possible role of peroxisome proliferator-activated receptors agonists in the vascular reactivity and myocardial changes induced by long-term blockade of nitric oxide synthesis in the rat

ABSTRACT

Peroxisome proliferator-activated receptors [PPARs] are a family of ligand-activated nuclear transcription factors. PPAR alpha and gamma are the most extensively key modulators of lipid and glucose homeostasis. They are predominantly expressed in adipose tissues, some non adipose tissues including heart, kidney, spleen, and all relevant cells of the vasculature endothelial cells, smooth muscle cells, and macrophages. The vascular distribution suggests their involvement in the control of cardiovascular function. The present experimental work was designed to study the effects of fenofibrate and rosiglitazone treatment on blood pressure, antioxidant enzymes, vascular reactivity and cardiac hypertrophy in N[G]-nitro-L-arginine methyl ester [L-NAME] induced hypertension in rats. Fifty male albino rats weighing from 150-200 g were included in this study. Rats were divided into two main groups. Group 1, [10 rats] served as a control group for group II, and was received 1 ml of physiological saline [0.9%], orally for seven weeks.Group II hypertensive group [40 rats] was given daily L-NAME in a dose of 40 mg/kg orally for seven weeks. Rats were further subdivided into A, B, C, and D, each of ten rats. Group- A, received 1ml of 2% gum acacia daily orally for six weeks, starting one week after L-NAME administration.Groups B,C and D treated with daily fenofibrate [30 mg / kg.b.wt. orally] and rosiglitazone [3 mg / kg.b.wt.], alone or together for six weeks. Blood pressure, serum tumor necrosis factor- alpha [TNF- alpha], body weight [BW] and heart weight [HW] were measured. Malondialdehyde [MDA] and reduced glutathione [GSH] were estimated in cardiac tissues. Thoracic aorta was isolated and the aortic rings were allowed to achieve maximal tension by cumulative addition of phenylephrine [PE] [10[-9]-10[-5] M] to the bath solution. Fenofibrate and rosiglitazone, alone or together produced significant decreases in blood pressure and TNF- alpha. Higher oxidative stress accompanying hypertension was significantly reduced by fenofibrate and rosiglitazone treatment. The results showed that both drugs significantly attenuated the augmented contractile response to PE in hypertensive rats. In addition, they inhibited the cardiac hypertrophy [reduction in HW/BW ratio]. These data suggest that PPAR alpha and gamma activation contribute to normal regulation of blood pressure and exert protective actions in hypertension via inhibition of generation of free radicals