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.

Prostaglandin E2sequentially activates E‐prostanoid receptor‐3 and thromboxane prostanoid receptor to evoke contraction and increase in resistance of the mouse renal vasculature

“…The fact that a higher concentration of PGE 2 did not cause a further increase of flow (as against that to 0.3 μM PGE 2 ) in perfused TP −/− /EP3 −/− kidneys suggests that the dilator effect of PGE 2 also peaks at a concentration similar to that of its action on EP3. As a result, the ability of EP3's activity to overcome the concurrent dilator effect explains why in some vessels PGE 2 evokes relaxation at low concentrations, 18,25 whereas in mouse renal arteries (where EP3 has a strong function) it evokes contraction from ≤0.001 μM. 20 Previously, PGE 2 has been reported to evoke contraction of rat interlobular renal arteries or to increase Ang II-evoked contraction of rat afferent arteriole; however, in these prior F I G U R E 7 Effects of TP −/− and/or EP3 −/− on expressions or functions of undeleted EPs and TP.…”

“…19,20 A question thus arises whether the above-mentioned increase of in vivo depressor or renal vasodilator response results from a loss of the direct vasoconstrictor activity of EP3 activated by PGE 2 . In addition, although commonly considered a vasodilator in the renal circulation, [21][22][23][24][25][26] PGE 2 is found to evoke a direct contraction of rat interlobular renal arteries or to increase the Ang II-evoked contraction of rat afferent arteriole. 27,28 A chronic infusion of PGE 2 into dog kidneys has been reported to cause hypertension.…”

Low serum selenium concentration is associated with preeclampsia in pregnant women from Bangladesh

“…Thromboxane is a potent vasoconstrictor and stimulator of platelet aggregation, whereas prostacyclin inhibitsplatelet aggregation.An imbalance between thromboxane and prostacyclin causes increased blood pressure [10,11].Peroxynitrite is a potential oxidizing and nitrating agent produced in vivo from superoxide and nitric oxide in endothelium [12]. It is produced at significantly higher rate in preeclampsia patients than the healthy pregnant women [13] and being potential oxidizing and nitrating agent, peroxynitrite causes vasoconstriction, platelet aggregation and thrombus formation [8].…”

P/Q‐type and T‐type voltage‐gated calcium channels are involved in the contraction of mammary and brain blood vessels from hypertensive patients

“…Increasing concentrations of KCl induce depolarization of vascular smooth muscle cell leading to a concentration‐dependent contraction of human internal mammary arteries with an EC70 of 29 mmol L −1 in agreement with previous published results (Eskildsen et al . ). The application of KCl (40 mmol L −1 ) induced a contraction that was affected by ω ‐agatoxin IVA with variable effect between individual patients with variations from 60% inhibition of the contraction to potentiation of the contraction induced by potassium (Fig.…”