Comparison of two soluble guanylyl cyclase inhibitors, methylene blue and ODQ, on sodium nitroprusside-induced relaxation in guinea-pig trachea.
To clarify further the role of cyclic GMP in mediating the relaxant response in guinea-pig trachea induced by sodium nitroprusside (SNP), the effects of soluble guanylyl cyclase inhibitors, methylene blue and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on SNP-induced muscle relaxation and cyclic GMP accumulation were determined. SNP (0.3-100 microM) evoked a concentration-dependent relaxation of guinea-pig isolated tracheas precontracted with 0.3 microM carbachol. Preincubation of the preparations with methylene blue (10, 30 and 100 microM) resulted in a slight but concentration-dependent prevention of the relaxant response to SNP. In contrast, the relaxation to SNP was extensively prevented by 3 microM ODQ and almost abolished by 10 microM ODQ. SNP (30 microM) induced a significant elevation of cyclic GMP accumulation (from 1.34+/-0.14 to 5.39+/-0.28 pmol mg(-1) protein, n= 5; P<0.001), which was partially attenuated by 100 microM methylene blue (3.11+/-0.51 pmol mg(-1) protein, n=5; P<0.05), whereas completely abolished by 10 microM ODQ (1.31+/-0.28 pmol mg(-1) protein, n = 5; P<0.001). Methylene blue, but not ODQ and Nomega-nitro-L-arginine methyl ester (L-NAME), caused a concentration-dependent contraction in the tracheal preparation. The tension produced by 100 microM methylene blue was 41.8+/-4.3% (0.3 microM carbachol as 100%; n = 12). Moreover, the non-selective muscarinic receptor antagonist atropine and the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methiodine greatly inhibited the contractile effect evoked by methylene blue (100 microM). In conclusion, this study provides substantial evidence that SNP-induced muscle relaxation in guinea-pig trachea is completely via a cyclic GMP-dependent mechanism. Furthermore, ODQ, but not methylene blue, will likely become an important tool in differentiating between cyclic GMP-dependent and -independent effects of nitric oxide.
Hwang
T L
TL
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
Wu
C C
CC
Teng
C M
CM
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors*; D006168:Guinea Pigs; D008751:Methylene Blue / Q000494:pharmacology*; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester