Novokinin

A Study of the Relaxed Mechanisms Induced by Novokinin in the Isolated Porcine Coronary Artery Ring Segments.[Pubmed:26392269]

Protein Pept Lett. 2015;22(12):1083-8.

Novokinin is a vasorelaxing peptide designed according to the structure of ovokinin(2-7) that is released from ovalbumin by chymotryptic digestion. It has attracted much attention due to its variety of pharmacological and biological characteristics. The purpose of this research was to judge the effect and the mechanism of Novokinin on porcine coronary arteries. The isometrical tension of coronary arterial rings getted from porcine hearts was measured and its reaction to Novokinin (10(-12)-10(-5) mol/L) was observed. It was found that Novokinin inhibited the vasocontractivity to KCl and CaCl2 and evidently decreased the isomeric tensile force of both quiescent and prostaglandin F2alpha (PGF2alpha) precontracted porcine coronary arterial ring segments. This relaxing effect of Novokinin on porcine coronary arteries was apparently cutted down by getting rid of endothelium, and by the addition of methylene blue, N-nitro-L-arginine (L-NNA) or indomethacin, but not by propranolol. Novokini also inhibited the KCl- and CaCl2-induced vasocontraction. The experimental results show that relaxed effect of Novokinin on porcine coronary arteries might relate to the function of nitric oxide (NO), cyclic guanosine monophosphate (cGMP) and the synthesis of prostaglandin, but not involve adrenergic beta-receptor.

The pharmacological effects of novokinin; a designed peptide agonist of the angiotensin AT2 receptor.[Pubmed:23176213]

Curr Pharm Des. 2013;19(17):3009-12.

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.

The effects of novokinin, an AT2 agonist, on blood pressure, vascular responses, and levels of ADMA, NADPH oxidase, and Rho kinase in hypertension induced by NOS inhibition and salt.[Pubmed:27513432]

Turk J Med Sci. 2016 Jun 23;46(4):1249-57.

BACKGROUND/AIM: The effects of AT2 receptor agonist Novokinin on blood pressure, eNOS, NADPH oxidase, protein arginine methyltransferases (PRMTs), and Rho kinase in hypertension were investigated. Furthermore, in isolated thoracic aorta rings, contractile and dilator responses were studied. MATERIALS AND METHODS: To develop hypertension, L-NAME was administered intraperitoneally and salt was given with tap water (1%) for 4 weeks. Novokinin was administered intraperitoneally for the last 2 weeks. Blood pressures were measured using the tail-cuff method and enzyme levels by real-time polymerase chain reaction in aortic tissues. RESULTS: Blood pressure increased significantly in hypertensive rats. Novokinin reduced the blood pressure in the hypertensive group. While the contractile responses to increasing doses of angiotensin II were increased, vascular reactivity (Emax) and sensitivity (EC50) to acetylcholine were decreased in hypertensive rats. In Novokinin-treated hypertensive groups, the EC50 value decreased and the Emax value for acetylcholine significantly increased. The levels of Rho kinase and PRMT expression increased and the level of eNOS expression decreased in the hypertensive group. In Novokinin-treated rats, ADMA, NADPH oxidase, and Rho kinase tended to decreased, but these changes did not reach statistical significance. CONCLUSION: Although further studies are needed to determine its effectiveness, the AT2 agonist Novokinin may be a novel agent that is promising in terms of protective effects for the treatment of hypertension.

Novokinin inhibits gastric acid secretion and protects against alcohol-induced gastric injury in rats.[Pubmed:27814789]

Alcohol. 2016 Nov;56:1-8.

Novokinin (Arg-Pro-Leu-Lys-Pro-Trp), a potent vasorelaxing and hypotensive peptide modified from ovokinin, exhibits highly selective affinity for the AT2 receptor. However, its role in gastrointestinal functions is still not fully understood. In this study, we found that Novokinin inhibited basal gastric acid secretion and protected gastric mucosa from alcohol-induced injury in a dose-related manner in rats after intracerebroventricular (i.c.v.) administration. Novokinin significantly decreased basal gastric acid output at the dose of 50 and 100 nmol/rat. The effect of Novokinin on gastric acid secretion was reversed by central injection of PD 123319 (10 nmol/rat), an AT2 receptor antagonist, and peripheral injection of indomethacin (10 mg/kg), an inhibitor of prostaglandin synthesis. Meanwhile, pre-treatment with Novokinin at doses of 10, 50, and 100 nmol/rat significantly reduced the alcohol-induced gastric mucosal injury compared to the ulcer-control group, which was inhibited by indomethacin (10 mg/kg). The result showed a remarkable increase in the level of prostaglandin E2 (PGE2), glutathione (GSH), and a decrease in malondialdehyde (MDA) after i.c.v. administration of Novokinin. These findings suggest that the inhibitory effect of Novokinin on gastric acid secretion is probably mediated via an AT2 receptor-prostaglandins (PGs) pathway. The gastroprotective effect of Novokinin might be attributed to the inhibition of acid secretion, the cytoprotection of PGs, and the antioxidant property.

Orally administered novokinin, an angiotensin AT2 receptor agonist, suppresses food intake via prostaglandin E2-dependent mechanism in mice.[Pubmed:19463743]

Peptides. 2009 Jun;30(6):1105-8.

Novokinin (Arg-Pro-Leu-Lys-Pro-Trp), having affinity for the AT(2) receptor, is a potent vasorelaxing and hypotensive peptide designed based on the structure of ovokinin(2-7), a bioactive peptide derived from ovalbumin. Here we show that intracerebroventricularly (i.c.v.) administered Novokinin dose-dependently suppresses food intake at a dose of 30-100 nmol/mouse in fasted conscious mice. Orally administered Novokinin (30-100mg/kg) also suppressed food intake. Novokinin suppressed food intake in wild-type and AT(1) receptor-knockout mice but not in AT(2) receptor-knockout mice after i.c.v. or oral administration. Novokinin-induced anorexigenic activity after i.c.v. administration was blocked by indomethacin, a cyclooxygenase inhibitor, or ONO-AE3-208, an antagonist for EP(4) receptor for PGE(2). Taken together, Novokinin may suppress food intake via activation of PGE(2)-EP(4), downstream of the AT(2) receptor.

A potent hypotensive peptide, novokinin, induces relaxation by AT2- and IP-receptor-dependent mechanism in the mesenteric artery from SHRs.[Pubmed:18175894]

Biosci Biotechnol Biochem. 2008 Jan;72(1):257-9.

In this study, we found that Novokinin (Arg-Pro-Leu-Lys-Pro-Trp), a potent hypotensive peptide acting through the AT(2) receptor, has vasorelaxing activity in the mesenteric artery isolated from spontaneously hypertensive rats. The vasorelaxing activity was significantly blocked by PD123319, indomethacin, and CAY10441, which are an AT(2) receptor antagonist, a cyclooxygenase inhibitor, and an IP receptor antagonist, respectively. N(G)-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, did not block the vasorelaxing activity. These results suggest that the vasorelaxing activity of Novokinin, which contributes to the hypotensive effect, is mainly mediated by prostaglandin I(2) (prostacyclin) and the IP receptor downstream of the AT(2) receptor.

Hypotensive activity of novokinin, a potent analogue of ovokinin(2-7), is mediated by angiotensin AT(2) receptor and prostaglandin IP receptor.[Pubmed:18207609]

Peptides. 2008 Mar;29(3):412-8.

Novokinin (Arg-Pro-Leu-Lys-Pro-Trp) is a potent hypotensive peptide previously designed based on the structure of ovokinin(2-7) (Arg-Ala-Asp-His-Pro-Phe), a vasorelaxing and hypotensive peptide derived from ovalbumin. Novokinin exhibited an affinity for the angiotensin AT(2) receptor (Ki=7.35 microM). Novokinin significantly lowered systolic blood pressure at a dose of 0.03 and 0.1 mg/kg after intravenous and oral administration, respectively, in spontaneously hypertensive rats (SHRs), and the hypotensive activity was blocked by PD123319, an antagonist of the AT(2) receptor. Novokinin lowered blood pressure in C57BL/6J mice after oral administration at a dose of 50 mg/kg. However, in AT(2) receptor-deficient mice, Novokinin did not reduce blood pressure. These results demonstrate that the hypotensive activity of Novokinin is mediated by the AT(2) receptor. The hypotensive activity of Novokinin in SHRs was completely blocked by indomethacin and CAY10441, an inhibitor of cyclooxygenase and an antagonist of the prostaglandin IP receptor, respectively. These suggest that the hypotensive activity is mediated by prostacyclin and the IP receptor downstream of the AT(2) receptor.