Coronary vascular responsiveness to adenosine is impaired additively by blockade of nitric oxide synthesis and a sulfonylurea

Objectives. We sought to define effects of glibenclamide, a sulfonylurea known to block ATP-dependent potassium (K-ATP) channels, and N-omega-nitro-L-arginine methyl ester (L-NAME), an L-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 K-ATP channel function or NO synthesis is impaired. Both variables are potentially altered in patients with coronary artery disease taking a sulfonylurea. Methods. Dose-response curves relating coronary conductance to plasma adenosine concentration were obtained by using intracoronary infusions of adenosine (10 to 1,000 mu g/min) in chronically instrumented dogs. Results. ED50, the plasma 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 L-NAME. ED50 also increased in response to glibenclamide in a dose-related fashion (5.7-fold increase per 1 mg/kg body weight of glibenclamide). Effects of combined blockade of K-ATP channels and NO synthesis were additive, with increases in ED50 as high as 15-fold. Both L-NAME and glibenclamide increased systemic pressure and reduced coronary conductance, confirming the roles of NO and K-ATP 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 L-NAME and glibenclamide. Effects of the sulfonylurea and blockade of NO synthesis are additive and can limit coronary vasodilation as well as other responses involving K-ATP channels and NO. (C) 1998 by the American College of Cardiology.