Coronary Vascular Responsiveness to Adenosine Is Impaired Additively by Blockade of Nitric Oxide Synthesis and Sulfonylure

Objectives. We sought to define effects of glibenclamide, sulfonylure known to block ATP-dependent potassium (KATP) channels, and Nω-nitro-image-arginine methyl ester (image-NAME), an image-arginine analog known to block nitric oxide (NO) synthesis, on coronary vascular responsiveness to adenosine. Background. The role of adenosine in coronary flow regulation becomes increasingly important when KATP channel function or NO synthesis is impaired. Both variables are potentially altered in patients with coronary artery disease taking sulfonylurea. Methods. Dose-response curves relating coronary conductance to plasm adenosine concentration were obtained by using intracoronary infusions of adenosine (10 to 1,000 μg/min) in chronically instrumented dogs. Results. ED50, the plasm concentration of adenosine needed to produce 50% of the maximal increase in conductance under baseline conditions, increased threefold after either 1 or 10 mg/kg of image-NAME. ED50 also increased in response to glibenclamide in dose-related fashion (5.7-fold increase per 1 mg/kg body weight of glibenclamide). Effects of combined blockade of KATP channels and NO synthesis were additive, with increases in ED50 as high as 15-fold. Both image-NAME and glibenclamide increased systemic pressure and reduced coronary conductance, confirming the roles of NO and KATP channels in regulating coronary and systemic vascular tone under rest conditions as well as during stress. Conclusions. Coronary vascular responsiveness to adenosine is blunted in vivo by both image-NAME and glibenclamide. Effects of the sulfonylure and blockade of NO synthesis are additive and can limit coronary vasodilation as well as other responses involving KATP channels and NO.