8-bromocyclic-gmp and talipexole

The participation of NO production and the role of cyclic GMP in inhibitory function of endothelium were investigated in rat aortic rings exposed to alpha-adrenoceptor agonists. Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) depressed more markedly not only maximal contractions but also equipotent contractions elicited by two partial agonists (indanidine and B-HT 920) than responses to the full agonist phenylephrine. The influence of endothelium on maximal responses to the three agonists was abolished by both the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methylester (L-NAME, 30 microM) and by the guanylate cyclase inhibitor methylene blue (methylene blue, 0.3 and 1 microM). Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) increased the EC50 value of phenylephrine. This effect was more pronounced in the case of endothelium (10-fold), however, than in the case of 8-Br cyclic GMP (fourfold at 30 microM), and the rightward shift produced by endothelium remained significant (twofold) in the presence of L-NAME or methylene blue. In addition, the effect of 8-Br cyclic GMP on phenylephrine-induced contractions was considerably enhanced in the presence of endothelium or after partial alkylation of receptors by phenoxybenzamine in endothelium-denuded rings. These results indicate that the L-arginine-NO-cyclic GMP pathway accounts for most of the inhibitory influence of endothelium on alpha-adrenergic responses in aortic rings. They indicate differential effects of cyclic GMP depending on the agonist and show that 8-Br cyclic GMP does not impair the basal inhibitory effect of endothelium on aortic contraction to alpha-adrenergic agonists.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adrenergic alpha-Agonists; Animals; Aorta, Thoracic; Arginine; Azepines; Clonidine; Cyclic GMP; Endothelium, Vascular; Female; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phenylephrine; Rats; Rats, Inbred Strains

The purpose of the present study was to determine if 8-bromo cyclic guanosine monophosphate (cGMP) mimics the actions of nitroglycerin in inhibiting alpha 1- versus alpha 2-mediated constrictor responses in vitro using rings prepared from isolated canine saphenous vein. Contractions were produced by phenylephrine, a selective alpha 1-adrenoceptor agonist and B-HT 920, a selective alpha 2-adrenoceptor agonist. The inhibitory effects of nitroglycerin and 8-bromo cGMP on contractions produced by submaximal concentrations (EC75) of phenylephrine and B-HT 920 were determined. 8-Bromo cGMP like nitroglycerin produced a selective antagonism of alpha 2-adrenoceptor-mediated responses and had minimal effects on alpha 1-adrenoceptor-induced constriction. However, after removal of spare postsynaptic vascular alpha 1-adrenoceptors by treatment with the irreversible alpha-adrenoceptor antagonist phenoxybenzamine (5 X 10(-8) M, 1 X 10(-7) M), the alpha 1-adrenoceptor-mediated vasoconstrictor responses of phenylephrine became highly sensitive to antagonism by 8-bromo cGMP and nitroglycerin. These data suggest that the action of 8-bromo cGMP like nitroglycerin is 'buffered' by the presence of a large alpha 1-adrenoceptor reserve in canine saphenous vein. The similarity in the efficacy and potency of these two agents suggests that the effects of nitroglycerin in canine saphenous vein may be the result of an increase in intracellular cGMP.

Topics: Animals; Azepines; Calcium; Cyclic GMP; Dogs; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Male; Nitroglycerin; Nitroprusside; Phenylephrine; Receptors, Adrenergic, alpha; Saphenous Vein; Vasodilation