In normotensive rats, the arterial vasodilator minoxidil causes right ventricular hypertrophy (RVH) and eccentric left ventricular hypertrophy (LVH). To assess whether this trophic effect of minoxidil extends to the vasculature and to examine possible mechanisms involved, alterations in cardiac and arterial (superior, large and small mesenteric arteries, carotid and basilar arteries) structure were evaluated in relation to changes in indexes of cardiac volume load and cardiac and arterial sympathetic activity during long-term (35 and 70 days) treatment of normotensive rats with minoxidil alone or in combination with the diuretic hydrochlorothiazide (HCTZ). Minoxidil alone increased LV and RV weights, LV internal diameter, and medial area of the superior mesenteric artery but did not affect any of the other arteries evaluated. When combined with HCTZ, long-term minoxidil caused concentric LVH rather than eccentric LVH and no longer increased the medial area of the superior mesenteric artery. Neither treatment had any persistent effect on blood pressure, heart rate, or plasma catecholamines. However, minoxidil significantly increased cardiac and arterial (superior and large mesenteric artery) norepinephrine turnover rates, cardiac filling pressures, and plasma and blood volumes. When combined with HCTZ, short-term (1 wk) minoxidil still increased cardiac filling pressures. However, intravascular volume expansion during chronic treatment was significantly attenuated. These results suggest that chronic cardiac volume load appears to determine the type of cardiac hypertrophy induced by a nonhemodynamic mechanism (possibly cardiac sympathetic activity) activated by minoxidil. Intravascular volume expansion or increased arterial flow appears to be responsible for medial hypertrophy of the superior mesenteric artery, but absence of a trophic response in other arteries suggests that another, local mechanism contributes.