The pharmacological effects of novokinin; a designed peptide agonist of the angiotensin AT2 receptor

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=7x10(-6) M, 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 AT 1 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 PGE 2-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.