Inhibition of nitric oxide synthesis induces coronary vascular remodeling and cardiac hypertrophy associated with the activation of p70 S6 kinase in rats

Chronic inhibition of nitric oxide (NO) synthesis is reported to induce the thickening of coronary artery walls and cardiac hypertrophy in vivo via an giotensin II receptors. Increased protein synthesis is the main feature of these structural changes. Activation of 70 kD S6 kinase (p70(S6K)) phosphor ylates the 40S ribosomal protein S6 that regulates protein synthesis. We ex amined the role of p70(S6K) in the vascular and myocardial structural chang es induced by the chronic inhibition of NO synthesis. The following 5 group s were studied: untreated Wister-Kyoto rats, those treated with an inhibito r of NO synthase, N-omega-nitro-L-arginine methyl ester (L-NAME), those tre ated with L-NAME and an angiotensin I converting enzyme inhibitor (imidapri l), those treated with L-NAME and hydralazine, and those treated with L-NAM E and an inhibitor of p70(S6K) (rapamycin). After 8 weeks, wall-to-lumen ra tio in myocardium and cardiomyocyte cross-sectional areas were quantified. L-NAME increased systolic blood pressure, wall-to-lumen ratio, and cardiomy ocyte cross-sectional area compared with control animals. Imidapril or rapa mycin, but not hydralazine, markedly reduced these structural changes. L-NA ME increased p70(S6K) activity in myocardium compared with control rats. Im idapril or rapamycin prevented the activation of p70(S6K) activity in myoca rdium induced by L-NAME. These results suggest that activation of p70(S6K) plays an important role in coronary vascular remodeling and cardiac hypertr ophy induced by the chronic inhibition of nitric oxide synthesis in vivo.