L-NMMA blocks carbachol-induced increases in cGMP levels but not decreases in tension in the presence of forskolin in rabbit papillary muscles.
OBJECTIVE
The purpose of the present investigation was to determine whether stimulation of the nitric oxide synthase pathway contributes to the muscarinic receptor-mediated elevation in cGMP levels and reversal of the positive inotropic response to the adenylyl cyclase activator forskolin in rabbit papillary muscles.


METHODS
Intact rabbit papillary muscles suspended under tension in isolated tissue baths were incubated in the absence or presence of the nitric oxide synthase inhibitor L-NG-monomethyl arginine (L-NMMA) and then treated with forskolin followed by the muscarinic agonist carbachol. The developed tension of the preparations was monitored during their exposure to drug. Papillary muscles were then frozen and subsequently assayed for cGMP levels by radioimmunoassay. Tension and cGMP levels were also measured in some papillary muscles treated with forskolin followed by sodium nitroprusside.


RESULTS
Incubation of papillary muscles with L-NMMA completely blocked increases in cGMP levels produced by carbachol, but had no effect on the reversal by carbachol of the increase in tension in response to forskolin. Sodium nitroprusside also caused a marked elevation of cGMP levels in rabbit papillary muscle, but had no significant effect on the forskolin-induced increase in tension.


CONCLUSIONS
These data demonstrate that activation of muscarinic receptors results in increases in cGMP levels largely through the nitric oxide synthase pathway in rabbit papillary muscles. However, the cGMP produced through this pathway or by sodium nitroprusside does not appear to contribute to the reversal of the positive inotropic response to forskolin.
Hui
J
J
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Tabatabaei
A
A
MacLeod
K M
KM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D009599:Nitroprusside / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D019323:omega-N-Methylarginine
D018721:Muscarinic Agonists; D009599:Nitroprusside; D005576:Colforsin; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D002217:Carbachol; D001120:Arginine; D006162:Guanylate Cyclase; D006152:Cyclic GMP