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 hypotensive 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 analogues. 2 Bioassays in rats for activities characteristic of neurohypophysial peptides showed that the four VP peptides possessed little or no V-1a, V-2 or oxytocin (OT) receptor agonistic or antagonistic activities. 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 cholinoceptors, adrenoceptors and bradykinin B-2 receptors, and inhibition of prostaglandin synthesis had little effect on their vasodepressor action. 5 Classical V-1a, V-2 and OT receptor antagonists did not block the vasodepressor response. 6 L-NAME, 0.2 mg kg(-1) min(-1), markedly 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 attenuated both the vasodepressor response and the duration of action. 7 These findings indicate that the vasodepressor action of these VP peptides is independent of the peripheral autonomic, bradykinin and PG systems 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 development of new tools for the investigation of the complex cardiovascular actions 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.