Prostaglandin I 2 and Prostaglandin E 2 Modulate Human Intrarenal Artery Contractility Through Prostaglandin E2-EP4, Prostacyclin-IP, and Thromboxane A2-TP Receptors

Abstract

Cyclooxygenase inhibitors decrease renal blood flow in settings with decreased effective circulating volume. The present study examined the hypothesis that prostaglandins, prostaglandin E 2 (PGE 2 ) and prostacyclin (PGI 2 ), induce relaxation of human intrarenal arteries through PGE 2 -EP and PGI 2 -IP receptors. Intrarenal arteries were microdissected from human nephrectomy samples (n=53, median diameter ≈362 μm, 88% viable, 76% relaxed in response to acetylcholine). Rings were suspended in myographs to record force development. In vessels with K + -induced tension (EC 70 : –log [mol/L]=1.36±0.03), PGE 2 and PGI 2 induced concentration-dependent relaxation (–log EC 50 : PGE 2 =7.1±0.3 and PGI 2 =7.7). The response to PGE 2 displayed endothelium dependence and desensitization. Relaxation by PGE 2 was mimicked by an EP4 receptor agonist (CAY10598, EC 50 =6.7±0.2). The relaxation after PGI 2 was abolished by an IP receptor antagonist (BR5064, 10 –8 mol/L). Pretreatment of quiescent arteries with PGE 2 for 5 minutes (10 –6 mol/L) led to a significant right shift of the concentration–response to norepinephrine (EC 50 from 6.6±0.1–5.9±0.1). In intrarenal arteries with K + -induced tone, PGE 2 and PGI 2 at 10 –5 mol/L elicited increased tension. This was abolished by thromboxane receptor (TP) antagonist (S18886, 10 –6 mol/L). A TP agonist (U46619, n=6) evoked tension (EC 50 =8.1±0.2) that was inhibited by S18886. Polymerase chain reaction and immunoblotting showed EP4, IP, and TP receptors in intrarenal arteries. In conclusion, PGE 2 and PGI 2 may protect renal perfusion by activating cognate IP and EP4 receptors associated with smooth muscle cells and endothelium in human intrarenal arteries and contribute to increased renal vascular resistance at high pathological concentrations mediated by noncognate TP receptor.