NO is involved in MCh-induced accentuated antagonism via type II PDE in the canine blood-perfused SA node.
The possible role of type II (cGMP-stimulated cAMP hydrolysis) phosphodiesterase (PDE) in the accentuated antagonism of muscarinic effects on heart rate during beta-stimulation via endogenous nitric oxide (NO) was evaluated. The canine isolated sinoatrial node preparation was cross circulated with arterial blood of a support dog. The sinoatrial rate of the preparation was 96 +/- 5 beats/min (n = 16) at control. Methacholine (MCh; 0.01-1 microg) injected into the right coronary artery in a bolus fashion caused dose-dependent decreases in sinoatrial rate. Under an intra-arterial infusion of isoproterenol (1 microM), resulting in approximately 50% increase in sinoatrial rate, MCh-induced decreases were markedly augmented from -18 +/- 3% to -44 +/- 4% at 0.3 mg of MCh. When N(G)-nitro-L-arginine methyl ester (100 microM) or N(G)-monomethyl-L-arginine (100 microM) were continuously infused, the augmented MCh-induced decreases in sinoatrial rate were significantly suppressed (-29 +/- 3% or -25 +/- 3%, respectively, P < 0.01). Pretreatment with either 3-isobutyl-1-methylxanthine (IBMX; 20 microM), a non-selective PDE inhibitor, or amrinone (20 microM), a selective type III (cGMP inhibited cAMP hydrolysis) PDE inhibitor, doubled the isoproterenol-induced increase in the sinoatrial rate. However, the augmented MCh-induced decreases in sinoatrial rate were significantly depressed by IBMX (from -23 +/- 5% to -14 +/- 1%, P < 0.01) but not by amrinone (to -20 +/- 3%). These results suggest that MCh-induced accentuated antagonism in the sinoatrial node pacemaker activity can be modulated by endogenous NO via an activation of the type II cyclic GMP-stimulated cAMP PDE.
Sasaki
S
S
Department of Pharmacology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan.
Daitoku
K
K
Iwasa
A
A
Motomura
S
S
D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005092:Exonucleases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010210:Papillary Muscles / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D012849:Sinoatrial Node / Q000187:drug effects* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011943:Receptors, Adrenergic, beta; D016210:Methacholine Chloride; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D005092:Exonucleases; C022650:spleen exonuclease; D000109:Acetylcholine