Vascular effects of a tripeptide fragment of novokinine in hypertensive rats: Mechanism of the hypotensive action

Background: Activation of angiotensin AT(2) receptors (AT(2)R) counteracts vasoconstrictor effects of AT(1)R stimulation and contributes to blood pressure control. We examined effects on mean arterial pressure (MAP) and renal hemodynamics of LKP, a tripeptide fragment of novokinine, an established AT(2)R agonist. Methods: Effects of intravenous LKP infusion and then superimposed losartan (AT(1)R antagonist) on MAP, total renal (RBF, Transonic probe) and renal medullary blood flows (laser-Doppler), and on renal excretion, were examined in anesthetized (1) Wistar rats with acute norepinephrine-induced hypertension, untreated or pretreated with AT(2)R antagonist (PD 123319) and (2) spontaneously hypertensive rats (SHR) maintained on standard or high-sodium (HS) diet. Results: In Wistar rats LKP decreased MAP (-4%, p < 0.01) and increased renal medullary perfusion, these effects were abolished in rats pretreated with PD 123319 in which a post-LKP increase in MAP (+6%, p < 0.02) occurred. LKP did not alter MAP in SHR; in those on HS diet RBF decreased (-14%, p < 0.02), the response that was reverted by losartan. Addition of losartan always decreased or tended to decrease MAP. Conclusions: LKP lowered MAP in norepinephrine-induced hypertension, probably via activation of AT(2)R. At reduced availability of AT(2)R, as in SHR, LKP appeared to bind to different receptors, possibly AT(1), and induced systemic or renal vasoconstriction. Compared to the parent novokinine, a smaller LKP molecule might be easier absorbed after oral application and more useful in therapy. (C) 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. Z o.o. All rights reserved.