Single injection of a small quantity of phenol into the cortex of one kidney in rats results in development of persistent hypertension (HTN) which is thought to be mediated by activation of renal afferent and efferent sympathetic pathways and sodium retention. Nitric oxide (NO) plays a major role in regulation of renal vascular resistance, tubular Na⁺ reabsorption, pressure natriuresis and thereby systemic arterial pressure. The present study was performed to test the hypothesis that chronic renal injury-induced HTN may be associated with dysregulation of NO system in the kidney. Accordingly, urinary NO metabolite (NOx) and cGMP excretions as well as renal cortical tissue (right kidney) expressions of NO synthase isoforms (eNOS, nNOS and iNOS), NOS-regulatory factors (Caveolin-1, phospho-AKt and calmodulin) and second-messenger system (soluble guanylate cyclase [sGC] and phosphodiesterase-5 [PDE-5]) were determined in male Sprague-Dawley rats 4 weeks after injection of phenol (50 l of 10% phenol ) or saline into the lower pole of left kidney. The phenol-injected group exhibited a significant elevation of arterial pressure, marked reductions of urinary NOx and cGMP excretions, down-regulations of renal tissue nNOS, eNOS, Phospho-eNOS, iNOS and alpha chain of sGC. However, renal tissue AKt, phospho-AKT, Calmodulin and PDE-5 proteins were unchanged in the phenol-injected animals. In conclusion, renal injury in this model results in significant down-regulations of NOS isoforms and sGC and consequent reductions of NO production and cGMP generation by the kidney, events that may contribute to maintenance of HTN in this model.