ENDOTHELINS INDUCE PROSTACYCLIN RELEASE IN BOTH VASCULAR AND NONVASCULAR TISSUE

The effects of an i.v. administration of endothelin-1, -2 and -3 (0.25 - 3 nmol kg(-1)) or their corresponding proendothelins (1 - 20 nmol k g(-1)) on blood pressure and 6 keto-prostaglandin F-1 alpha (6 keto-PG F(1 alpha)) release in the anaesthetized ganglion-blocked rat were eva luated. The same peptides were tested for their ability to release 6 k eto-PGF(1 alpha) from the rat vas deferens in vitro. Endothelins and p roendothelins showed a transient hypotensive effect followed by a pote nt, long lasting vasopressor response. Blood pressure increase induced by endothelins was found to be dose-dependently correlated with 6 ket o-PGF(1 alpha) plasma level increases. On the other hand proendothelin s produced similar presser responses, but their effect on 6 keto-PGF(1 alpha) plasma levels was much less intense at equipressor doses. The effects of endothelins on arterial pressure and 6 keto-PGF(1 alpha) re lease were phosphoramidon-insensitive, while the activities of proendo thelins were reduced by phosphoramidon (10 mg kg(-1) i.v.). Both endot helins (5 - 15 nmol/l) and proendothelins (100 - 300 nmol/l) were able to increase to a similar extent 6 keto-PGF(1 alpha) levels in the rat vas deferens incubation buffer. The releasing activity of endothelins was not modified by the pretreatment with phosphoramidon (50 mu mol/l ). This pretreatment strongly inhibited proendothelin-1 and -2 effects , but not that of proendothelin-3. In conclusion, the results presente d in this study indicate that all tested peptides induce 6 keto-PGF(1 alpha) release in both vascular and non vascular tissue; all three pro endothelins are activated by the same phosphoramidon-sensitive endothe lin converting enzyme in our in vivo model, while proendothelin-3 may be processed by a different enzyme(s) in the rat vas deferens, in vitr o. They also suggest a different localization of the sites where the p eptides are activated and/or exert presser activity and the sites wher e they induce 6 keto-PGF(1 alpha) release. Finally, prostacyclin relea se could have a general counter-regulatory activity on effects of endo thelin peptides.