Nitric oxide (NO) is essential for the normal functioning of the cardiovascular system. This study has determined whether chronic administration of L-arginine, the biological precursor of NO, attenuates the development of structural and functional changes in the hearts and blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Uninephrectomised rats treated with DOCA, 25mg every 4th day sc, and 1% NaCl in the drinking water for 4 weeks developed hypertension, left ventricular hypertrophy with an increased left ventricular wall thickness and decreased ventricular internal diameter, increased ventricular interstitial and perivascular collagen deposition, increased passive diastolic stiffness, prolonged action potential duration and an inability to increase purine efflux in response to an increased workload. Administration of L-arginine (5% in food; 3.4?0.3 g/kg/day body weight) markedly attenuated or prevented these changes. Noradrenaline and acetylcholine produced decreased maximal responses in isolated thoracic aortic rings of DOCA-salt rats; L-arginine normalised these responses. Thus, L-arginine treatment prevents the development of hypertension and an increased cardiac stiffness following DOCA-salt treatment and attenuates ventricular and vascular remodelling, action potential prolongation and increased purine efflux. This study suggests that a functional NO deficit in blood vessels and the heart due to decreased NO synthase activity or increased release of reactive oxygen species such as superoxide may be a key change initiating many aspects of the cardiovascular impairment observed in DOCA-salt hypertensive rats. These changes can be prevented or attenuated by administration of L-arginine.