CONTRACTILE RESPONSES TO SUMATRIPTAN IN ISOLATED BOVINE PULMONARY-ARTERY RINGS - RELATIONSHIP TO TONE AND CYCLIC-NUCLEOTIDE LEVELS

We examined responses to the 5-hydroxytryptamine(1D) (5-HT1D)-receptor agonist sumatriptan in bovine pulmonary artery rings (2-3 mm ID). The effects of agonist-induced tone and agents that alter intracellular c yclic AMP [cyclic AMP](i) or [cyclic GMP](i) on responses to sumatript an were investigated, At resting tension, responses to sumatriptan wer e slight or not evident. In the presence of tone induced by U46619, re sponses to sumatriptan (1 nM-30 mM) were greatly potentiated, as were responses to the alpha(2)-adrenoceptor agonist UK14304, Responses to t he alpha(1)-adrenoceptor agonist phenylephrine (PE) were potentiated o nly slightly. In the presence of U46619, addition of the adenylyl cycl ase activator, forskolin (1 nM-0.1 mu M) or isoprenaline (ISO 1 mu M) induced relaxations and increases in [cyclic AMP](i) and resulted in f urther potentiation of the contractile response to sumatriptan. Additi on of 0.1 mu M sodium nitroprusside (SNP) inhibited sumatriptan-induce d contractions, Whereas sumatriptan alone did not significantly affect [cyclic AMP](i), in the presence of U46619 it decreased [cyclic AMP]( i). This effect of sumatriptan was further enhanced in the presence of forskolin. Sumatriptan increased [cyclic GMP](i). Using a nitric oxid e (NO) synthase inhibitor and vessels denuded of endothelium, we showe d that the increased [cyclic GMP](i) in response to sumatriptan was en dothelium-dependent and mediated by NO. This increase in [cyclic GMP]( i) was not observed in the presence of U46619. By measuring cyclic AMP and cyclic GMP phosphodiesterase (PDE) levels, we demonstrated that t he point of ''cross-talk'' between cyclic nucleotides may not be at th e level of total PDE activity. These results highlight the important r ole of [cyclic AMP](i), [cyclic GMP](i), and endothelium function in t he control of 5-HT1D receptor-mediated vasoconstriction, which is depe ndent on a decrease in [cyclic AMP](i) in the absence of an increase i n [cyclic GMP](i).