In SHR-SP, oxidative stress participates to altered relaxation in response to acetylcholine (ACh) and sodium-nitroprusside (SNP). The aim of this study was to evaluate the effects of the activator of soluble guanylate cyclase (sGC) BAY 58-2667 on SHR-SP in comparison to control Wistar-Kyoto rats (WKY). Aortas from 15 week-old SHRSP and WKY were removed and isometric tension as well as cGMP generation were determined in response to ACh, SNP and BAY 58-2667. After contraction of aortic rings by phenylephrine (10-6 M), the relaxations of SHR-SP rings were smaller in response to ACh (60 % vs. 90 % maximal relaxation, n=15), to SNP (EC50 : 6.4 vs. 0.9nM, n=20) and to BAY 58-2667 (EC50 : 95 vs. 9nM, n=6). In contrast, cGMP generation (in the presence of the PDE inhibitor IBMX, 2mM) caused by 10-8M BAY 58-2667 was not significantly altered in SHR-SP vs. WKY (34¡Ó11 vs. 64¡Ó23 pmol/mg protein, ns t-test, n=7) whereas that caused by 10-5M ACh and 10-6M SNP were significantly smaller (−90 % and −60 % vs. WKY, respectively, p,,T0.05, t-test, n=9). Moreover, the amount of (fÑf¡fyfÒf¡)-sGC subunits, quantified by western-blot, was decreased by 35 % in SHR-SP aorta (n=12). Interestingly, an oral chronic treatment of rats with 1 mg/kg/day of BAY 58-2667 for 5 days (mini-pump Alzet, IP, n=11-13) decreased SHR-SP systolic blood pressure by 15¡Ó4 mmHg, proteinuria by 50¡Ó5 % and was associated with a aortic and urinary cGMP increase (20¡Ó2 vs. 9¡Ó1.3pmol/mg proteins and 11¡Ó1 vs. 7.6¡Ó1.4nmol/24h, respectively, t-test). These results demonstrate that BAY 58-2667 activates sGC in SHRSP aorta, even if the enzyme amount is decreased and suggest the presence of oxidized and/or heme free form of sGC unresponsive to NO in SHR-SP. In conclusion, activators of sGC may constitute an alternative treatment of resistant hypertension associated to vascular complications.