pertussis toxin–sensitive G proteins. This signaling leads to the production and release of NO, which subsequently activates smooth muscle soluble guanylyl cyclase for vasodilation. On the other hand, adenosine activates smooth muscle KATP channels and leads to vasodilation through hyperpolarization. It appears that the latter vasodilatory process is independent of G proteins and of cAMP/cGMP pathways.
Key Words: adenosine • microcirculation • nitric oxide • K+ channel
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