Renin angiotensin aldosterone system and fibrinolytic activity in experimentally induced diabetic and hypertensive rats

ABSTRACT

Many evidences pointed to certain relations between renin angiotensin aldosterone system [RAAS] and endogenous fibrinolytic system. To examine the effect of low salt supplement, as an activator to endogenous RAAS on plasma fibrinolytic function in alloxan diabetic L-NAME induced hypertensive ncphritic rats in the presence or absence of angiotensin converting enzyme inhibitor [ACEI] and/or aldosterone antagonist. Diabetes was induced in male Wistar rats by a single intraperitoneal [i.p] injection of alloxan [150 mg/kg]. Rats were received low salt supplement [0.08% NaCI] and N[G]-nitro-L-arginine methyl ester [L-NAME, 0.1 mg/ml] in the drinking water during the experimental periods. Treatment of diabetic hypertensive nephritic rats with ACEI [mocxipril hydrochloride, 7 mg/kg body weight daily and orally], aldosterone antagonist [spiranolactone, 25 mg/kg body weight daily and orally] or their combined administration for 6 weeks. Glucose, creatinine, sodium, potassium, aldosterone, ACE activity, transforming growth factor-beta 1 [TGF-beta] were determined in serum, whereas, renin, plasminogen activator inhibitors [PAI-1 were estimated in plasma. In urine nitric oxide [NO] concentration was evaluated and total. DNA and RNA were recorded in kidney tissues. During low salt intake, activation of the RAAS was monitored through observed significant Increase in serum alciosterone, sodium, potassium, and ACE activity. Impairment of renal function following diabetes and L-NAME administration was manifested By increase in serum glucose, mean arterial pressure [MAP] heart rate [HR]. serum creatinine and low urinary NO level, these data demonstrated that activation of RAAS in diabetic hypertensive nephritic rats significantly increased PAI-1 activity, TGF-beta1 and dry thrombus weight. It markedly decreased total DNA contents in kidney homogenate. Interruption of the RAAS with the ACEI, aldosterone antagonist or their combined administration lot 6 weeks significantly decreased PAl-1 activity TGF-beta1 and thrombus weight [fibrinolytic actvity]. However urinary NO, kidney content of total DNA showed significant increase. Combined form therapy has a better effect regarding PAI-1 TGF-beta 1 and NO than monotherapy. Data obtained provides an evidence of direct functional association between the RAAS and the fibrinolytic system in rats. This may help to elucidate possible mechanisms by which ACE inhibition and aldosterone antagonist exerts antagonist exerts vasculoprotective effects and reduce the risk of renal atherothromhotic events closely related to uncontrolled diabetes