CHRONIC L-ARGININE TREATMENT INCREASES CARDIAC CYCLIC GUANOSINE 5'-MONOPHOSPHATE IN RATS WITH AORTIC-STENOSIS - EFFECTS ON LEFT-VENTRICULARMASS AND BETA-ADRENERGIC CONTRACTILE RESERVE

Objectives. We tested the hypothesis that nitric oxide (NO) cyclic gua nosine 5'-monophosphate (GMP) signaling is deficient in pressure overl oad hypertrophy due to ascending aortic stenosis, and that long-term L -arginine treatment will increase cardiac cyclic GMP production and mo dify left ventricular (LV) pressure overload hypertrophy and beta-adre nergic contractile response. Background. Nitric oxide cyclic GMP signa ling is postulated to depress vascular growth, but its effects on card iac hypertrophic growth are controversial. Methods. Forty control rats and 40 rats with aortic stenosis left ventricular hypertrophy ([LVH] group) were randomized to receive either L-arginine (0.40 g/kg/day) or no drug for 6 weeks. Results. The dose of L-arginine did not alter sy stemic blood pressure. Animals with LVH had similar LV constitutive ni tric oxide synthase (cNOS) mRNA and protein levels, and LV cyclic GMP levels as compared with age-matched controls. In rats with LVH L-argin ine treatment led to a 35% increase in cNOS protein levels (p = 0.09 v s untreated animals with LVH) and a 1.7-fold increase in LV cyclic GMP levels (p < 0.05 vs untreated animals with LVH). However, L-arginine treatment did not suppress LVH in the animals with aortic stenosis. In contrast, in vivo LV systolic pressure was depressed in L-arginine tr eated versus untreated rats with LVH (163 +/- 16 vs 198 +/- 10 mm Hg, p < 0.05). In addition, the contractile response to isoproterenol was blunted in both isolated intact hearts and isolated myocytes from L-ar ginine treated rats with LVH compared with untreated rats with LVH. Th is effect was mediated by a blunted increase in peak systolic intracel lular calcium in response to beta-adrenergic stimulation. Conclusions. Left ventricular hypertrophy due to chronic mechanical systolic press ure overload is not characterized by a deficiency of LV cNOS and cycli c GMP levels. In rats with aortic stenosis, L-arginine treatment incre ased cardiac levels of cyclic GMP, but it did not modify cardiac mass in rats with aortic stenosis. However, long-term stimulation of NO-cyc lic GMP signaling depressed in vivo LV systolic function in LVH rats a nd markedly blunted the contractile response to beta-adrenergic stimul ation.