tacrolimus and candesartan

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcineurin; Cardiomegaly; Echocardiography; Fibrosis; Gene Expression Regulation; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; RNA, Messenger; Stress, Mechanical; Tacrolimus; Tetrazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

The development of progressive glomerulosclerosis (GS) has been attributed to a number of humoral and hemodynamic factors, however, neither the exact pathomechanism nor the prevention and treatment have been clearly established. Renin-angiotensin system (RAS), interleukin-2 (IL-2)-activated T cells, systemic BP, and serum lipid levels all have been recognized as pathogenetic factors. According to our working hypothesis, a combination therapy with the inhibition of RAS and IL-2 system may be more potent in the prevention of the progression of GS than a monotherapy. After 5/6 subtotal nephrectomy, rats were treated with either the angiotensin-converting enzyme-blocker enalapril (E), the angiotensin II AT1 receptor blocker candesartan cilexetil (CA), the IL-2 synthesis inhibitor tacrolimus (T), or a combination of these agents. Proteinuria, as a functional hallmark of GS, was determined regularly, and at week 16, systolic BP, plasma total cholesterol, and triglyceride (TG) levels were measured and kidneys were harvested for morphologic and immunohistochemical analysis. Combination therapy was more effective (proteinuria: CA + T: 29.3+/-12.8 mg/24 h, E + T: 31.3+/-13.0 mg/24 h; GS: CA + T: 10.7+/-4.1%, E + T: 8.3+/-4.6%, P < 0.01) than monotherapy (proteinuria: T: 49.3+/-17.3 mg/24 h, CA: 53.2+/-18.1 mg/24 h, E: 51.1+/-26.6 mg/24 h; GS: T: 10.9+/-4.4%, CA: 23.8+/-4%, E: 14.2+/-5.3%, P < 0.05, with control values of proteinuria: 77.6+/-27.1 mg/24 h and GS: 28+/-2.9%). The number of infiltrating ED-1 (rat macrophage marker) macrophages (T: 161.5+/-51.2 cells/field of view, CA: 203.6+/-102.3, E: 178.6+/-35.3, CA + T: 140.2+/-63.2, E + T:128.2+/-75.6), and CD-5+ (rat T cell marker) T lymphocytes (CA + T: 261.5+/-103.6, E + T: 236+/-94.8) was significantly reduced by the treatment protocols (controls: ED-1: 356+/-100, CD-5: 482.9+/-154.5). These results indicate that an inhibition of RAS either with angiotensin-converting enzyme or AT1 receptor blockade, together with the inhibition of IL-2 synthesis, is more effective in the prevention of GS than a single treatment alone.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cholesterol; Disease Models, Animal; Enalapril; Glomerulosclerosis, Focal Segmental; Immune System; Immunosuppressive Agents; Interleukin-2; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Tacrolimus; Tetrazoles; Triglycerides