Oral administration of an inhibitor of endothelin-converting enzyme attenuates cerebral vasospasm following experimental subarachnoid haemorrhage in rabbits

Abstract

Increasing evidence has implicated endothelin-1 (ET-1), a potent vasoconstrictive peptide, in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). Endothelin-converting enzyme-1 (ECE-1), the protease involved in the final step of post-translational processing of ET-1, cleaves the inactive precursor big ET-1 at the Trp(21)-Val (22) peptide bond. In our previous study, we found that an inhibitor of ECE-1, CGS 26303, could prevent and reverse the arterial narrowing after SAH in rabbits. CGS 26393, a prodrug of CGS 26303, is an orally active, long-acting inhibitor of ECE-1. The present study examined the effects of CGS 26393 on the prevention and reversal of cerebral vasospasm after SAH. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. In the prevention study, the drug was given orally 1 h before the induction of SAH. All drug treatments in the reversal study were initiated at 23 h after induction of SAH. One of three dosages (3, 10 or 30 mg/kg) of CGS 26393 or vehicle was administrated orally twice daily, and all animals were sacrificed by perfusion and fixation 48 h after SAH. Basilar arteries were removed and sectioned, and cross-sectional areas were measured. Cerebrospinal fluid (CSF) was collected prior to perfusion. Oral administration of CGS 26393 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and reversal groups. These effects achieved statistical significance at all dosages when compared with the SAH-only or SAH plus vehicle groups. Moreover, the attenuation of vasospasm following oral administration of CGS 26393 was more efficacious than that obtained with bolus injections of CGS 26303. The levels of free CGS 26303 in the CSF were increased in a dose-dependent manner in all three CGS 26393-treated groups. This study provides the first evidence that oral administration of an inhibitor of ECE-1, CGS 26393, is capable of preventing and reversing cerebral vasospasm following SAH. These findings also reinforce evidence demonstrating that treatment with an ECE-1 inhibitor is a potentially viable therapeutic approach for reducing cerebral vasospasm after SAH.

Efficacy of remote limb ischemic conditioning on poststroke cognitive impairment

“…As the most potent vasoconstrictor so far (Kwan et al, 2002), ET-1 is synthesized in vascular endothelial cells, smooth muscle cells, neurons, and glial cells, while its receptors are readily available in the cerebrovascular system. Cerebral ischemia and hypoxic conditions greatly increase the production and release of ET-1.…”

Role of calcitonin gene-related peptide in cerebral vasospasm, and as a therapeutic approach to subarachnoid hemorrhage

“…Levels of ET-1 are high in the plasma and cerebrospinal fluid (CSF) of SAH patients, correlate with the persistence of cerebral vasospasm (Seifert et al, 1995;Juvela, 2000), and decline in the absence of vasospasm (Seifert et al, 1995). Conversely, the administration of ET-1 antagonists or endothelin converting enzyme inhibitors prevents vasospasm (Kwan et al, 2002;Macdonald et al, 2008). Lastly, ET-1 induces NADPH oxidase expression and oxidative stress in human endothelial cells (Duerrschmidt et al, 2000).…”

ET‐1‐associated vasomotion and vasospasm in lymphatic vessels of the guinea‐pig mesentery

“…In contrast, high [ET-1] would cause vasospasm and interrupt the flow of lymph. The latter is unfortunately a common event for blood vessels where events such as haemorrhage can lead to vasospasm through marked enhancement of ET-1 production (Kwan et al, 2002). While vasospasm would be a less catastrophic event in lymphatic vessels, it remains a phenomenon of considerable interest, as the underlying mechanisms are likely to share the same properties as for blood vessels.…”