Effects of combination of vasodilator drugs and hypertonic solutions on methotrexate distribution into the rat brain

The present experiments were designed to find a method to facilitate methotrexate (MTX) transfer into rat brain tissue. Adult male Wistar-Kyoto strain rats, anesthetized with pentobarbital-Na, received an infusion of the drug solution to be tested into the right internal carotid artery (5 ml/min, 30 sec) 5 min before injection of MTX (7 mg/kg). After 10 min, the MTX levels in the cerebral hemispheres were estimated as a peak height ratio unit of MTX vs. the internal standard by high performance liquid chromatography. MTX was undetectable in either hemisphere after the pretreatment with saline alone or 15% mannitol-saline. The MTX levels in the right hemisphere were about 10 after the pretreatment with 20% mannitol-saline, while MTX was undetectable in the left hemisphere. In contrast, the MTX levels in the right hemisphere were dose-dependently increased to about 25, 130 and 60, 100, respectively, when nitroglycerin (NTG, 2.5 or 7.5 micrograms/rat) or nicardipine-HCl (NIC, 1.25 or 2.5 micrograms/rat) was administered together with 20% mannitol-saline. These vasodilator drugs, however, had no effect when tested in combination with saline or 15% mannitol-saline. It is assumed that an increase in cerebrovascular blood flow induced by NTG or NIC enhances the MTX transfer into the brain once the blood brain barrier is opened by hypertonic solutions.