Effects of microsomal prostaglandin E synthase‐1 inhibition on resistance artery tone in patients with end stage kidney disease.

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]