The Pharmacological Effects of Novokinin; a Designed Peptide Agonist of the Angiotensin AT2 Receptor

Masaaki      Yoshikawa; Kousaku      Ohinata; Yuko      Yamada

doi:10.2174/1381612811319170006

Abstract

Novokinin (RPLKPW) was designed based on ovokinin (FRADHPFL), a vasorelaxing peptide derived from ovalbumin. Novokinin relaxed a mesenteric artery isolated from the spontaneously hypertensive rat (SHR) at 10^-5 M, and reduced SHR blood pressure at a dose of 0.1 mg/kg (po.) emulsified in 30% egg yolk. Novokinin exhibited an affinity for the AT₂ receptor (Ki = 7 x 10^-6M), and its antihypertensive and vasorelaxing activities were blocked by PD123319, an AT₂ receptor antagonist. The hypotensive effect of novokinin in normotensive mice was not observed in the AT₂ receptor-knockout mice. Its antihypertensive and vasorelaxing activities in SHR were also blocked by CAY-10441, an antagonist of the IP receptor for prostaglandin I₂ (PGI₂) suggesting that these activities are mediated by the AT₂ receptor, followed by the prostaglandin I₂-IP receptor pathway.

Novokinin suppressed food intake after icv. or po. administration in mice. The anorexigenic activity was not observed in the AT₂ receptor- knockout mice, but was observed in the AT₁ receptor-knockout mice. The anorexigenic activities of novokinin and angiotensin II were blocked by PD123319, and ONO-AE3-208, an antagonist of the EP₄ receptor suggesting that the anorexigenic activities of the AT₂ agonists are mediated by the PGE₂-EP₄ receptor pathway downstream of the AT₂ receptor.

Novokinin given icv. in mice antagonized the antinociceptive effect of morphine. The antiopiod activites of novokinin and angiotensin II were are blocked by PD123319, and by ONO-AE3-240, an antagonist of the EP₃ receptor, suggesting that the antiopioid activities of AT₂ agonists is mediated by the PGE₂-EP₃ receptor downstream of the AT₂ receptor.

Keywords: Angiotensin, AT₂ receptor, novokinin, compound 21, prostaglandin, vasorelaxation, opioid, food intake