Inhibition of left ventricular ®brosis by tranilast in rats with renovascular hypertension Berthold Hocher a,b , Michael Godes a,b , Jan Olivier a , Joachim Weil d , Thomas Eschenhagen d , Torsten Slowinski a,b , Hans-H. Neumayer b , Christian Bauer b , Martin Paul c and Yigal M. Pinto c Background Growth factors such as transforming growth factor-beta (TGFâ) are believed to have an essential role in cardiac ®brosis. Tranilast (N(3,4-dimethoxycinnamoyl) anthranilic acid) attenuates the increased expression of TGFâ mRNA in vitro. Objective To investigate whether tranilast reduces cardiac ®brosis in rats with two-kidney, one-clip (2K1C) renovascular hypertension. In addition, we tested the in- vitro effects of tranilast on cardiac myocytes and non- myocyte cells. Methods We analysed hearts from four groups of rats: sham-operated controls; rats with 2K1C renovascular hypertension; rats with 2K1C renovascular hypertension treated for 12 weeks with the angiotensin converting enzyme (ACE) inhibitor, quinapril (6 mg/kg per day); rats with 2K1C renovascular hypertension treated for 12 weeks with tranilast (400 mg/kg per day). Results Systolic blood pressure was reduced after quinapril treatment. Tranilast did not alter blood pressure (2K1C: 223 6 19 mmHg; 2K1C quinapril: 149 6 15 mmHg (P < 0.01 compared with 2K1C); 2K1C tranilast: 204 6 32 mmHg). Left ventricular weight was likewise reduced signi®cantly by quinapril, but not signi®cantly by tranilast (2K1C: 1.52 6 0.2 g; 2K1C quinapril: 1.26 6 0.18 g (P < 0.05 compared with 2K1C); 2K1C tranilast: 1.37 6 0.27 g). Using a computer- aided image analysis system, we demonstrated that tranilast prevented cardiac ®brosis in a blood-pressure- independent manner (P < 0.01 compared with 2K1C). Determination of the cardiac hydroxyproline content similarly revealed a signi®cant reduction in cardiac ®brosis by tranilast (2K1C: 4.92 6 0.48 mg/mg; 2K1C tranilast: 3.97 6 0.46 mg/mg; P < 0.05). The effect of tranilast on cardiac ®brosis was comparable to the effects of a blood- pressure-decreasing dose of the ACE inhibitor, quinapril. Cell culture experiments revealed that tranilast signi®cantly decreased the proliferation of cardiac non- myocyte cells. Proliferation of cardiac myocytes was not altered. Conclusion This study revealed that long-term treatment with tranilast markedly attenuated left ventricular ®brosis in rats with renovascular hypertension. This was most probably the result of an antiproliferative effect of tranilast on cardiac non-myocyte cells. Tranilast thus offers a unique new therapeutic approach to the reduction of TGFâ-mediated cardiac ®brosis in vivo. J Hypertens 20:745±751 & 2002 Lippincott Williams & Wilkins. Journal of Hypertension 2002, 20:745±751 Keywords: renovascular hypertension, tranilast, cardiac ®brosis a Department of Nephrology, University Hospital Charite  , Humboldt University of Berlin, b Institute of Molecular Biology and Biochemistry and c Institute of Clinical Pharmacology and Toxicology, Free University of Berlin, and d Institute of Experimental and Clinical Pharmacology and Toxicology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany. Sponsorship: This study was supported by grants from the Deutsche Forschungsgemeinschaft (Ho 1665/2-2) and Go È decke Parke Davis. Correspondence and requests for reprints to Priv. Doz. Dr Berthold Hocher, Universita È tsklinikum Charite  der Humboldt Universita È t zu Berlin, Abteilung fu Èr Nephrologie, Schumannstr. 20-21, 10098 Berlin, Germany. Tel: +49 30 450514098; fax: + 49 30 450514902 e-mail: berthold.hocher@charite.de Received 10 September 2001 Revised 9 November 2001 Accepted 29 November 2001 Introduction Cardiac myocytes are surrounded by a network of collagen ®bres that are generated primarily by cardiac ®broblasts [1]. As part of the cardiac response to pressure overload in renovascular hypertension, cardiac ®broblasts proliferate and extracellular matrix proteins accumulate disproportionately and excessively [2,3]. This process, which has been termed `reactive ®brosis', leads to increased ventricular stiffness, and hence to diastolic and later systolic dysfunction of the heart [4]. In addition, excessive cardiac ®brosis may damage the cardiac conducting system [5,6]. As a result, cardiac ®brosis is recognized as a key process in the progression from compensated cardiac hypertrophy to cardiac dys- function and heart failure. Growth factors, especially transforming growth factor- beta (TGFâ), are believed to have an essential role in Original article 745 0263-6352 & 2002 Lippincott Williams & Wilkins