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Background: The microvasculature is a target organ for the early manifestations of cardiovascular disease. Therefore, a better understanding of the prostaglandin system and characterising the effects of mPGES‐1 inhibition and concomitant reduction of PGE2 in vascular beds are of interest. Experimental Approach The effects of mPGES‐1 inhibition on constriction and relaxation of resistance arteries (diameter: 100–400 μm) from patients with end stage kidney disease (ESKD) and controls (Non‐ESKD) were studied using wire‐myography in combination with immunological and mass‐spectrometry based analyses. Key Results: Inhibition of mPGES‐1 in arteries from ESKD patients and Non‐ESKD controls significantly reduced adrenergic vasoconstriction, which was unaffected by the COX‐2 inhibitors NS‐398 and Etoricoxib, or by the COX‐1/COX‐2 inhibitor Indomethacin tested in Non‐ESKD controls. However, a significant increase of acetylcholine‐induced dilatation was observed for mPGES‐1 inhibition. In IL‐1β treated arteries, inhibition of mPGES‐1 significantly reduced PGE2 levels while PGI2 levels remained unchanged. In contrast, COX‐2 inhibition blocked the formation of both prostaglandins. Blockade of PGI2 signalling with an IP receptor antagonist did not restore the reduced adrenergic constriction, neither did blocking PGE2‐EP4 or signalling through PPARγ. A biphasic effect was observed for PGE2, inducing dilatation at nanomolar and constriction at micromolar concentrations. Immunohistochemistry demonstrated expression of mPGES‐1, COX‐1, PGIS, weak expression for COX‐2, as well as receptor expression for PGE2 (EP1–4), thromboxane (TP) and PGI2 (IP) in ESKD and Non‐ESKD. Conclusion: Our study demonstrates vasodilating effects following mPGES‐1 inhibition in human microvasculature and suggests that several pathways besides shunting to PGI2 are involved. [ABSTRACT FROM AUTHOR]

1: The a1-adrenoceptor subtypes involved in responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries were characterised using a small vessel myograph, with antagonists prazosin (nonsubtype selective), 5-methyl-urapidil (a1A-selective), BMY 7378 (a1D-selective) and the alkylating agent chloroethylclonidine (preferential for a1B-). 2: Prazosin and 5-methyl-urapidil produced rightward shifts of the exogenous noradrenaline concentration - response curve (CRC) with pA2 values of 9.2 and 9.1 respectively, in agreement with the presence of a1A-adrenoceptors. BMY 7378 (1?µM) shifted the noradrenaline CRC with an apparent pKB of 6.7, in agreement with the presence of a1A-, but not a1D-, adrenoceptors. Chloroethylclonidine at 1?µM had no effect and at 10?µM produced only a small reduction (c. 20%) in the maximum response to noradrenaline, indicating little, if any, contribution from a1B-adrenoceptors. 3: Responses of the rat femoral resistance arteries to electrical field stimulation (EFS) at 5-30?Hz for 10?s and 0.05?ms pulse width were principally due to a1-adrenoceptor stimulation. Prazosin and 5-methyl-urapidil inhibited EFS-mediated responses with pIC50s of 9.3 and 8.2, respectively, consistent with the a1A-adrenoceptor being the predominant subtype. Responses to EFS at 10-30?Hz were relatively insensitive to BMY 7378 (pIC50, 6.5-6.7), while responses to 5?Hz were inhibited with a significantly higher pIC50 of 8.02, suggesting the contribution of a1D-adrenoceptors. Chloroethylclonidine had no effect on responses to EFS, ruling out the contribution of an a1B-subtype. 4: In the presence of cocaine, the predominant subtype involved in responses to EFS was the a1A-adrenoceptor, with a contribution from a1D-adrenoceptors at low frequency, as seen in the absence of cocaine. However, there was also a significant increase in the sensitivity to BMY 7378 at higher frequencies, suggesting that a further small a1D-adrenoceptor component may be uncovered in the presence of cocaine. 5: The present study has shown a predominant role of the a1A-adrenoceptor in contractions due to exogenous noradrenaline and to neurally released noradrenaline in rat femoral resistance arteries. a1D-Adrenoceptors are not involved in responses to exogenous noradrenaline but appear to be activated by neurally released noradrenaline at a low frequency of stimulation and at higher frequencies in the presence of neuronal-uptake blockade.British Journal of Pharmacology (2004) 141, 915-924. doi:10.1038/sj.bjp.0705690 [ABSTRACT FROM AUTHOR]

1 The mechanism underlying the enhancement by superoxide dismutase (SOD) of endothelium-dependent relaxation was investigated in rabbit mesenteric resistance arteries. 2 SOD (200 U ml -1) increased the production of H2O2 in smooth muscle cells (as indicated by the use of an H2O2-sensitive fluorescent dye). 3 Neither SOD nor catalase (400 U ml-1) modified either the resting membrane potential or the hyperpolarization induced by acetylcholine (ACh, 1 μM) in smooth muscle cells. 4 In arteries constricted with noradrenaline, the endothelium-dependent relaxation induced by ACh (0.01 -1 μM) was enhanced by SOD (200 U ml-1) (P<0.0l). This action of SOD was inhibited by L-NG-nitroarginine (nitric oxide (NO)-synthase inhibitor) but not by either charybdotoxin + apamin (Ca2+-activated-K+-channel blockers) or diclofenac (cyclooxygenase inhibitor). 5 Neither ascorbate (50μM) nor tiron (0.3mM), superoxide scavengers, had any effect on the ACh-induced relaxation, but each attenuated the enhancing effect of SOD on the ACh-induced relaxation. Similarly, catalase (400 U ml-1) inhibited the effect of SOD without changing the ACh-induced relaxation. 6 In endothelium-denuded strips constricted with noradrenaline. SOD enhanced the relaxation induced by the NO donor l-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-l-triazene (NOC-7) (P<0.05). Ascorbate and catalase each attenuated this effect of SOD. 7 H2O2 (I μM) enhanced the relaxation on the noradrenaline contraction induced by NOC-7 and that induced by 8-bromo-cGMP. a membrane-permeable analogue of guanosine 3′.5′ cyclic monophosphate (cGMP). 8 SOD had no effect on cGMP production, whether measured in endothelium-intact strips following an application of ACh (0.1 μM) or in endothelium-denuded strips following an application of NOC-7 (0.1μM). 9 It is suggested that in rabbit mesenteric resistance arteries, SOD increases the ACh-induced. endothelium-dependent relaxation by enhancing the action of NO in the smooth muscle via its H2O2-producing action (rather than via a superoxide-scavenging action). [ABSTRACT FROM AUTHOR]