Evidence of a possible PPARalpha‐independent vasodilatory action of the fibric acid analogue gemfibrozil

Abstract

Knocking out the gene for peroxisome proliferator‐activated receptor‐alpha (PPARalpha) was recently reported to abolish hypertension associated with an overactive human renin‐angiotensin‐aldosterone system (RAAS) transgenically expressed in mice (Hyper 50:945–51, 2007). Thus, attention is now focused on whether fibrates (PPARalpha agonists often used to lower plasma triglycerides) are capable of aggravating related forms of hypertension in humans (Hyper 50:847–50, 2007). We recently reported acute relaxant effects of high concentrations of gemfibrozil (e.g. 500 micromolar) on various smooth muscle preparations, including rat ventral tail arteries pre‐contracted with either arginine‐vasopressin (AVP) or serotonin (FASEB J 21:A1162, 2007). In the present work, we show that 4‐hour exposure of the same arterial tissue to much lower but more therapeutically‐relevant levels of gemfibrozil (e.g. 50 micromolar) also relaxes AVP‐ and serotonin‐induced contractions. Thus, we suspect that fibrates exert delayed but nonetheless direct and likely PPARalpha‐independent vasodilatory activity which could offset any potential they have to exert a PPARalpha‐dependent, RAAS‐mediated hypertension. Supported by Midwestern University.