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Use of the hydrated rat to assay diuretic and antidiuretic activity of drugs
Author(s) -
DeFelice Albert,
Harris Alex,
Brousseau Armand
Publication year - 1991
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430220109
Subject(s) - hydralazine , diuretic , hydrochlorothiazide , diuresis , aminophylline , kaliuresis , endocrinology , chemistry , medicine , verapamil , excretion , natriuresis , pharmacology , kidney , blood pressure , calcium
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 differents effects in SHR and SD rats. That is, it elicited diuresis in the SHR at 10mg/kg (Δ Na + = +155%) and no change in urine volume or Na + and K + cutput at 30 mg/kg, where as 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 the 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.