DISCOVERY OF NOVEL SELECTIVE HYPOTENSIVE VASOPRESSIN PEPTIDES THAT EXHIBIT LITTLE OR NO FUNCTIONAL INTERACTIONS WITH KNOWN OXYTOCIN VASOPRESSIN RECEPTORS/

1 Arginine-vasopressin (VP) has both vasoconstricting and vasodilating action. We report here the discovery of four novel selective hypotens ive VP analogues: d(CH2)(5)[D-Tyr(Et)(2),Arg(3),Val(4)]AVP; d(CH2)(5)[ D-Tyr(Et)(2), Lys(3),Val(4)]AVP and their iodinatable Tyr-NH29 analogu es. 2 Bioassays in rats for activities characteristic of neurohypophys ial peptides showed that the four VP peptides possessed little or no V -1a, V-2 or oxytocin (OT) receptor agonistic or antagonistic activitie s. 3 In anaesthetized rats, these peptides (0.05 - 0.10 mg kg(-1) i.v. ) elicited a marked fall in arterial blood pressure. 4 Blockade of cho linoceptors, adrenoceptors and bradykinin B-2 receptors, and inhibitio n of prostaglandin synthesis had little effect on their vasodepressor action. 5 Classical V-1a, V-2 and OT receptor antagonists did not bloc k the vasodepressor response. 6 L-NAME, 0.2 mg kg(-1) min(-1), markedl y suppressed the hypotensive response to ACh but not the vasodepressor response to the hypotensive VP peptides. However, the duration of the vasodepressor response was shortened. Very high doses of L-NAME atten uated both the vasodepressor response and the duration of action. 7 Th ese findings indicate that the vasodepressor action of these VP peptid es is independent of the peripheral autonomic, bradykinin and PG syste ms and is not mediated by the known classical OT/VP receptors. NO does not appear to have an important role in their vasodepressor action. 8 The discovery of these novel VP peptides could lead to the developmen t of new tools for the investigation of the complex cardiovascular act ions of VP and the introduction of a new class of hypotensive agents. The two iodinatable hypotensive VP peptides could be radiolabelled as potential markers for the localization of the receptor system involved .