FAVORABLE AMPHIPHILICITY OF NIMODIPINE FACILITATES ITS INTERACTIONS WITH BRAIN MEMBRANES

Nimodipine is a 1,4-dihydropyridine (DHP) calcium channel blocker whic h is used in the treatment of neurological deficits associated with su barachnoid hemorrhage. Small angle x-ray diffraction, differential sca nning calorimetry, and equilibrium and kinetic binding techniques were used to study the interaction of nimodipine with bovine brain phospha tidylcholine (BBPC) membranes of varying cholesterol content. At conce ntrations (5 x 10(-10) M) near its K-d, the membrane partition coeffic ient of nimodipine was inversely related to the cholesterol to phospho lipid (C:P) mole ratio in both model and native (rat synaptoneurosome) membranes. The nonspecific dissociation rate of nimodipine from BBPC was significantly slower at low C:P mole ratio (0.1:1) than at high C: P mole ratio (0.6:1). Calorimetric analysis showed that nimodipine dec reased both the main phase transition temperature and cooperative unit size of melt for dimyristoyl phosphatidylcholine, dependent on membra ne cholesterol content. Small angle x-ray diffraction analysis showed that nimodipine occupies a position in BBPC approx +/-15 Angstrom from the center of the hydrocarbon core, near the hydrocarbon core/water i nterface. These data indicate that nimodipine is an amphiphilic molecu le which rapidly washes out of and transports across membrane bilayers , facilitating its interactions with membranes and possibly its transp ort across the blood-brain barrier.