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

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

study of the effect of estrogen hormonal modulation on liver ischemic reperfusion in rats

Ischemia/reperfusion [I/R] injury of the liver impaired hepatic regeneration and predisposed to liver failure. The prime factors contributing to injury are decreased nitric oxide [NO] level which favor vasoconstriction, increased production of reactive oxygen species [ROS], increased level of adhesion molecules and leukostasis, which further impair the hepatic microcirculation in the early reperfusion phase. Heat shock protein 70 [HSP70] was shown to be induced by stress. Of the present work was to study the effect of estrogen hormonal modulation on hepatic injury during I/R model in male rats and to investigate the possible involvement of HSP 70 in the gender dimorphic response of the liver to this injury. Forty adult male albino rats were used in this work. They were divided into 5 groups [each of eight rats]; eight rats were taken as normal sham operated group.The remaining rats were subjected to total hepatic I/R. Each group received a specific treatment given intraperitoneally [ip] including: 17-beta estradiol [E[2]], raloxifene [Ral.] and genistein [Gen.] one hour before surgical procedure. The sham operated rats were injected with the veichle dimethyl sulfoxide solution. The I/R group was pretreated with the vehicle. Several parameters including: serum transaminases, HSP 70, ROS, Myeloperoxidase activity[MPO] and nitrite content were measured using standard assay procedures. I/R produced a significant increase in serum transaminases, MPO and ROS in liver tissue. HSP 70 was induced to a significantly higher level in I/R versus sham operated group but nitrite was significantly reduced in I/R versus sham operated rats. E[2+] I/R group had significantly lower transaminases, MPO and ROS versus I/R untreated group. A significantly higher nitrite level and HSP 70 was detected in liver tissue of E[2+] I/R versus I/R group. Ral.+I/R group showed significant lower serum transaminases, MPO and ROS in liver tissue versus I/R. Also Ral+ I/R showed significant higher nitrite and HSP70 versus I/R group. Gen.+I/R group showed decreased serum transaminases, lower MPO and ROS versus I/R. Nitrite level was significantly higher in Gen.+I/R versus I/R .Compared to E[2+] I/R or Ral.+I/R, geinstein pretreatment showed significantely lower HSP70. 17-beta estradiol pretreatment produced significant protection during hepatic I/R injury through multiple pathways. The protection was related to HSP70 induction, greater NO release, inhibition of ROS and MPO activity in liver tissue. Both the synthetic estrogen receptor modulator [SERM] raloxifene and the phytoestrogen genistein exerted significant estrogen agonist protective effects on the liver I/R injury. The mechanism of raloxifene protection was similar to estradiol, although protection due to genistein pretreatment did not involve HSP70 induction. Protection by genistein could be attributed to enhanced NO release and inhibition of ROS