Experimental Studies with Isradipine in Stroke

Summary

The effects of isradipine in a rat model of embolic stroke [permanent occlusion of the left middle cerebral artery (MCA)] are reviewed. Isradipine, when present or given up to 4 hours after the onset of stroke, reduces the infarct size, determined by magnetic resonance imaging (MRI) 24 hours, and by histology 5 days, after MCA occlusion. These cytoprotective effects seem to be permanent and are paralleled by an improvement in the neurological deficit. Isradipine has proved to be the most potent and effective calcium antagonist for reducing the infarct size compared with other representatives of this class of drugs such as nimodipine, nicardipine and flunarizine.

Isradipine is cytoprotective after a stroke when used as an antihypertensive: at doses which normalise high blood pressure in spontaneously hypertensive rats, isradipine reduces by more than 60% the infarct size caused by a subsequent stroke. Since the lowering of blood pressure, e.g. by a calcium antagonist that does not cross the blood-brain barrier, is ineffective in reducing the infarct size, normalisation of blood pressure alone cannot account for the reductions in infarct size observed with isradipine. The antihypertensive drug isradipine seems rather to offer the additional benefit of attenuating the consequences of an eventual stroke. If clinically confirmed, this will be of considerable therapeutic importance.

Evidence is presented that isradipine has at least 2 mechanisms within the brain that might be responsible for cytoprotection in stroke. Firstly, isradipine improves blood flow to the ischaemic brain areas that are at risk of becoming necrotic, as demonstrated in MCA-occluded rats by in vivo measurements of regional cerebral blood flow using MRI. Secondly, isradipine reduces the turnover rate of high energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] by inhibiting the cerebral consumption of ATP. This is supported by 2 findings: a reduction in the rate constant of the forward creatine kinase reaction, measured by magnetic resonance spectroscopy, and a reduction in the glucose utilisation rate, measured by the deoxyglucose method.