British journal of pharmacology · 2026
sGC stimulator BAY 41-8543 improves survival and ventricular function in a rat model of doxorubicin-induced cardiomyopathy with nephrotic syndrome.
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Gawrys Olga, Škaroupková Petra, Kikerlová Soňa, Vaňourková Zdeňka, Hüttl Martina, Lenčová Olga, Anandam Kasin Yadunandam, Stomberg Svenja, Behrends Sönke, Bačová Barbara Szeiffová, Sykora Matúš, Dietz Lisa, Sandner Peter, Červenka Luděk, Štěrba Martin
Аннотация
BACKGROUND AND PURPOSE: Anthracyclines such as doxorubicin (DOXO) remain a cornerstone of cancer therapy but are associated with a high risk of cardiotoxicity and subsequent heart failure (HF). Impairment of NO/soluble guanylyl cyclase (sGC)/cGMP pathway has been reported in anthracycline-induced cardiomyopathy. This raises the hypothesis that increasing cGMP by sGC stimulation could preserve cardiac function even after HF has developed. This study aimed to evaluate the long-term effects of treatment with sGC stimulator BAY 41-8543 in a model of DOXO-induced HF with nephrotic syndrome in hypertensive rats.
EXPERIMENTAL APPROACH: Male Ren-2 transgenic rats received five weekly intravenous injections of DOXO (cumulative dose 10 mg·kg-1) to induce cardiomyopathy. After two additional weeks, animals were treated with either BAY 41-8543 (10 mg·kg-1·day-1) or an ACE inhibitor (ACEi; trandolapril, 0.25 mg·kg-1·day-1). Echocardiography, blood and urine collection were performed at baseline (week -1) and 4 weeks after the treatment started to assess cardiac ventricular function, cardiac and renal biomarkers; survival at 20 weeks.
KEY RESULTS: Treatment with BAY 41-8543 improved long-term survival, preserved left and right ventricular systolic function and reduced myocardial expression of inflammation-related genes, particularly those linked to type I interferon signalling. ACEi provided stronger benefits in survival and structural remodelling. Kidney damage and function was not improved by any treatment compared to placebo.
CONCLUSION AND IMPLICATIONS: The sGC stimulator BAY 41-8543 exerted significant cardioprotective effects in DOXO-induced HF. Therefore, sGC stimulators may represent a promising therapeutic option for anthracycline-induced cardiomyopathy, although additional studies are required to fully investigate their therapeutic potential.
EXPERIMENTAL APPROACH: Male Ren-2 transgenic rats received five weekly intravenous injections of DOXO (cumulative dose 10 mg·kg-1) to induce cardiomyopathy. After two additional weeks, animals were treated with either BAY 41-8543 (10 mg·kg-1·day-1) or an ACE inhibitor (ACEi; trandolapril, 0.25 mg·kg-1·day-1). Echocardiography, blood and urine collection were performed at baseline (week -1) and 4 weeks after the treatment started to assess cardiac ventricular function, cardiac and renal biomarkers; survival at 20 weeks.
KEY RESULTS: Treatment with BAY 41-8543 improved long-term survival, preserved left and right ventricular systolic function and reduced myocardial expression of inflammation-related genes, particularly those linked to type I interferon signalling. ACEi provided stronger benefits in survival and structural remodelling. Kidney damage and function was not improved by any treatment compared to placebo.
CONCLUSION AND IMPLICATIONS: The sGC stimulator BAY 41-8543 exerted significant cardioprotective effects in DOXO-induced HF. Therefore, sGC stimulators may represent a promising therapeutic option for anthracycline-induced cardiomyopathy, although additional studies are required to fully investigate their therapeutic potential.