Heterogeneity of the mechanisms underlying activation of adenylate cyclase by endothelin-1 in rabbit and bovine iris sphincter and tracheal smooth muscles

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In the bovine and rabbit iris sphincters and tracheas, endothelin-1 (ET-1) activated adenylate cyclase (AC) in a concentration-dependent manner. The rate of cAMP formation decreased in the order, bovine iris sphincter > rabbit trachea >> rabbit iris sphincter >> bovine trachea. Maximal values for AC activation in bovine iris sphincter and rabbit trachea were 398% and 392% of basal activity respectively. Pretreatment with indomethacin (1 μM), a cyclooxygenase inhibitor, virtually abolished the increase by ET-1 of cAMP levels in rabbit trachea and bovine trachea and bovine trachea (96% reduction). In the rabbit iris sphincter, indomethacin and nordihydroguairetic acid (NDGA) (1 μM), a lipoxygenase inhibitor, brought about 60 and 28% reduction of ET-1 response, respectively. Co-treatment with both eicosanoid inhibitors (1 μM, each) eliminated the ET-1-evoked cAMP formation. Quinacrine (50 μM), a phospholipase A2 (PLA2) inhibitor, attenuated cAMP production by ET-1 at a less prominent rate than that of indomethacin (38 to 70% reduction in cAMP increments). At odds, in the bovine iris sphincter, the cAMP response was unaltered by all prostanoid inhibitors. Moreover, challenge with nicardipine-a Ca2+ channel blocker, trifluoperazine-a calmodulin inhibitor, a staurosporine-a PKC inhibitor, had no significant effect on the responsiveness to ET-1, suggesting lack of mediators in the coupling of ET-receptors to AC system, in the bovine iris sphincter. In conclusion, activation of AC by ET-1 may represent a widespread phenomenon in smooth muscles. The mechanism whereby ET-1 elicits cAMP production is diverse and may include eicosanoids both from cyclooxygenase and lipoxygenase origins as mediators.

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