Sildenafil increases the force of right atrial contractions in vitro via the NO-guanylyl cyclase pathway involving β-adrenoceptor linked mechanisms.
Sildenafil, a drug used in the treatment of erectile dysfunction, is a phosphodiesterase 5A inhibitor that increases cyclic guanosine monophosphate (cGMP) levels. In addition to its vascular actions, sildenafil is also known to alter cardiac functions. This study was undertaken to elucidate the effect of sildenafil on cardiac contractility and the underlying mechanisms. The experiments were conducted on spontaneously-beating right atria isolated from adult rats. The effect of sildenafil on the isometric contractions in vitro was examined in the absence or presence of antagonists. Sildenafil (0.001-10 microM) produced a concentration-dependent increase in the atrial force of contraction without altering the atrial rate, even up to 10 microM. A concentration as low as 0.001 microM produced a significant increase (16%) in force and the increase was about 50% at 10 microM. Pretreatment with methylene blue (a guanylyl cyclase inhibitor) or N-omega-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor) blocked the force changes induced by sildenafil. Sildenafil-induced increase in force of contraction was also blocked by propranolol (a beta-adrenoceptor antagonist) and diltiazem (an L-type Ca(2+) channel antagonist). The present results demonstrate that sildenafil increases the atrial force of contraction involving cGMP-beta-adrenoceptor-Ca(2+) channel-dependent mechanisms.
Kanoo
Sadhana
S
Department of Physiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221 005, India.
Deshpande
Shripad B
SB
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006162:Guanylate Cyclase / Q000187:drug effects / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*
D015220:Calcium Channels; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011943:Receptors, Adrenergic, beta; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D006162:Guanylate Cyclase; D006152:Cyclic GMP