Magnetic resonance imaging study on the effect of levemopamil on the size of intracerebral hemorrhage in rats.

Abstract

Beneficial effects of calcium antagonists in cerebral ischemia and trauma have been attributed in part to improved cerebral blood flow. Enhancement of cerebral blood flow, however, could aggravate the pathological situation if brain injury is associated with intracerebral hemorrhage. In this study we used high-field magnetic resonance imaging in an animal model of intracerebral hemorrhage to determine noninvasively the effect of the calcium and serotonin antagonist levemopamil [international nonproprietary name for (S)-emopamil] when infused in a dose (6 mg/kg) that is known to increase cerebral blood flow. Intracerebral hemorrhage was induced in rats by stereotaxic microinfusion of collagenase into the caudate putamen. Two series of experiments were performed. (1) Levemopamil was intravenously infused 30 minutes after intracerebral infusion of collagenase (0.05 U), which represents the time of intracranial bleeding. Another group of animals was given heparin (55 IU.kg-1.min-1) to evaluate the capability of this animal model to demonstrate drug-induced worsening of intracerebral hemorrhage. (2) The effects of hyperacute infusion of levemopamil (30 minutes after infusion of 0.5 U of collagenase) were compared with those of a 2-hour delayed administration. In both experimental settings, the extent of intracerebral hemorrhage was determined by T1-weighted magnetic resonance images (spin-echo; repetition time, 400 milliseconds; echo time, 23 milliseconds) taken in vivo in a coronal and a transverse brain plane 24 hours after collagenase infusion. (1) Hemorrhagic brain areas measured 10.1 +/- 2.9 mm2, 8.5 +/- 2.1 mm2, and 18.8 +/- 2.5 mm2 in the coronal brain plane (10 mm anterior to the interaural line) of control, levemopamil-, and heparin-infused rats, respectively (8 animals per group, mean +/- SD). In the transverse brain plane (6 mm dorsal to the interaural line) the hemorrhagic area was 11.5 +/- 3.6 mm2, 9.7 +/- 2.4 mm2, and 19.9 +/- 3.3 mm2 in control, levemopamil-, and heparin-infused rats, respectively. (2) Animals with 2-hour delayed levemopamil infusion displayed intracerebral hemorrhage similar in size to that of control rats. (3) Neither small nor large hemorrhagic lesions were increased by levemopamil. Aggravation of intracerebral hemorrhage was not observed by magnetic resonance imaging in levemopamil-infused animals. However, infusion of heparin caused a significant (P < .05), almost twofold increase in the size of intracerebral hemorrhage. These results justify clinical trials with levemopamil in cerebral disorders such as stroke, brain trauma, and peritumoral brain edema, which may be accompanied by intracerebral hemorrhage from the beginning or where transition to intracerebral hemorrhage may occur.