MAGNETIC-RESONANCE-IMAGING STUDY ON THE EFFECT OF LEVEMOPAMIL ON THE SIZE OF INTRACEREBRAL HEMORRHAGE IN RATS

Background and Purpose Beneficial effects of calcium antagonists in ce rebral ischemia and trauma have been attributed in part to improved ce rebral blood flow. Enhancement of cerebral blood flow, however, could aggravate the pathological situation if brain injury is associated wit h intracerebral hemorrhage. In this study we used high-field magnetic resonance imaging in an animal model of intracerebral hemorrhage to de termine noninvasively the effect of the calcium and serotonin antagoni st levemopamil [international nonproprietary name for (S)-emopamil] wh en infused in a dose (6 mg/kg) that is known to increase cerebral bloo d flow. Methods Intracerebral hemorrhage was induced in rats by stereo taxic microinfusion of collagenase into the caudate putamen. Two serie s of experiments were performed. (1) Levemopamil was intravenously inf used 30 minutes after intracerebral infusion of collagenase (0.05 U), which represents the time of intracranial bleeding. Another group of a nimals was given heparin (55 IU . kg(-1) . min(-1)) to evaluate the ca pability of this animal model to demonstrate drug-induced worsening of intracerebral hemorrhage. (2) The effects of hyperacute infusion of l evemopamil (30 minutes after infusion of 0.5 U of collagenase) were co mpared with those of a 2-hour delayed administration. In both experime ntal settings, the extent of intracerebral hemorrhage was determined b y T-1-weighted magnetic resonance images (spin-echo; repetition time, 400 milliseconds; echo time, 23 milliseconds) taken in vivo in a coron al and a transverse brain plane 24 hours after collagenase infusion. R esults (1) Hemorrhagic brain areas measured 10.1+/-2.9 mm(2), 8.5+/-2. 1 mm(2), and 18.8+/-2.5 mm(2) in the coronal brain plane (10 mm anteri or to the interaural line) of control, levemopamil-, and heparin-infus ed rats, respectively (8 animals per group, mean+/-SD). In the transve rse brain plane (6 mm dorsal to the interaural line) the hemorrhagic a rea was 11.5+/-3.6 mm(2), 9.7+/-2.4 mm(2), and 19.9+/-3.3 mm(2) in con trol, levemopamil-, and heparin-infused rats, respectively. (2) Animal s with 2-hour delayed levemopamil infusion displayed intracerebral hem orrhage similar in size to that of control rats. (3) Neither small nor large hemorrhagic lesions were increased by levemopamil. Conclusions Aggravation of intracerebral hemorrhage was not observed by magnetic r esonance imaging in levemopamil-infused animals. However, infusion of heparin caused a significant (P<.05), almost twofold increase in the s ize 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 he morrhage may occur.