Effects of SQ 22536, an adenylyl cyclase inhibitor, on isoproterenol-induced cyclic AMP elevation and relaxation in newborn ovine pulmonary veins

Abstract

The effects of inhibition of adenylyl cyclase on isoproterenol-induced relaxation were determined in isolated pulmonary veins of newborn lambs (7–12 days old). In veins constricted with endothelin-1, isoproterenol at concentrations ≤3×10 −9 M had no effect on the cyclic AMP (cAMP) content but caused up to 56% relaxation. At higher concentrations (≥10 −8 M), isoproterenol elevated cAMP content and caused further relaxation. In veins constricted with endothelin-1 or U46619 (9,11-dideoxy-11, 9-epoxymethanoprostaglandin prostaglandin F2α), the cAMP elevation but not relaxation caused by isoproterenol was abolished by SQ 22536 [9-(tetrahydro-2-furanyl)-9 H-purin-6-amine; an adenylyl cyclase inhibitor]. The effects of isoproterenol on vessel tension and cAMP content were inhibited by propranolol. Rp-8-CPT-cAMPS [8-(4-Chlorophenylthio)-adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer] and Rp-8-Br-PET-cGMPS [β-phenyl-1, N 2-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothioate, Rp-isomer], inhibitors of cAMP- and guanosine-3′,5′-cyclic monophosphate (cGMP)-dependent protein kinases, respectively, attenuated relaxation caused by a cAMP analog but not that by isoproterenol. In the crude membrane preparations of pulmonary veins, an increase in the activity of adenylyl cyclase caused by isoproterenol was abolished by propranolol and SQ 22536. These results suggest that cAMP may not play a critical role in isoproterenol-induced relaxation of pulmonary veins of newborn lambs.