Pharmacodynamics of atrial natriuretic peptide in isolated perfused Dahl rat kidneys

Atrial natriuretic peptide (ANP) has been implicated in the development of hypertension in Dahl R and S rats. To test the responses of DR and DS kidneys in the absence of the influence of neural and humoral mechanisms, we investigated the pharmacokinetics and pharmacodynamics of ANP in isolated perfused DR and DS kidneys, obtained from rats given a high or low sodium diet, after a bolus injection of ANP (1 microgram) or after a bolus injection plus infusion of ANP to maintain the perfusate concentration at 1000 pg/ml. The elimination rate constant was not different between the groups (DR, 0.044 min-1 vs. DS, 0.050 min-1). Clearance of ANP was 4 times greater than the glomerular filtration rate, indicating that a receptor-mediated peritubular clearance is probably the primary route of elimination. DS kidneys excreted 50% less sodium than DR kidneys. However, ANP caused a 5-fold increase in fractional sodium excretion in both DR and DS. ANP also increased sodium excretion, creatinine clearance, and urine flow. No alteration in ANP kinetics occurred to account for the reportedly increased circulating concentrations of ANP seen in DS rats. We conclude that isolated DR and DS kidneys respond differently to ANP after bolus ANP administration to concentrations of 10,000 pg/ml. This difference in response is due to the sodium excretory defect inherent in the DS kidney and not to an alteration in the DS kidney's ANP responsiveness.