Delayed
cerebral ischemia due to
cerebral vasospasm is a major cause of morbidity and mortality in patients with
aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent
vasoconstrictor peptide endothelin (ET) in the pathophysiology of
cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting
enzyme (ECE),
CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits.
Injections of
CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of
CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy. Treatment with
CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of
CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via
intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of
cerebral vasospasm. The ECE inhibitor
CGS 26303 thus represents a promising therapeutic agent for the treatment of
cerebral vasospasm following aneurysmal SAH.