Endothelium-derived relaxing factors contribute to smooth muscle relaxation. The aim of the present study was to investigate the contribution of nitric oxide (NO) produced in the endothelial cells to the vasodilatation stimulated with forskolin in rat aorta. Forskolin that directly activates adenylyl-cyclase, induced complete relaxation in phenylephrine-contracted aortas. Endothelium removal reduced the potency (pEC<sub>50</sub>) of forskolin without changes in the maximum effect (Emax). However, the inhibitor of endothelial NO-synthase (10 μM L- NG-Nitroarginine, L-NNA) reduced both Emax and pEC<sub>50</sub> in intact endothelium aortic rings. L-NNA or L-NNA plus cyclooxygenase inhibitor indomethacin (10 μM) reduced both Emax and pEC<sub>50</sub> of forskolin. Forskolin increased both the cytosolic Ca<sup>+2</sup> concentration and the cytosolic NO concentration ([NO]c) in the endothelial cells. The PKA inhibitor KT5720 reduced the NO production activated by forskolin in the endothelial cells. The enhanced [NO]c in the endothelial cells increased cyclic guanosine-monophosphate (cGMP) in smooth muscle cells, which was abolished by L-NNA. Taken together, our results indicate that vasodilatation mediated by forskolin in rat aortic rings is potentiated by NO production in endothelial cells that increases the cGMP levels in the smooth muscle cells that along with cAMP contribute to the vasodilatation.
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