tranilast and Cardiomegaly

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiomegaly; Fibrosis; Humans; Hypertension; ortho-Aminobenzoates

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.

Topics: Angiotensin II; Animals; Antioxidants; Cardiomegaly; Doxorubicin; Fibrosis; Heart Diseases; Male; Mast Cells; Myocardium; ortho-Aminobenzoates; Oxidative Stress; Rats; Rats, Wistar

In order to study the association between myocardial fibrosis and inflammatory cell infiltration in the hypertensive heart, we investigated whether N(3,4-dimethoxycinnamoyl) anthranilic acid (tranilast), an anti-inflammatory drug, would suppress myocardial fibrosis via inhibition of inflammatory cell infiltration in deoxycorticosterone-acetate (DOCA) hypertensive rats.. Sprague-Dawley rats treated with DOCA combined with the addition of 1% NaCl and 0.2% KCl in the drinking water after left nephrectomy were given tranilast (100 mg/kg per day, n = 15) or vehicle (n = 15) for up to 4 weeks. Systolic blood pressure (SBP), amount of myocardial interstitial fibrosis, perivascular fibrosis and type I and III collagen, and mRNA expression of procollagen I (PI) and procollagen III (PIII), transforming growth factor (TGF)-beta1, type-1 plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were determined.. SBP was increased significantly 2 weeks after treatment with DOCA and salt. Myocardial interstitial fibrosis, perivascular fibrosis and collagen accumulation increased significantly 4 weeks after the treatment. Two weeks after the treatment with DOCA and salt, mRNA expression of PI and PIII, TGF-beta1, PAI-1, MCP-1 and IL-6 increased significantly. Although the SBP was similar in animals treated with tranilast or vehicle, monocyte/macrophage infiltration was suppressed, mRNA expression of TGF-beta1, PAI-1, MCP-1, IL-6, PI and PIII was attenuated, and myocardial fibrosis and collagen accumulation were suppressed in hypertensive animals receiving tranilast.. Myocardial fibrosis seen in DOCA/salt hypertensive rats might be associated with the inflammation/wound healing response. Tranilast suppresses both infiltration of monocytes/macrophages and myocardial fibrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Cardiomegaly; Chemokine CCL2; Collagen Type I; Collagen Type III; Desoxycorticosterone; Fibrosis; Hypertension; Interleukin-6; Macrophages; Male; Monocytes; Myocardium; Nephrectomy; Organ Size; ortho-Aminobenzoates; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

Angiotensin II recruits transforming growth factor beta(1) (TGFbeta(1)) and is related to left ventricular fibrosis. However, it is unclear whether chronic in vivo reduction in left ventricular TGFbeta(1) expression blunts fibrosis and improves outcome in angiotensin II-dependent hypertension. Four-week-old male hypertensive TGR(mRen2)27 (Ren2) rats received either normal food, low-dose losartan (0.5 mg. kg(-1). d(-1)), or tranilast (a nonspecific TGFbeta inhibitor; 400 mg. kg(-1). d(-1)) (n=10 for each group) for 12 weeks and were compared with Sprague-Dawley control rats. The effect of tranilast on survival was evaluated in 34 additional untreated homozygous Ren2 rats. Tranilast or low-dose losartan did not lower blood pressure. However, the increase in left ventricular weight (Ren2 versus SD 3.1+/-0.16 versus 2.1+/- 0.06 mg/g body wt; P<0.05) was significantly (P<0.05) blunted by both tranilast (2.7+/-0.05) and losartan (2.7+/-0.07). Both drugs prevented the increase in left ventricular TGFbeta(1) mRNA and fibronectin mRNA and blunted the increase in hydroxyproline content and the increase in perivascular fibrosis. The perivascular fibrosis score correlated significantly with the level of expression of TGFbeta(1) (r=0.62; P=0.019). In situ hybridization demonstrated increases in TGFbeta(1) mRNA, predominantly in perivascular and nonmyocyte areas. Both drugs did not prevent the decrease in systolic or diastolic dP/dt, but tranilast significantly improved the survival of untreated Ren2 rats (P=0.029). In conclusion, TGFbeta(1) mRNA expression is increased predominantly in nonmyocyte regions in the hypertrophied left ventricle in this angiotensin II-dependent model of hypertension. This increase is probably due to high angiotensin II levels rather than to hypertension. This is the first study to suggest that chronic inhibition of TGFbeta(1) expression attenuates left ventricular hypertrophy and fibrosis, even without lowering blood pressure.

Topics: Animals; Cardiomegaly; Disease Models, Animal; Fibrosis; Heart Diseases; Heart Ventricles; Hypertension; Losartan; Male; ortho-Aminobenzoates; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Receptors, Transforming Growth Factor beta; RNA, Messenger; Survival Analysis; Transforming Growth Factors; Ventricular Function

Tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, a widely used antiallergy drug in Japan, has been shown to inhibit transforming growth factor-beta1 release from fibroblasts and reduce collagen synthesis in keloid cells. In the present study, we have investigated the effect of this drug on cardiac hypertrophy in spontaneously hypertensive rats (SHR), with a focus on the cardiac collagen matrix, which is associated with myocardial stiffness. Twenty-four-week-old SHRs and Wistar Kyoto rats (WKYs) were administered tranilast (300 mg/kg) orally once a day for 4 weeks. This treatment significantly suppressed increases in left ventricular collagen concentration (P < 0.05) and the left ventricular weight/body weights ratios (P < 0.05) in SHRs, and tranilast was ineffective on collagen concentration and ventricular weight/body weights ratios in WKYs. Tranilast did not affect systolic or diastolic blood pressure, end-diastolic left ventricular pressure and heart rate in both SHRs and WKYs, and the agent did not change positive dp/dt or cardiac output in SHRs. The pressure-volume relationship curve was shifted to the left by the drug; the slope (k) of the logarithm of the pressure-volume relationship curve was significantly increased (P < 0.05) in SHRs. It is concluded that the suppression of increases in cardiac collagen and left ventricular mass by tranilast results in a corresponding prevention of cardiac stiffness as studied in the SHR.

Topics: Animals; Anti-Allergic Agents; Blood Pressure; Body Weight; Cardiac Output; Cardiomegaly; Collagen; Heart; Heart Rate; Heart Ventricles; Hemodynamics; Hydroxyproline; Male; Myocardium; Organ Size; ortho-Aminobenzoates; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Species Specificity; Ventricular Function, Left