Renal dose response and pharmacokinetics of atrial natriuretic factor in dogs

The present studies investigated the dose-plasma level-response relationships with the use of increasing doses of atrial natriuretic factor [ANF-(99-126)] administered by constant infusion in conscious dogs. The preinfusion plasma immunoreactive ANF increased 12, 19, 23, and 35 times during 45-min consecutive infusions of 50, 75, 125, and 175 ng.kg-1.min-1, respectively. Over this pharmacological range, natriuresis increased linearly with the infused dose (r = 0.99, n = 5) to a maximum response of +1,550%, despite the significant gradual fall of blood pressure, which attained a minimum of 83 mmHg (-26%) at 125 ng.kg-1.min-1. There was no change of glomerular filtration rate (GFR) or renal plasma flow at any dose. A very similar renal response was found in 13 other dogs infused with the highest dose only in which the pharmacokinetic parameters of ANF-(99-126) were estimated. Metabolic clearance rate during the infusion was 1.09 +/- 0.19 l/min. The postinfusion decay curve of plasma immunoreactive ANF was best described by a biexponential function. Plasma disappearance half time was 1.44 min during the rapid phase and 10.3 min during the slow phase of elimination. The results show that 1) natriuretic response to ANF in the pharmacological range is dose dependent and occurs despite a pronounced hypotension, 2) increase in GFR is not a prerequisite of ANF-induced natriuresis, and 3) ANF is rapidly eliminated from the circulation, suggesting an intensive uptake and/or degradation in the target tissues.