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Studies on the mechanism of the synergistic antihypertensive activity of captopril and hydrochlorothiazide following acute administration in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHR), captopril at 30 and hydrochlorothiazide (HCTZ) at 100 mg/kg/day p.o. for 2 days lowered mean arterial blood pressure (MABP) 16 and 10 mm Hg, respectively. Treatment with the combination of captopril plus HCTZ for one day lowered MABP to the same extent as captopril alone, but produced a synergistic 44 mm Hg MABP lowering after the second day combination treatment. Bilateral ureteral ligation did not prevent the synergistic antihypertensive effect demonstrating that removal of electrolytes was not the cause of this effect. Cardiovascular responses to angiotensin-I and -II, norepinephrine or bradykinin did not differ in rats given the combination or captopril alone. After the combination treatment for one day, captopril but not HCTZ alone on the second day lowered MABP in rats to the same degree as in those receiving the combination treatment for 2 days, suggesting that the diuretic action per se is unimportant. Captopril and HCTZ increased plasma renin activity (PRA) but only the combination of captopril and HCTZ produced a greater and longer lasting increase of PRA. It is concluded that the mechanism for the synergism is the renin dependency, created by the combination of HCTZ and captopril, resulting in a greater role of the renin system in blood pressure control and increased responsiveness to angiotensin converting enzyme inhibition by captopril.