Background and Purpose (±)-SB 209670, a potent nonpeptide endothelin (ET) receptor antagonist, was used to investigate the potential role of ET in cerebral vasospasm associated with subarachnoid hemorrhage.Methods The effects of (±)-SB 209670 were evaluated in isolated segments of canine posterior cerebral arteries in vitro, vascular smooth muscle cells in culture, and in the canine two-hemorrhage model of delayed cerebral vasospasm in vivo.Results In the canine basilar and anterior spinal arteries, (±)-SB 209670 caused a dose-related inhibition of contractile responses mediated by ET (X B =4.6 nmol/L and apparent K B =2.7 nmol/L, respectively). The effects of (±)-SB 209670 were mediated by inhibition of ETA receptors since the ETB selective agonist sarafotoxin 6c did not contract these posterior cerebral vessels. (±)-SB 209670 also produced a concentration-dependent inhibition (IC 5O =1 nmol/L) of the mitogenic response induced by ET-1 in vascular smooth muscle cell culture. In the canine model of delayed cerebral vasospasm,
Erythrocyte lysate increases intracellular Ca2+ ([Ca2+]i)and contracts cerebral arteries in vitro and has been suggested to be the cause for cerebral vasospasm. We investigated the effect of hemolysate on L-type Ca2+ channels directly by using patch clamp techniques in freshly isolated single smooth muscle cells from rat basilar artery. Patch clamp studies revealed a whole-cell current which resembles the L-type Ca2+ current reported by others. Hemolysate reduced the amplitude of the L-type Ca2+ channel current. The effect of hemolysate was reversible by washout and repeatable. Hemolysate was separated into two fractions by using filter membranes. The fraction > 1 kDa which contains oxyhemoglobin and other proteins mimicked the effect of hemolysate, while the fraction < 1 kDa and ATP were without effect. We conclude that hemolysate does not increase [Ca2+]i by activation of L-type Ca2+ channel.
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