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In rats with severe two-kidney, one clip (2-K.1C) hypertension the time-course of changes in left and right ventricular (LV and RV) weight and LV dimensions was assessed following initiation of chronic treatment with minoxidil, enalapril or removal of the clipped kidney in relation to changes in blood pressure (BP) and sympathetic activity, as well as plasma and blood volumes. Minoxidil decreased BP markedly, but tolerance to the antihypertensive effect developed after 2-3 weeks. In contrast, enalapril or uninephrectomy caused a rapid and persistent normalization of BP.Significant increases in LV and RV weight occurred after 3-5 weeks of treatment with minoxidil. Left ventricular wall thickness decreased over the initial 1-2 weeks and then returned to untreated levels. Left ventricular internal dimensions showed an increase after 1-2 weeks of minoxidil, which persisted with more prolonged treatment. With enalapril, regression to normal occurred for both LV and RV weight within 1 week of treatment. Following uninephrectomy a more gradual regression took place and normal cardiac weight was not obtained until 3 weeks.Indices of sympathetic activity (plasma catecholamines, BP response to hexamethonium or heart rate) did not differ significantly in minoxidil treatment versus untreated hypertensive rats from 2 to 35 days of treatment. A significant increase in heart rate was found after 1 day of minoxidil and a decrease after enalapril. Plasma and blood volumes were elevated in minoxidil-treated rats from 7 to 35 days, as well as initially after uninephrectomy.Therefore, in 2-K.1C hypertensive rats long-term treatment with minoxidil induces both RV hypertrophy and LV eccentric hypertrophy. Changes in cardiac volume load may play a major role in the differing effects of different antihypertensive therapies on cardiac hypertrophy.