Effect of cGMP inhibitors on the actions of nitrodilators in rat aorta.
1. The involvement of cGMP in vasodilatation produced by a range of nitrodilators was investigated using two different protein kinase G inhibitors, R(p) 8-bromoguanosine-3'5'-cyclic monophosphothioate (RBrcGMPS) and KT 5823. 2. The nitric oxide donors sodium nitroprusside (SNP), glyceryltrinitrate (GTN) and s-nitroso-acetylpenicillamine (SNAP), the endothelium-dependent vasodilator acetylcholine (ACh) as well as the cGMP analogues 8-(4-chlorophenylthio)-cGMP(CPTcGMP) and beta-phenyl-1-N2-etheno-8-bromo-cGMP (PETcGMP) all relaxed rat aortic rings preconstricted with phenylephrine (0.1 micromol/L). 3. The protein kinase G inhibitor KT 5823 (10 micromol/L) produced a very small inhibition of the vasodilatation produced by GTN, but had no effect against vasodilatation produced by SNP, CPTcGMP or PETcGMP, which suggests that KT 5823 is not a useful tool in this system. 4. In contrast, RBrcGMPS (0.5 mmol/L) produced a rightward shift of the concentration-response curves to SNP, CPTcGMP and PETcGMP. RBrcGMPS (0.5 mmol/L) also completely abolished vasodilatation to ACh and GTN but, surprisingly, had no effect on vasodilatation produced by SNAP. 5. The guanylate cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 and 10 micromol/L) completely inhibited the relaxation produced by GTN, whereas SNAP still had an appreciable relaxant effect after ODQ (1 micromol/L). 6. The differential effect of RBrcGMPS and ODQ on the nitrodilators suggests that there are differences in the mechanism of dilatation between the nitrodilators.
van der Zypp
A
A
Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia. andrea.van.zypp@med.monash.edu.au
Majewski
H
H
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006165:Guanylyl Imidodiphosphate / Q000037:antagonists & inhibitors; D007211:Indoles; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013873:Thionucleotides; D014665:Vasodilator Agents / Q000494:pharmacology*
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D013873:Thionucleotides; D014665:Vasodilator Agents; C073601:KT 5823; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; D009599:Nitroprusside; D006165:Guanylyl Imidodiphosphate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP