Recent in vitro studies on isolated coronary and mesenteric arteries have shown that hyperlipidemia appears to hypersensitize the vascular arterial smooth muscle to drugs such as ergonovine and that this increased contractility seems to be mediated by a serotinergic mechanism. This results in vasospasm with exposure to certain vasoactive drugs such as serotonin or norepinephrine. However, in vivo quantification of this observed phenomenon has not been done. In the present study we used Watanabe hereditary hyperlipidemic (WHHL) rabbits (cholesterol level 459±216 mg/dL) and the normal lipidemic New Zealand white (NZW) rabbit (cholesterol level 35±19) as a control in the study of hyperlipidemia and blood flow changes in response to various vasoactive drugs. Blood flow measurements were made by the video dilution technique (VDT) following catheterization of the superior mesenteric artery. The serotinergic vasoactive drug ergonovine maleate was injected into the superior mesenteric artery at low dose (0.002 mg/kg) and high dose (0.004 mg/kg). A significant decrease (p<. 05) in blood flow was observed in response to high-dose ergonovine maleate in WHHL rabbits compared to the NZW rabbits. This in vivo experiment confirms the in vitro studies showing that hyperlipidemia sensitizes mesenteric arteries in the presence of serotinergic stimuli. The vasodilators verapamil hydrochloride and calcitonin gene-related peptide (CGRP) injected into the superior mesenteric artery caused a marked increase in flow in both the WHHL and the normal lipidemic NZW rabbits. This model can be used in the assessment of superior mesenteric artery ischemia and its reversal.