sirolimus and imidapril

Chronic inhibition of nitric oxide (NO) synthesis is reported to induce the thickening of coronary artery walls and cardiac hypertrophy in vivo via angiotensin II receptors. Increased protein synthesis is the main feature of these structural changes. Activation of 70 kD S6 kinase (p70S6K) phosphorylates the 40S ribosomal protein S6 that regulates protein synthesis. We examined the role of p70S6K in the vascular and myocardial structural changes induced by the chronic inhibition of NO synthesis. The following 5 groups were studied: untreated Wister-Kyoto rats, those treated with an inhibitor of NO synthase, Nomega-nitro-L-arginine methyl ester (L-NAME), those treated with L-NAME and an angiotensin I converting enzyme inhibitor (imidapril), those treated with L-NAME and hydralazine, and those treated with L-NAME and an inhibitor of p70S6K (rapamycin). After 8 weeks, wall-to-lumen ratio in myocardium and cardiomyocyte cross-sectional areas were quantified. L-NAME increased systolic blood pressure, wall-to-lumen ratio, and cardiomyocyte cross-sectional area compared with control animals. Imidapril or rapamycin, but not hydralazine, markedly reduced these structural changes. L-NAME increased p70S6K activity in myocardium compared with control rats. Imidapril or rapamycin prevented the activation of p70S6K activity in myocardium induced by L-NAME. These results suggest that activation of p70S6K plays an important role in coronary vascular remodeling and cardiac hypertrophy induced by the chronic inhibition of nitric oxide synthesis in vivo.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Coronary Vessels; Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Hydralazine; Imidazoles; Imidazolidines; Immunosuppressive Agents; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Inbred WKY; Ribosomal Protein S6 Kinases; Sirolimus; Ventricular Remodeling