Vardenafil increases coronary flow response to hypercapnic acidosis in isolated guinea pig heart.
The hypothesis was tested that vardenafil, a PDE5 inhibitor, specifically enhances coronary vasodilation during acidosis. In isolated constant pressure perfused guinea pig hearts, infusion of vardenafil (<or= 1 microM) increased coronary flow concentration-dependently 34 % above baseline. In parallel, cGMP release increased (0.44 +/- 0.094 vs. 0.14 +/- 0.017 pmol/min x g at 0.5 microM vardenafil vs. baseline). Flow increases occurred in the absence of changes in heart function (LVP, heart rate, dP/dt(max), heart rate - pressure product). Infusion of the NO synthase blocker L-NMMA (100 microM) caused a rightward shift of the dose-response curve of vardenafil. To test whether vardenafil treatment may enhance metabolic coronary vasodilation, arterial pCO(2) was raised from 38 to 61 mmHg, which resulted in a steady state flow increase of 18.8 +/- 4.5%. Infusion of vardenafil, given at a threshold flow enhancing concentration, doubled the coronary flow response during hypercapnic acidosis to 38.4 +/- 4.2 % (p=0.004). This flow amplification during acidosis was not shared by the K(ATP) channel opener cromakalim, indicating a specific effect of vardenafil on flow control during myocardial acidosis. We conclude that vardenafil specifically relaxes coronary resistance vessels through NO/cGMP-dependent pathways and increases the coronary flow response toward hypercapnic acidosis. This finding further supports the importance of the NO-cGMP axis in mediation of this flow response.
Brand
Markus
M
Department of Physiology, Medical Faculty Carl Gustav Carus TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany.
Deussen
Andreas
A
D000138:Acidosis / Q000188:drug therapy*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D019806:Cromakalim / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006935:Hypercapnia / Q000188:drug therapy; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D000069058:Vardenafil Dihydrochloride; D014664:Vasodilation / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D013450:Sulfones; D014227:Triazines; D019806:Cromakalim; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000069058:Vardenafil Dihydrochloride; D006152:Cyclic GMP