Long-term treatment with soluble guanylyl cyclase stimulator BAY41-8543 abolishes malignant hypertension-related mortality and attenuates organ damage: studies in Ren-2 transgenic rats treated with L-NAME.

OBJECTIVE: Malignant hypertension (MH) remains a life-threatening condition and new pharmacological strategies and drugs with potential new mode of actions are currently investigated. The aim of the present study was to evaluate the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the long-term MH-related mortality and morbidity. METHODS: As a model of MH, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor, [Nω-nitro-l-arginine methyl ester - (L-NAME)], was used. Systolic blood pressure (SBP) was measured by tail-cuff method. The treatment with sGC stimulator, BAY41-8543, was started 3 days before administration of L-NAME. The follow-up period was 120days after L-NAME administration. RESULTS: Untreated TGR + L-NAME rats developed MH (SBP on day +10 was 207 ± 4 mmHg) associated with development of marked albuminuria and high mortality (median survival rate 8 days). The treatment with sGC stimulator BAY41-8543 completely abolished MH-related mortality in TGR receiving L-NAME (all animals survived until end of the study) and prevented rises in SBP and development of albuminuria. CONCLUSION: The treatment with sGC stimulator BAY41-8543 provided long-term protection against MH-related mortality and morbidity. On the whole, these results suggest that pharmacological targeting NO/sGC pathway should be considered in attempts to develop new pharmacological strategies for treatment of MH.