tranilast and Hypertension

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

Left ventricular hypertrophy (LVH) in patients with hypertension is associated with an increased risk for many cardiovascular events and predicts a higher mortality rate. The pathogenesis of LVH is complicated. In addition to the hemodynamic burden (pressure or volume overload) and demographic factors, several trophic humoral factors, such as angiotensin II, aldosterone, endothelin, leptin, and catecholamines, may also contribute to the development and progression of LVH. Effective antihypertensive therapy can reverse LVH as well as prevent its development. Regression of LVH decreases subsequent cardiovascular morbidity and mortality. The commonly used drugs have various effects on LVH. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors seem most effective. Several new agents, including direct antifibrotic drugs, aldosterone blockade, vasopeptidase inhibitors, and endothelin receptor antagonists that more specifically target the underlying pathogenesis of LVH may provide us with innovative approaches to treat LVH.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Endothelin Receptor Antagonists; Humans; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; ortho-Aminobenzoates; Protease Inhibitors; Pyridines; Thiazepines

Topics: Animals; Collagen; Fibrosis; Humans; Hypertension; Hypertrophy, Left Ventricular; ortho-Aminobenzoates; Rats; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Transforming Growth Factor beta; Transforming Growth Factor beta1

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