Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage

Abstract

Cerebral vasospasm is a major complication of subarachnoid hemorrhage (SAH) after the rupture of an intracranial aneurysm. Although the cause of cerebral vasospasm has not been fully established, several lines of evidence suggest that the vasoconstrictor peptide endothelin (ET) may play a crucial role. In the present study the potential of TBC 11251 (TBC), a newly developed ET A receptor antagonist, to prevent and/or reverse cerebral vasospasm was examined in a well-established rabbit model of SAH. Sixty-five New Zealand White rabbits were assigned to one of six groups. Experimental SAH was induced in rabbits comprising five of the groups by injecting autologous arterial blood into the cisterna magna. The treatment groups were as follows: 1) control (no SAH); 2) SAH only; 3) SAH + placebo at 24 and 36 hours (24/36); 4) SAH + TBC (24/36); 5) SAH + placebo twice daily (BID); and 6) SAH + TBC BID. All drug-treated animals received an intravenous dosage of 5 mg/kg TBC. After 48 hours, the animals were killed by intracardiac perfusion with fixative. The brainstems were removed and the basilar arteries (BAs) were prepared for histological examination. The cross-sectional area of each BA was measured using computer-assisted videomicroscopy by an investigator blind to the group from which it came. A one-way analysis of variance and paired group mean comparisons with the post-hoc Fisher least significant difference test were used for analysis of BA diameters and physiological parameters. The model provided reliable vasospasm, with the mean BA cross-sectional area constricting from 0.388 mm 2 in the control group to 0.106 mm 2 (27.4% of control) in the SAH only group. Treatment with TBC (24/36) after SAH (reversal protocol) produced a mean BA area of 0.175 mm 2 (44.2% of control) which, although larger than the placebo group value of 0.135 mm 2 (39.9% of control), was not statistically significant. However, treatment with TBC BID (prevention protocol) produced a mean BA area of 0.303 mm 2 (78.1% of control) compared with the placebo BID value of 0.134 mm 2 (34.6% of control); this effect was statistically significant (p < 0.01). There were no side effects noted and no differences in the mean arterial pressures between drug and placebo groups. These findings demonstrate that systemic administration of the ET A receptor antagonist TBC significantly attenuates cerebral vasospasm after SAH when given as a preventative therapy, and they provide additional support for the role of ET in the establishment of vasospasm.