The expression of the natriuretic peptide clearance receptor is abundant in human and rat adipose tissue, where it is specifically inhibited by fasting. In obese hypertensives, plasma atrial natriuretic peptide (ANP) levels were found to be lower than in obese normotensives. Therefore, the increased adipose mass might influence ANP levels and/or its biological activity. The aim of the present study was to evaluate whether the humoral, hemodynamic, and renal effects of exogenous ANP in obese hypertensives might be enhanced by a very low calorie diet. Eight obese hypertensives received a bolus injection of ANP (0.6 mg/kg) after 2 weeks of a normal calorie/normal sodium diet, and blood pressure (BP), heart rate, ANP, cGMP, plasma renin activity, and aldosterone were evaluated for 2 hours before and after the injection. Diuresis and natriuresis were measured every 30 minutes. The patients then started a low calorie/normal sodium diet (510 kcal/150 mmol/d) for 4 days, and then the ANP injection protocol was repeated. The low calorie diet induced a slight weight loss (from 90.6+/-1.1 to 87. 7+/-1.2 kg; P<0.01), which was accompanied by increase of cGMP excretion (from 146.0+/-10.1 to 154.5+/-9.5 nmol/24 h; P<0.05) together with a reduction of BP (P<0.01 versus basal levels). ANP injection after diet was followed by an increase of ANP levels similar to that observed before diet, but plasma cGMP, diuresis, and natriuresis increased significantly only after diet. Similarly, the decrease of BP after ANP administration was significantly higher after diet (change in mean arterial pressure, -6.4+/-0.7 versus -4. 0+/-0.6 mm Hg; P<0.05) as well as that of aldosterone (P<0.01). These data show that a low calorie diet enhances the humoral, renal, and hemodynamic effects of ANP in obese hypertensives and confirm the importance of caloric intake in modulating the biological activity of ANP, suggesting that the natriuretic peptide system can play a role in the acute changes of natriuresis and diuresis associated with caloric restriction.