Abstract P473: Group IV Cytosolic Phospholipase A2α is Critical for Norepinephrine-Induced Hypertension

Abstract

Previously we reported that angiotensin (Ang) II-induced hypertension and associated cardiovascular and renal dysfunction are mediated by cytosolic phospholipase A 2 α (cPLA 2 α) activation, the release of arachidonic acid (AA), and production of eicosanoids predominantly with pro-hypertensive effects ( Hypertension. 2015; 65: 784-792; 2016; 29: 258-265 ). We have also shown that norepinephrine (NE) by activating cPLA 2 releases AA, and production of prostanoids in vascular smooth muscle cells ( J Biol Chem. 1996; 217:30149-30157; J. Pharmacol. Exp. Ther. 1993; 266: 1113–1124 ). This study was conducted to determine the contribution of cPLA 2 α in NE-induced hypertension. Eight weeks old male wild-type (cPLA 2 α +/+ ) and cPLA 2 α gene disrupted (cPLA 2 α -/- ) mice were infused with NE (10 mg/kg/day, s.c.) or its vehicle using mini-osmotic pumps for 2 weeks, and the systolic blood pressure (SBP) was measured by tail-cuff. Infusion of NE increased the SBP in cPLA 2 α +/+ mice (148±3 vs. 118±3 mmHg, P<0.05, n=4-5); but not in cPLA 2 α -/- mice (122±5 mmHg, n=5). The NE-induced increase in SBP was minimized by treatment with AA metabolism inhibitor, 5,8,11,14-eicosatetraynoic acid (ETYA) (25 mg/kg, i.p., every 3 rd day) in cPLA 2 α +/+ mice (125±5 vs. 148±3 mmHg, P<0.05, n=4-5). Prostaglandin (PG) E2-EP1 and EP3 receptor activation that increase blood pressure have been implicated in Ang II-induced hypertension. In our study antagonists of the EP3 receptor (L-798106) (10 mg/kg, i.p. every 3 rd day) decreased the NE-induced increase in SBP (130±5 vs. 148±3 mmHg, P<0.05, n=5/group). These data suggest that cPLA 2 α contributes to NE-induced increase in SBP via cPLA 2 α activation, the release of AA and generation of eicosanoids, most likely PGE2 that exerts pro-hypertensive effects by stimulating EP3 receptors. Therefore, the development of agents that selectively inhibit the cPLA 2 α activity or block EP3 receptors could be useful in treating hypertension and its pathogenesis.