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,
Many β-adrenoceptor antagonists are weak partial agonists, possessing significant intrinsic sympathomimetic activity (ISA). Under certain conditions, ISA may be deleterious through stimulation of β1- and/or β2-adrenoceptors in the heart. Drugs with ISA are particularly problematic in the treatment of congestive heart failure since agents that activate cardiac β-adrenoceptors, such as xamoterol, have been associated with increases in the incidence of arrhythmia and mortality. Carvedilol was recently approved for the treatment of congestive heart failure, and bucindolol is currently in large clinical trials for this indication. In the present study, the ISA of bucindolol and carvedilol was evaluated in a standard model used to investigate ISA, the pithed rat. Both compounds produced dose-dependent inhibition of the positive-chronotropic effects of the non-selective β-adrenoceptor agonist, isoproterenol, confirming that these drugs are β-adrenoceptor antagonists. However, cumulative administration of bucindolol (10–1,000 µg/kg i.v.) in the pithed rat produced a significant dose-related increase in heart rate. The maximal increase in heart rate produced by bucindolol was 44% of that obtained with isoproterenol (90 ± 6 vs. 205 ± 11 bpm, respectively). In marked contrast, cumulative administration of carvedilol (10–1,000 µg/kg i.v.) had no significant effect on resting heart rate in the pithed rat. The maximal increase in heart rate elicited by bucindolol (1,000 µg/kg i.v.) was inhibited by treatment with the competitive β-adrenoceptor antagonist, propranolol (99 ± 8.7 vs. 26 ± 2.6 bpm), confirming that the ISA observed with bucindolol was mediated through stimulation of myocardial β-adrenoceptors. Carvedilol, which had no ISA, antagonized the ISA of bucindolol, and was as effective as propranolol in blocking the ISA of bucindolol (99 ± 8.7 vs. 27 ± 2.3 bpm). In summary, bucindolol and carvedilol are both potent β-adrenoceptor antagonists in the pithed rat; however, only bucindolol possesses β-adrenoceptor-mediated ISA.
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