No abstract

Our previous in vivo studies (Hou et al. J Clin Invest. 1995;96:2469-2477.) demonstrated that chronic inhibition of nitric oxide synthase led to an exaggerated response to relatively low doses of angiotensin II, resulting in a rapid and marked cardiac fibrosis. To examine further the importance of angiotensin II in inducing cardiac fibrosis and the possibility that nitric oxide serves as a modulator of the proliferative effects of angiotensin II, we used cultured rat cardiac fibroblasts to study the interrelationships between these substances. Angiotensin II induced a delayed DNA synthetic response in quiescent cells that occurred 30 hours after exposure to the hormone. The most pronounced effect of angiotensin II on thymidine uptake occurred 36 to 42 hours after the addition to cells. This response was inhibited in a dose-dependent manner by the addition of either S-nitroso-N-acetylpenicillamine or sodium nitroprusside, each a source of nitric oxide. The nitric oxide donor was most effective in reducing thymidine incorporation when added 12 hours after angiotensin II, whereas the metabolite N-acetylpenicillamine had no effect at any time. The inhibitory effect of S-nitroso-N-acetylpenicillamine was mimicked by 8-bromoguanosine 3':5'-cyclic monophosphate but not by 8-bromoadenosine 3':5'-cyclic monophosphate. Nitric oxide donors did not appear to inhibit the induction of c-fos, Egr-1, or other immediate-early genes in response to angiotensin II. The results suggest that nitric oxide affects the cell cycle following the transition into G, and modulates the proliferation of fibroblasts during cardiac fibrosis induced by angiotensin II.

We studied the effects of chronic blockade of the renin-angiotensin system on hypertension and cardiac left ventricular hypertrophy (LVH) in Dahl salt-sensitive (DS) rats given a high-salt or low-salt diet. [Experiment 1] Twelve-week-old male DS rats were fed an 8% NaCI diet and received the angiotensin II receptor (AT1) antagonist, candesartan (3 mg/kg/d), the angiotensin converting enzyme inhibitor enalapril (30 mg/kg/d), or vehicle for 6 wk after 3 wk of 8 % salt-loading. Neither candesartan nor enalapril with concomitant high salt-loading attenuated the blood pressure (BP) elevation. LVH was also not attenuated significantly by these treatments. [Experiment 2] After 8 wk of 8 % salt-loading, the rats were given a 0.3% NaCI diet and concurrently received candesartan, enalapril, or vehicle for 5 wk. Switching from the high-salt to low-salt diet significantly decreased BP and left ventricular mass in the vehicle-treated animals. Both candesartan and enalapril normalized BP during salt-depletion; the blockade of the reninangiotensin system produced an additive reduction in LVH. These findings suggest that sodium intake and hemodynamic load, but not the renin-angiotensin system, may be major determinants of the development of LVH in DS rats. Numerous studies have demonstrated that angiotensin II (Ang II) plays a key role in the development and maintenance of hypertensive cardiac hypertrophy in experimental animals and humans. Blockade of Ang II receptors inhibits intracellular signaling of stretch-mediated hypertrophy of cultured cardiomyocytes, suggesting that pure mechanical stimuli can elicit myocardial cell hypertrophy by stimulating Ang II secretion from cardiomyocytes (1). It is thus conceivable that cardiac hypertrophy caused by mechanical (hemodynamic) load alone can be reduced by Ang II receptor antagonism.Dietary high-salt intake causes cardiac hypertrophy and hypertension in Dahl salt-sensitive (DS) rats and suppresses plasma renin activity (PRA). Thus, it appears that cardiac hypertrophy in saltloaded DS rats is induced mainly by hemodynamic load, with only a small contribution from the reninangiotensin system. However, if activation of a local renin-angiotensin system (RAS) is involved in cardiac left ventricular hypertrophy (LVH), blockade of the RAS could reduce LVH even in salt-loaded DS rats. We have previously demonstrated that angiotensin type I (AT1) receptor antagonists did not blunt hypertension or reduce LVH in DS rats fed a 4% NaCI diet (2, 3).Our findings suggest that sodium intake plays a major role in the development of LVH and hypertension in salt-loaded DS rats, and that the tissue RAS might not be activated in DS rats fed a 4% NaCI diet. It has been reported that an 8% sodium loading initially suppressed PRA and then increased its value after a 4-wk period of high-salt loading in DS rats (4). These findings suggest that the circulating RAS is activated even in DS rats given an 8% NaCI diet for a longer period, and suggest the possibility that the tissue renin-angiotensin system in DS...