Endothelins induce prostacyclin release in both vascular and non-vascular tissue

The effects of an iv. administration of endothelin-1, –2 and –3 (0.25–3 nmol kg^–1) or their corresponding proendothelins (1–20 nmol kg^–1) on blood pressure and 6 keto-prostaglandin F₁ (6 keto-PGF₁) release in the anaesthetized ganglion-blocked rat were evaluated. The same peptides were tested for their ability to release 6 keto-PGF_1a from the rat vas deferens in vitro. Endothelins and proendothelins showed a transient hypotensive effect followed by a potent, long lasting vasopressor response. Blood pressure increase induced by endothelins was found to be dose-dependently correlated with 6 keto-PGF₁ plasma level increases. On the other hand proendothelins produced similar pressor responses, but their effect on 6 keto-PGF₁ plasma levels was much less intense at equipressor doses. The effects of endothelins on arterial pressure and 6 keto-PGF₁ release were phosphoramidon-insensitive, while the activities of proendothelins were reduced by phosphoramidon (10 mg kg^–1 i.v.). Both endothelins (5–15 nmol/l) and proendothelins (100–300 nmol/l) were able to increase to a similar extent 6 keto-PGF₁ levels in the rat vas deferens incubation buffer. The releasing activity of endothelins was not modified by the pretreatment with phosphoramidon (50 mol/l). This pretreatment strongly inhibited proendothelin-1 and –2 effects, but not that of proendothelin-3. In conclusion, the results presented in this study indicate that all tested peptides induce 6 keto-PGF₁ release in both vascular and non vascular tissue; all three proendothelins are activated by the same phosphoramidon-sensitive endothelin converting enzyme in our in vivo model, while proendothelin-3 may be processed by a different enzyme(s) in the rat vas deferens, in vitro. They also suggest a different localization of the sites where the peptides are activated and/or exert pressor activity and the sites where they induce 6 keto-PGF₁ release. Finally, prostacyclin release could have a general counter-regulatory activity on effects of endothelin peptides.Company related with A. Menarini Pharmaceuticals, Italy