SUMMARYDespite a variety of biological roles for nitric oxide (NO) in the cardiovascular system, little is known about whether NO is involved in cardiac hypertrophy. We hypothesized that NO production following a sustained increase in shear stress by volumeoverload modifies the level of cardiac hypertrophy independent of hemodynamic changes. Volume-overload was induced by shunt formation between the left common carotid artery and the external jugular vein in 21 rabbits. These shunt rabbits were randomly assigned to 3 groups: shunt with no treatment (n=8), shunt treated with a low dose of N G -nitro-Larginine methyl ester (L-NAME, 0.5 g/L in drinking water, n=8), and shunt with a high dose of L-NAME (1.5 g/L, n=5). Eight sham operated rabbits were used as controls. Treatments were started immediately after operation and were continued for 6 weeks. Chronic volume-overload by shunt formation caused left ventricular dilatation and arterial enlargement proximal to the fistula. The relative wall thickness of the left ventricle was decreased, indicating eccentric cardiac hypertrophy. L-NAME elevated mean arterial blood pressure (P<0.01) and reduced the increment of cardiac output (P<0.05). L-NAME attenuated ventricular weight (P<0.01), ventricular cavity dilatation (P<0.01), and arterial enlargement (P<0.05). The re-capitulation of atrial natriuretic factor mRNA in the hypertrophied left ventricular myocardium by volume-overload was attenuated with L-NAME. In this model with chronic volume-overload, NO plays a pivotal role in the progression of cardiovascular remodeling by regulating the loading conditions of the heart. (Jpn Heart J 2003; 44: 127-137)