Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension.
BACKGROUND
Growth factors such as transforming growth factor-beta (TGF beta) are believed to have an essential role in cardiac fibrosis. Tranilast (N(3,4-dimethoxycinnamoyl) anthranilic acid) attenuates the increased expression of TGF beta mRNA in vitro.


OBJECTIVE
To investigate whether tranilast reduces cardiac fibrosis 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 +/- 19 mmHg; 2K1C + quinapril: 149 +/- 15 mmHg (P < 0.01 compared with 2K1C); 2K1C + tranilast: 204 +/- 32 mmHg). Left ventricular weight was likewise reduced significantly by quinapril, but not significantly by tranilast (2K1C: 1.52 +/- 0.2 g; 2K1C + quinapril: 1.26 +/- 0.18 g (P < 0.05 compared with 2K1C); 2K1C + tranilast: 1.37 +/- 0.27 g). Using a computer-aided image analysis system, we demonstrated that tranilast prevented cardiac fibrosis in a blood-pressure-independent manner (P < 0.01 compared with 2K1C). Determination of the cardiac hydroxyproline content similarly revealed a significant reduction in cardiac fibrosis by tranilast (2K1C: 4.92 +/- 0.48 mg/mg; 2K1C + tranilast: 3.97 +/- 0.46 mg/mg; P < 0.05). The effect of tranilast on cardiac fibrosis was comparable to the effects of a blood-pressure-decreasing dose of the ACE inhibitor, quinapril. Cell culture experiments revealed that tranilast significantly decreased the proliferation of cardiac non-myocyte cells. Proliferation of cardiac myocytes was not altered.


CONCLUSIONS
This study revealed that long-term treatment with tranilast markedly attenuated left ventricular fibrosis 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 TGF beta-mediated cardiac fibrosis in vivo.
Hocher
Berthold
B
Department of Nephrology, University Hospital Charité, Humboldt University of Berlin, Germany.berthold.hocher@charite.de
Godes
Michael
M
Olivier
Jan
J
Weil
Joachim
J
Eschenhagen
Thomas
T
Slowinski
Torsten
T
Neumayer
Hans-H
HH
Bauer
Christian
C
Paul
Martin
M
Pinto
Yigal M
YM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006909:Hydroxyproline / Q000378:metabolism; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000627:therapeutic use; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D000077583:Quinapril; D051381:Rats; D011921:Rats, Inbred WKY; D044005:Tetrahydroisoquinolines; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D020257:Ventricular Remodeling / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; C012293:tranilast; D000077583:Quinapril; D006909:Hydroxyproline