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

Abstract

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.

• Authors: Julia Steinmetz-Späh, Samsul Arefin, Karin Larsson, Jabin Jahan, Neja Mudrovcic, Lars Wennberg, Peter Stenvinkel, Marina Korotkova, Karolina Kublickiene, Per-Johan Jakobsson
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 7 Pg. 1433-1449 (04 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34766335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Chemical References

• Adrenergic Agents
• Cyclooxygenase 2 Inhibitors
• Nitrobenzenes
• Prostaglandins
• Sulfonamides
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• Cyclooxygenase 1
• Cyclooxygenase 2
• Prostaglandin-E Synthases
• Etoricoxib

Topics

• Adrenergic Agents
• Arteries (metabolism, physiology)
• Cyclooxygenase 1 (metabolism)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Etoricoxib
• Humans
• Kidney Failure, Chronic (complications)
• Microvessels (metabolism, physiology)
• Nitrobenzenes
• Prostaglandin-E Synthases (antagonists & inhibitors)
• Prostaglandins
• Sulfonamides