Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats

Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of alpha-rat atrial natriuretic peptide (alpha-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of alpha-rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.