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 sulfonylur ea known to block ATP-dependent potassium (K-ATP) channels, and N-omeg a-nitro-L-arginine methyl ester (L-NAME), an L-arginine analog known t o block nitric oxide (NO) synthesis, on coronary vascular responsivene ss to adenosine. Background. The role of adenosine in coronary flow re gulation becomes increasingly important when K-ATP channel function or NO synthesis is impaired. Both variables are potentially altered in p atients with coronary artery disease taking a sulfonylurea. Methods. D ose-response curves relating coronary conductance to plasma adenosine concentration were obtained by using intracoronary infusions of adenos ine (10 to 1,000 mu g/min) in chronically instrumented dogs. Results. ED50, the plasma concentration of adenosine needed to produce 50% of t he maximal increase in conductance under baseline conditions, increase d 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 incre ase per 1 mg/kg body weight of glibenclamide). Effects of combined blo ckade of K-ATP channels and NO synthesis were additive, with increases in ED50 as high as 15-fold. Both L-NAME and glibenclamide increased s ystemic pressure and reduced coronary conductance, confirming the role s of NO and K-ATP channels in regulating coronary and systemic vascula r tone under rest conditions as well as during stress. Conclusions. Co ronary 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 A merican College of Cardiology.