The role of prostaglandin E and thromboxane-prostanoid receptors in the response to prostaglandin E2 in the aorta of Wistar Kyoto rats and spontaneously hypertensive rats (original) (raw)
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Hypertension, 2014
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...
Hypertension, 2014
I n settings with decreased effective circulating volume and in patients with chronically reduced kidney function, renal perfusion and glomerular filtration rate are sensitive to inhibition of prostaglandin synthesis by cyclooxygenase inhibitors. 1 The detrimental effect is attributed predominantly to compromised renal perfusion. 1 An increase in endogenous angiotensin II and norepinephrine in response to extracellular volume contraction is associated with increased urinary excretion of prostaglandin E 2 (PGE 2), and infusion of angiotensin II and norepinephrine to humans leads to increased excretion of both PGE 2 and prostacyclin (PGI 2). 2,3 In experimental animals, the cyclooxygenase inhibitor ibuprofen potentiates angiotensin II-mediated renal preglomerular vasoconstriction. 4 This response is reversed by infusion of low concentrations of PGE 2 and restored paradoxically by higher doses of this prostanoid. 4,5 PGE 2 and prostacyclin elicit dilatation of renal pre-and postglomerular resistance vessels. 6-9 In rodents, the renal vasodilator response to prostaglandin E 2 is predominantly attributable to activation of EP4 receptors with a minor contribution from EP2 receptors. 4,10,11 EP4 receptors are found in rat and human preglomerular blood vessels and glomeruli. 4,11-14 Data on vascular expression of EP2 are less consistent. 11-13 Prostacyclin receptor (IP) has been detected in human preglomerular blood vessels and vasa recta. 15 Functional data on the role of prostanoid receptors and their reactivity to PGE 2 and prostacyclin in human preglomerular vasculature are not available. The present study was designed to test the hypothesis that PGE 2 and prostacyclin relax human renal preglomerular arteries through activation of prostanoid receptors (EP2/EP4/IP), which when activated lead to increased production of cAMP by adenylyl cyclase.
British Journal of Pharmacology, 2009
Background and purpose: Prostacyclin (PGI2) is usually described as an endothelium-derived vasodilator, but it can also induce vasoconstriction. We studied the vasomotor responses to PGI2 in resistance arteries and the role of thromboxane (TP) and prostaglandin E2 (EP) receptors in this effect. Experimental approach: Mesenteric resistance arteries were obtained from Sprague-Dawley rats. Vasomotion to PGI2 was studied in segments of these arteries with and without endothelium and in presence of the nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME), the potassium channel blockers apamin plus charybdotoxin, the non-selective EP receptor antagonist AH6809, the selective TP receptor antagonist SQ29548 or the EP1 receptor antagonist SC19220. PGI2induced NO release was analysed in the absence or presence of SQ29548, AH6809 or SC19220. Key results: PGI2 caused contractions in arterial segments that were increased by endothelium removal, L-NAME or L-NAME plus apamin plus charybdotoxin and abolished by SQ29548. In segments with endothelium, AH6809 or SC19220 almost abolished the contractions to PGI2; this effect was prevented by L-NAME, L-NAME plus apamin plus charybdotoxin or by endothelium removal. PGI2 induced NO release that was inhibited by the prostacyclin receptor (IP receptor) antagonist, RO1138452, and increased by SQ29548, SC19220 and AH6809. The increase in NO release induced by these separate drugs was inhibited by RO1138452. Conclusions and implications: PGI2 activated the TP receptor in mesenteric resistance arteries and produced vasoconstriction, which the endothelium modulated through TP and EP1 receptors. PGI2 also released endothelium-derived hyperpolarizing factor and, through IP receptor activation, induced NO release, which in turn, was antagonized by TP and EP1 receptor activation.
Hypertension, 2007
The present experiments were designed to test the hypothesis that prostaglandin (PG) E 2 causes vasodilatation through activation of endothelial NO synthase (eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE 2 were measured in conscious mice. Single doses of PGE 2 caused concentration-dependent relaxations during contractions to phenylephrine (EC 50 ϭ5*10 Ϫ8 mol/L). Relaxation after PGE 2 was absent in rings without endothelium and in rings from eNOS Ϫ/Ϫ mice and was abolished by N G -nitro-L-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H 1,2,4 -oxadiazolo-[4,3-a]quinoxalin-1-one. In PGE 2 -relaxed aortic rings, the cGMP content increased significantly. PGE 2 -induced relaxations were abolished by the EP4 receptor antagonist AE3-208 (10 Ϫ8 mol/L) and mimicked by an EP4 agonist (AE1-329, 10 Ϫ7 mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4 Ϫ/Ϫ mice but normal in EP2 Ϫ/Ϫ . Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10 Ϫ8 mol/L), abolished the PGE 2 -mediated relaxation. In aortic rings, PGE 2 dephosphorylated eNOS at Thr 495 . Chronically catheterized eNOS Ϫ/Ϫ mice were hypertensive (137Ϯ3.6 mm Hg, nϭ13, versus 101Ϯ3.9 mm Hg, nϭ9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE 2 compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE 2 elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr 495 resulting in guanylyl cyclase-dependent vasorelaxation and accumulation of cGMP in aortic rings. (Hypertension. 2007;50:525-530.)
British Journal of Pharmacology, 2005
In the spontaneously hypertensive rat (SHR) and aging Wistar-Kyoto rats (WKY), acetylcholine releases an endothelium-derived contracting factor (EDCF) produced by endothelial cyclooxygenase-1, which stimulates thromboxane A 2 receptors (TP receptors) on vascular smooth muscle. The purpose of the present study was to identify this EDCF by measuring changes in isometric tension and the release of various prostaglandins by acetylcholine. 2 In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H 2 , PGF 2a , PGE 2 , PGD 2 , prostacyclin (PGI 2) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619)8-isoprostane ¼ PGF 2a ¼ PGH 2 4PGE 2 ¼ PGD 2 4PGI 2). The contractions produced by PGH 2 and PGI 2 were fast and transient, mimicking endothelium-dependent contractions. PGI 2 did not relax isolated aortic rings of WKY and SHR. 3 Acetylcholine evoked the endothelium-dependent release of thromboxane A 2 , PGF 2a , PGE 2 , PGI 2 and most likely PGH 2 (PGI 2)PGF 2a XPGE 2 4TXA 2 48-isoprostane, PGD 2). Dazoxiben abolished the production of thromboxane A 2 , but did not influence the endothelium-dependent contractions to acetylcholine. 4 The release of PGI 2 was significantly larger in the aorta of SHR than in WKY, and the former was more sensitive to the contractile effect of PGI 2 than the latter. The inhibition of PGI-synthase was associated with an increase in PGH 2 spillover and the enhancement of acetylcholine-induced endothelium-dependent contractions. 5 Thus, in the aorta of SHR and aging WKY, the endothelium-dependent contractions elicited by acetylcholine most likely involve the release of PGI 2 with a concomitant contribution of PGH 2 .
British Journal of Pharmacology, 2002
The mechanism of transient contractions induced by the sarcoplasmic ± endoplasmic reticulum calcium ATPase (SERCA) blocker cyclopiazonic acid (CPA) in the presence of L-NAME was investigated in mouse aorta. 2 The contractions elicited by 10 mM CPA required an intact endothelium, were dependent upon external Ca 2+ and were prevented by 10 mM indomethacin, the inhibitor of prostaglandin synthesis, or 1 mM SQ29548, the speci®c prostaglandin H2/thromboxane A2 (PGH2/TXA2) receptor blocker. 3 A blocker of receptor/store operated Ca 2+ channels and voltage gated calcium channels (VGCC), SK&F 96365 (10 mM), completely abolished the contractions, while a speci®c blocker of VGCC nifedipine (1 mM) inhibited them by one third. 4 Dichlorobenzamyl hydrochloride, a blocker of Na + /Ca 2+ exchange eectively prevented return of tension to baseline value. 5 At higher concentrations (30 ± 100 mM) CPA induced indomethacin-resistant tonic contractions of mouse aorta. The CPA dose response curve for tonic contractions is shifted to the right compared to the transient contractions suggesting that smooth muscle is less sensitive to CPA than endothelium. 6 PGH2/TXA2 receptors in mouse aorta are highly sensitive to the thromboxane analogue U46619 (EC 50 : 1.93 nM). This compound stimulates contractions even in the absence of external Ca 2+ , which are abolished by the Rho-kinase inhibitor HA-1077. 7 The results suggest that 10 mM CPA induced capacitive Ca 2+ entry in endothelial cells stimulating the release of PGH2/TXA2, which subsequently caused smooth muscle contraction dependent on Ca 2+ in¯ux and myo®lament sensitization by Rho-kinase. Higher concentrations of CPA (30 ± 100 mM) directly induced contraction of mouse aortic smooth muscle.
Cardiovascular Research, 2009
Time for primary review: 31 days Aims Type 2 diabetes mellitus is frequently associated with hypertension, but the underlying mechanisms are not completely understood. We tested the hypothesis that activation of type 1 prostaglandin E 2 (PGE 2) receptor (EP1) increases skeletal muscle arteriolar tone and blood pressure in mice with type 2 diabetes. Methods and results In 12-week-old, male db/db mice (with homozygote mutation in leptin receptor), systolic blood pressure was significantly elevated, compared with control heterozygotes. Isolated, pressurized gracilis muscle arterioles (90 mm) of db/db mice exhibited an enhanced pressure-and angiotensin II (0.1-10 nM)-induced tone, which was reduced by the selective EP1 receptor antagonist, AH6809 (10 mM), to the level observed in arterioles of control mice. Exogenous application of PGE 2 (10 pM-100 nM) or the selective agonist of the EP1 receptor, 17-phenyl-trinor-PGE 2 (10 pM-100 nM), elicited arteriolar constrictions that were significantly enhanced in db/db mice (max: 31 + 4 and 29 + 5%), compared with controls (max: 20 + 2 and 14 + 3%, respectively). In the aorta of db/db mice, an increased protein expression of EP1, but not EP4, receptor was also detected by western immunoblotting. Moreover, we found that oral administration of the EP1 receptor antagonist, AH6809 (10 mg/kg/ day, for 4 days), significantly reduced the systolic blood pressure in db/db, but not in control mice. Conclusion Activation of EP1 receptors increases arteriolar tone, which could contribute to the development of hypertension in the db/db mice.
European Journal of Pharmacology, 1993
Subthreshold concentrations of endothelin-1 potentiated the norepinephrine-induced contraction in isometrically mounted rings of the rabbit aorta. Pretreatment with endothelin-1 (0.1 nM) for 10 minutes increased the sensitivity of the aortic rings to norepinephrine without affecting the maximal contraction. This amplification was unaffected by removal of the endothelium but was prevented by the protein kinase C inhibitors staurosporine (0.01 microM) and calphostin C (0.1 microM). Pretreatment of the aortic rings for 24 hours with phorbol 12-myristate 13-acetate (0.1 microM) also abolished the potentiation. Norepinephrine-induced contraction was potentiated by pretreating with phorbol 12-myristate 13-acetate (10 nM) and by increasing the concentration of K+ in the bath solution from 4.6 to 8.6 mM. The potentiation of the norepinephrine-induced contraction by endothelin-1 (0.1 nM) or by phorbol 12-myristate 13-acetate (10 nM) was not associated with an increase in norepinephrine-induced 45Ca2+ uptake or influx, whereas the potentiation due to an increase in the concentration of K+ in the bath solution from 4.6 to 8.6 mM was associated with an increase in norepinephrine-induced 45Ca2+ uptake. We conclude that endothelin-1 potentiation of the norepinephrine-induced contraction occurs in the absence of changes in stimulated Ca2+ entry and is endothelium independent. It is probable that endothelin-1 increases the sensitivity of the contractile apparatus to Ca2+ by activating protein kinase C-dependent mechanisms.
Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting
Journal of Clinical Investigation, 2007
Clinical use of prostaglandin synthase-inhibiting NSAIDs is associated with the development of hypertension; however, the cardiovascular effects of antagonists for individual prostaglandin receptors remain uncharacterized. The present studies were aimed at elucidating the role of prostaglandin E 2 (PGE 2 ) E-prostanoid receptor subtype 1 (EP1) in regulating blood pressure. Oral administration of the EP1 receptor antagonist SC51322 reduced blood pressure in spontaneously hypertensive rats. To define whether this antihypertensive effect was caused by EP1 receptor inhibition, an EP1-null mouse was generated using a "hit-and-run" strategy that disrupted the gene encoding EP1 but spared expression of protein kinase N (PKN) encoded at the EP1 locus on the antiparallel DNA strand. Selective genetic disruption of the EP1 receptor blunted the acute pressor response to Ang II and reduced chronic Ang II-driven hypertension. SC51322 blunted the constricting effect of Ang II on in vitro-perfused preglomerular renal arterioles and mesenteric arteriolar rings. Similarly, the pressor response to EP1-selective agonists sulprostone and 17-phenyltrinor PGE 2 were blunted by SC51322 and in EP1-null mice. These data support the possibility of targeting the EP1 receptor for antihypertensive therapy.