Our laboratory has recently shown increased renal expression of NO synthase 3 (NOS3) in the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension suggesting an up-regulation of the nitric oxide (NO)-cyclic guanosine-3′,5′-monophosphate (cGMP) pathway. The present study was designed to determine changes in renal soluble guanylyl cyclase (sGC) activity and expression in the DOCA-salt hypertensive rat. Rats were uninephrectomized and subcutaneously implanted with either a placebo or DOCA-salt pellet. Placebo-treated animals were given tap water ad libitum, while DOCA-treated animals received 0.9% NaCl solution to drink. Each week, rats were placed in metabolic cages for 24 h collection of urine samples. Urine samples were measured for cGMP concentrations using a scintillation proximity method. After 3 weeks, kidneys were removed and dissected into cortex, outer medulla, and inner medulla. Each region of the kidney was further separated into detergent-soluble and detergent-insoluble fractions. DOCA-treated rats exhibited significant increases in urinary cGMP excretion (27.0±1.4 fmol/mg creatinine) after 1 week compared to placebo control animals (8.7±0.6 fmol/mg creatinine). This was followed by a significant decrease by the second week of treatment (5.4±1.0 and 11.4±0.6 fmol/mg creatinine in DOCA-salt and placebo, respectively) and a return to placebo values by the third week of treatment (16.2±3.1 and 12.9±1.0 fmol/mg creatinine in DOCA-salt and placebo, respectively). Western blot analysis of inner medullary detergent-soluble fraction indicated a decrease in the expression of the β1-subunit of sGC in the third week of DOCA-salt-treated animals as compared to placebo controls (n=5 animals per group) while expression of the α1-subunit was unchanged. Western blot analysis of cortex and outer medullary preparations comparing placebo controls and DOCA-salt-treated animals revealed no difference in α1- or β1-sGC protein expression. These data suggest an uncoupling of NOS/NO and sGC/cGMP pathways in the renal inner medulla of the DOCA-salt hypertensive rat. © 2003 Elsevier Inc. All rights reserved.