Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension.

Abstract

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.

CONCLUSION:

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.

• Authors: Berthold Hocher, Michael Godes, Jan Olivier, Joachim Weil, Thomas Eschenhagen, Torsten Slowinski, Hans-H Neumayer, Christian Bauer, Martin Paul, Yigal M Pinto
• Journal: Journal of hypertension (J Hypertens) Vol. 20 Issue 4 Pg. 745-51 (Apr 2002) ISSN: 0263-6352 [Print] England
• PMID: 11910312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Isoquinolines
• Tetrahydroisoquinolines
• Transforming Growth Factor beta
• ortho-Aminobenzoates
• tranilast
• Quinapril
• Hydroxyproline

Topics

• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Blood Pressure (drug effects)
• Cell Division (drug effects)
• Fibrosis
• Heart Ventricles (drug effects, pathology)
• Hydroxyproline (metabolism)
• Hypertension, Renovascular (drug therapy, pathology, physiopathology)
• In Vitro Techniques
• Isoquinolines (therapeutic use)
• Male
• Myocardium (metabolism, pathology)
• Quinapril
• Rats
• Rats, Inbred WKY
• Tetrahydroisoquinolines
• Transforming Growth Factor beta (antagonists & inhibitors)
• Ventricular Remodeling (drug effects)
• ortho-Aminobenzoates (therapeutic use)