Effect of mefenidil on cerebral and peripheral hemodynamics in dogs

Mefenidil (5-methyl-2-phenyl-4-imidazole-acetonitrile) has been reported to be a selective cerebral vasodilator. We examined the specificity of this vasodilator by using the radiolabeled microsphere technique to compare changes in cerebral blood flow (CBF) with those in other organs. Measurements were made in pentobarbital-anesthetized dogs at 10 min of continuous i.v. infusion of mefenidil at rates of 0.025, 0.25 and 2.5 mg/min/kg. Systemic vascular resistance decreased at 0.25 mg/min/kg without a change in CBF. At the highest infusion rate, CBF increased by 54 ± 15% (± S.E.; n = 9) accompanied by a 9-mm Hg rise in intracranial pressure and a 14-mm Hg fall in mean aortic pressure. However, cardiac output increased by 68 ± 8%, which was distributed primarily to right ventricle (541 ± 95%), left ventricle (488 ± 109%), small intestine (136 ± 31%) and large intestine (57 ± 15%). Within the brain, thalamic and brainstem regions had larger increases in blood flow than cerebellum and cerebrum. Caudate nucleus had a greater percentage of response than white matter. Using the cerebral venous outflow technique in another series of seven dogs, mefenidil (40-mg/kg i.v. bolus) produced a 20 ± 8% increase in CBF with no change in O₂ uptake. These data show that mefenidil is capable of increasing CBF in healthy brain without stimulating O₂ uptake. However, the clinical usefulness of mefenidil as a cerebral vasodilator may be limited by the accompanying arterial hypotension due to systemic vasodilation, which was most prominent in heart and gut.