Endothelin-1 and big endothelin cause subarachnoid hemorrhage in the anesthetized rabbit

Intra-arterial injection of endothelin-1 (ET-1) (1 nmol/kg; n = 8) or human big endothelin-1 (b-ET-1; 3 nmol/kg; n = 8) into anesthetized rabbits produced a significant rise in left ventricular systolic pressure (LVSP) and caused subarachnoid hemorrhage (SAH) in 75 +/- 17% and 88 +/- 12% of the experiments, respectively. In all animals, the SAH occurred in the subarachnoid space around the distal part of the basilar artery complex. The cyclooxygenase inhibitor indomethacin (5 mg/kg i.v.) significantly potentiated the pressor effect of both peptides, and all animals pretreated with indomethacin prior to ET-1 (n = 3) or b-ET (n = 3) developed SAH. In contrast, rabbits treated with vehicle (saline; n = 7), indomethacin alone (n = 3), or the carboxy-terminal fragment of b-ET (CT 22-38; 3 nmol/kg i.a.; n = 3) developed neither a rise in LVSP nor SAH. A rise in blood pressure alone is unlikely to account for the SAH brought about by the peptides for angiotensin II (1 nmol/kg/min for 30 min; n = 7) produced a significantly greater increment in LVSP than ET-1 or b-ET, but did not cause SAH. In addition, there was no significant correlation between the rise in LVSP produced by ET-1 or b-ET and the severity of the SAH.