Diltiazem protects against functional changes in chronic cerebrovasospasm in monkeys.

Abstract

Diltiazem given 48 hours before experimental subarachnoid hemorrhage protects the cerebral vasculature of monkeys against the widespread cerebrovascular spasm seen on angiography after 5-6 days and against associated neurologic defects. In vitro examination of the cerebral arteries from treated monkeys shows that compared with untreated animals, the functional changes in the vascular smooth muscle cells, the increase in arterial wall stiffness, and the decrease in contractility, all of which were prominent in untreated monkeys, were relatively small. Other changes such as abnormal spontaneous myogenic tone, decreased responsiveness to constrictor and dilator nerve activation, and other indexes of neuronal function were little influenced by the drug. We suggest that chronic cerebrovasospasm may be initiated by the combined action of exceptionally high concentrations of a number of putative spasmogens causing injury to the larger cerebral arteries. However, the later development of intractable spasm is related to the location of blood clot and to the involvement of the vascular wall in an inflammatory process. The combined insult results in pathologic changes in the artery wall resulting in increased thickness and stiffness. Diltiazem acts on cerebrovascular smooth muscle in lower concentrations than on smooth muscle in other vascular beds, interfering with calcium entry through receptor-operated and potential-sensitive channels, and may protect against calcium-induced cell death through these and additional actions. Protection against early events presumably prevents the genesis of the subsequent chronic state.