Effects of captopril on the development of tolerance to guanethidine

Guanethidine is a sympatholytic antihypertensive drug used for the treatment of severe or resistant hypertension. Previous clinical studies have documented the development of tolerance to guanethidine in humans and suggested that fluid retention or increased sensitivity of arterioles to endogenous catecholamines may be responsible for the tolerance development. In this study we investigated the role of the renin-angiotensin system in the development of tolerance to guanethidine in one-kidney, one-clip renovascular and spontaneously hypertensive rats (SHR) using the angiotensin-converting enzyme inhibitor captopril. In the one-kidney model, captopril (30 mg/(kg X day), orally) had no effect on the development of tolerance to guanethidine (50 mg/(kg X day), i.p.) when the drugs were coadministered for 2 wk. However, captopril enhanced the day 1 blood pressure-lowering effect and prevented the development of tolerance to guanethidine in male SHR. These results suggest that the renin-angiotensin system plays a major role in the development of tolerance to guanethidine in SHR but not in one-kidney, one-clip renal hypertensive rats. Thus, the etiology of the hypertensive state may dictate which physiological compensatory mechanisms are activated after antihypertensive drug administration.