Effects of cyclic GMP and analogues on neurogenic transmission in the rat tail artery.
1. The effects of membrane permeable analogues of guanosine 3':5'-cyclic monophosphate (cyclic GMP), and of the NO donor, 3-morpholinosydnonimine-N-ethylcarbamide (SIN-1) were investigated on [3H]-noradrenaline release and neurogenic vasoconstriction in electrical field stimulated rat tail arteries. 2. Two 8-substituted analogues of cyclic GMP (8-bromoguanosine 3':5'-cyclic monophosphate; 8-bromo-cyclic GMP and 8-(4-chlorophenylthio)-guanosine 3':5'-cyclic monophosphate; 8-pCPT-cyclic GMP) concentration-dependently enhanced stimulation-induced [3H]-noradrenaline release. These prejunctional effects were antagonized by the cyclic AMP-dependent protein kinase (PKA) inhibitor N-[2-((3-(4-bromophenyl)-2-propenyl)-amino)-ethyl]-5 isoquinolinesulphonamide dihydrochloride (H-89; 100 nM) but not by the cyclic GMP-dependent protein kinase (PKG) inhibitors, Rp-8-bromoguanosine 3':5'-cyclic monophosphorothioate (Rp-8-bromo-cyclic GMPS; 10 microM) or Rp-8-(4-chlorophenylthio)-guanosine 3':5'-cyclic monophosphorothioate (Rp-8-pCPT-cyclic GMPS; 10 microM). 3. beta-Phenyl-1,N2-ethenoguanosine 3':5'-cyclic monophosphate (PET-cyclic GMP) had no effect on stimulation-induced [3H]-noradrenaline release but concentration-dependently decreased the stimulation-induced vasoconstriction. 4. The two 8-substituted cyclic GMP derivatives, PET-cyclic GMP and SIN-1, both decreased stimulation-induced vasoconstriction. In addition, SIN-1 relaxed rat tail arteries precontracted with phenylephrine (1 microM). The SIN-1 concentration-relaxation curve was shifted in parallel manner to the right by Rp-8-bromo-cyclic GMPS (10 microM) and Rp-8-pCPT-cyclic GMPS (10 microM) with no change in the maximum effect, showing that the relaxation was mediated by a cyclic GMP/PKG-dependent mechanism. 5. It is concluded that PKA activation is involved in the noradrenaline release enhancing effect of the two 8-substituted cyclic GMP analogues, whereas a cyclic GMP/PKG-operated pathway accounts for the inhibitory effects of the cyclic GMP and its analogues on vascular smooth muscle contraction.
Ouedraogo
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Laboratoire de Pharmacologie Cellulaire et Moléculaire, C.N.R.S., URA 600, Université Louis Pasteur Strasbourg, Illkirch, France.
Tschöpl
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Stoclet
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JC
Bucher
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B
D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000294:innervation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects*; D013623:Tail / Q000098:blood supply / Q000294:innervation; D014661:Vasoconstriction / Q000187:drug effects
D010656:Phenylephrine; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D009638:Norepinephrine