USE OF THE HYDRATED RAT TO ASSAY DIURETIC AND ANTIDIURETIC ACTIVITY OF DRUGS

This study compared oral renal excretory effects of several agents in three rat strains with that reported in man to assess predictive value of this species in cardiorenal drug development. Sprague-Dawley (SD), Wistar-Kyoto (WK), and spontaneously hypertensive rats (SHR) were hydrated and 3 hr urine volume, Na+, and K+ were measured, Normotensive SD and WK rats responded similarly, i.e., hydrochlorothiazide (HCTZ) and aminophylline were diuretic, while hydralazine and milrinone caused Na+ retention. Accordingly, the more economical SD rat was then compared with SHR. Aminophylline (3-30 mg/kg) and the more effective HCTZ (1-30 mg/kg) achieved dose-related diuresis and kaliuresis in both strains, increasing Na+ excretion by a maximum of 5-14-fold, whereas the vasodilators hydralazine (3-30 mg/kg) and milrinone (1-10 mg/kg) reduced Na+, K+, and volume dose-relatedly with Na+ output being 5-50% of control values. Verapamil promoted Na+ excretion in both strains by 1.5- to 4-fold at 30 mg/kg, but was antinatriuretic at 80 mg/kg. Conversely, nifedipine had qualitatively different effects in SHR and SD rats. That is, it elicited diuresis in the SHR at 10 mg/kg (DELTA-Na+ = + 155%) and no change in urine volume or Na+ and K+ output at 30 mg/kg, whereas the Ca++-antagonist provoked dose-related volume, Na+, and K+ retention in the normotensive rat with 3 hr output being ca. 15-22% of that of vehicle-treated controls. Accordingly the SD rat predicted renal effects typically seen clinically for all agents except milrinone (Cody et al.: Clinical Pharmacology and Therapeutics 39:128-135, 1986), supporting use of the economical SD rat as a primary assay for effects on renal excretion with the SHR strain reserved for assessing Ca++-channel blockers in the hypertensive state.