Sequential Method for Combined Screening Antihypertensive and Diuretic Agents in the Same Spontaneously Hypertensive Rat (SHR)

Abstract

A combined method for detecting compounds with antihypertensive and diuretic activity simultaneously in the same spontaneously hypertensive (SH) rat is described. The present method, utilizing the advantages of sequential probability test analysis, the spontaneously hypertensive rats and the direct measurement of arterial blood pressure, proves to be feasible and efficient in detecting both activities. This is a 3-stage sequential test requires one to three rats per compound. One adult SH rat was dosed by gavage with a compound at 100 mg/kg, p.o. and loaded with 0.9% NaCl at 25 ml/kg, p.o. at 0-hr. The rat was put in a metabolism cage. The 0-5 hr. urine was collected and urinary Na⁺, K⁺ and C1^- were determined. A second identical dose was given without NaCl loading at 24-hr. Mean arterial blood pressure (MABP) of conscious rats was measured directly by fermoral-iliac artery puncture at 28-hr. The criteria to accept, retest or reject a compound were based on the testing of known antihypertensives and diuretics. A 2nd and 3rd rat may be needed for a test compound depending on the outcome of the MABP and urinary electrolytes of the 1st rat. Based on MABP, guancydine, hydralazine, clonidine, reserpine, α-methyldopa, guanethidine and pargyline were accepted as active. Based on urinary sodium excretion, furosemide, quinethazone, acetazolamide, hydrochlorothiazide, metolazone, triamterene and clonidine were accepted as active.