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(CH 2 ) 5 [D‐Tyr(Et) 2 ,Arg 3 ,Val 4 ]AVP; d(CH 2 ) 5 [D‐Tyr(Et) 2 ,Lys 3 ,Val 4 ]AVP and their iodinatable Tyr‐NH 2 9 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.British Journal of Pharmacology (1998) 125 , 803–811; doi: 10.1038/sj.bjp.0702114