Relationship between cyclic guanosine monophosphate accumulation and relaxation of canine trachealis induced by nitrovasodilators.
The role of cyclic GMP (cGMP) in mediating relaxation of canine trachealis produced by nitrovasodilators (NVDs), compounds that activate guanylate cyclase, was examined. Sodium nitroprusside (SNP) produced a concentration-dependent relaxation of the canine trachealis that was accompanied by a concentration-related increase in cGMP content. In time course studies, relaxation of isolated trachealis strips induced by 30 microM SNP was paralleled by an increase in cGMP that reached a maximum of 18-fold above basal levels within 2 min. Zaprinast, an inhibitor of the cGMP-specific phosphodiesterase, potentiated both SNP-induced relaxation and cGMP accumulation. A cell-permeable analog of cGMP, 8-bromo-cGMP, mimicked the relaxant effects of SNP. Also assessed were the effects of methylene blue, an agent that inhibits soluble guanylate cyclase activity, and hemoglobin, an agent that competitively binds NO-containing compounds. In these experiments, tissues were pretreated with the above agents for 10 min, contracted with 1 or 3 microM methacholine, and then relaxed by the cumulative addition of SNP or two other NVDs, S-nitroso-N-acetyl-penicillamine (SNAP) and glyceryl trinitrate (GTN). Tissues were flash-frozen after adding the final concentration of the various NVDs and assayed for cGMP. Methylene blue and hemoglobin suppressed both cGMP accumulation and relaxation in response to SNAP and GTN. in contrast, methylene blue and hemoglobin inhibited SNP-induced cGMP accumulation but, paradoxically, potentiated SNP-induced relaxation. The results of this study generally support a role for cGMP in NVD-induced relaxation of airway smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Division of Pharmacological Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
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D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004357:Drug Synergism; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006454:Hemoglobins / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D013997:Time Factors; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D006454:Hemoglobins; D011688:Purinones; D014665:Vasodilator Agents; D009599:Nitroprusside; C016276:8-bromocyclic GMP; D026423:S-Nitroso-N-Acetylpenicillamine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D010396:Penicillamine; C011145:zaprinast; D006152:Cyclic GMP; D007545:Isoproterenol; D008751:Methylene Blue