From the Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark (M.P.E., P.B.L.H., J.S., B.L.J.); State Key Laboratory for Pharmaceutical Biotechnologies and Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong (P.M.V.); and Departments of Urology, Biochemistry and Clinical Pathology, Odense University Hospital, Odense, Denmark (M.P.E., P.B.L.H., J.S., A.T., S.W., N.M., L.M.R.).
Hypertension. 2014 Sep;64(3):551-6. doi: 10.1161/HYPERTENSIONAHA.113.03051. Epub 2014 Jun 9.
Cyclooxygenase inhibitors decrease renal blood flow in settings with decreased effective circulating volume. The present study examined the hypothesis that prostaglandins, prostaglandin E2 (PGE2) and prostacyclin (PGI2), induce relaxation of human intrarenal arteries through PGE2-EP and PGI2-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 (EC70: -log [mol/L]=1.36±0.03), PGE2 and PGI2 induced concentration-dependent relaxation (-log EC50: PGE2=7.1±0.3 and PGI2=7.7). The response to PGE2 displayed endothelium dependence and desensitization. Relaxation by PGE2 was mimicked by an EP4 receptor agonist (CAY10598, EC50=6.7±0.2). The relaxation after PGI2 was abolished by an IP receptor antagonist (BR5064, 10(-8) mol/L). Pretreatment of quiescent arteries with PGE2 for 5 minutes (10(-6) mol/L) led to a significant right shift of the concentration-response to norepinephrine (EC50 from 6.6±0.1-5.9±0.1). In intrarenal arteries with K(+)-induced tone, PGE2 and PGI2 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 (EC50=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, PGE2 and PGI2 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.
环氧化酶抑制剂会降低有效循环血容量减少时的肾血流量。本研究旨在检验以下假设：前列腺素、前列腺素 E2（PGE2）和前列环素（PGI2）通过 PGE2-EP 和 PGI2-IP 受体诱导人肾内动脉舒张。从肾切除术样本中分离出肾内动脉（n=53，中位直径≈362μm，76%对乙酰胆碱有反应，88%存活，76%舒张）。将血管环悬挂在肌动描记器上以记录力的产生。在 K+诱导张力的血管中（EC70：-log[mol/L]=1.36±0.03），PGE2 和 PGI2 诱导浓度依赖性舒张（-log EC50：PGE2=7.1±0.3，PGI2=7.7）。PGE2 的反应具有内皮依赖性和脱敏性。PGE2 的舒张可被 EP4 受体激动剂（CAY10598，EC50=6.7±0.2）模拟。PGI2 后的舒张被 IP 受体拮抗剂（BR5064，10(-8)mol/L）阻断。用 PGE2（10(-6)mol/L）预处理 5 分钟可使去甲肾上腺素的浓度-反应曲线显著右移（EC50 从 6.6±0.1-5.9±0.1）。在 K+诱导张力的肾内动脉中，10(-5)mol/L 的 PGE2 和 PGI2 引起张力增加，这一作用被血栓素受体（TP）拮抗剂（S18886，10(-6)mol/L）阻断。TP 激动剂（U46619，n=6）引起张力（EC50=8.1±0.2），该张力被 S18886 抑制。聚合酶链反应和免疫印迹显示肾内动脉中存在 EP4、IP 和 TP 受体。结论：PGE2 和 PGI2 可能通过激活与人类肾内动脉平滑肌细胞和内皮相关的同源 IP 和 EP4 受体来保护肾灌注，并在高病理浓度下通过非同源 TP 受体介导增加肾血管阻力。
