Recent reports have demonstrated a potential role of tissue prorenin in the pathogenesis of cardiovascular and renal damage. This study was designed to examine the role of prorenin in the pathogenesis of target organ damage in spontaneously hypertensive rats, the best naturally occurring experimental model of essential hypertension. To this end, we studied 20-week-old male SHR receiving a normal diet and 8-week old male SHR given food with 8% NaCl. One-half the rats in each group were given prorenin inhibitor (PRAM 1, 0.1 mg/kg/day) via osmotic mini-pumps; the other half served as controls. Arterial pressure, left ventricular function, cardiovascular mass indices, cardiac fibrosis, and renal function were examined at the end of the experiment. Arterial pressure was unaffected by PRAM 1 in rats on either regular or salt-excess diets. In those rats receiving a normal diet, blockade of prorenin activation consistently reduced left ventricular mass, but affected no other variable. Salt-loaded rats given PRAM1 for 8 weeks demonstrated: (i) reduced serum creatinine level, (ii) decreased left ventricular mass, (iii) improved left ventricular function, and (iv) reduced left ventricular fibrosis. These data demonstrated that blockade of nonproteolytic activation of prorenin exerted significant cardiovascular and renal benefit in SHR with cardiovascular damage produced by salt excess and suggested that activation of cardiovascular or renal prorenin may be a major mechanism that mediates cardiac and renal damage in this form of accelerated hypertension.