title: Prevention of vasospasm after subarachnoid hemorrhage in dogs by continuous intravenous infusion of PD156707.
abstract: This randomized, blinded study tested the prophylactic effect of PD156707, a nonpeptide competitive antagonist of endothelin A receptors, against vasospasm after subarachnoid hemorrhage in dogs. Twenty-two dogs were allocated on day 0 to undergo cerebral angiography followed by injection of arterial blood (0.5 ml/kg) into the cisterna magna. Dogs had central venous catheters implanted for continuous infusion of drug vehicle (n = 10) or PD156707 (n = 12). Cisternal blood injection was repeated on day 2. Drug levels were measured in plasma on days 2, 4, 6, and 7 and in cerebrospinal fluid (CSF) on days 2 and 7. Angiography was repeated on day 7 to assess vasospasm. After angiography on day 7, acute effects of infusion of PD156707, 100 mg, or drug vehicle on established vasospasm were assessed. Analysis of physiological variables within (analysis of variance) groups across time and between (unpaired t-test) groups at each time showed that drug-treated animals had significantly increased heart rate on day 7 compared to day 0 (p < 0.005). Comparison of basilar artery diameters at day 7 showed that PD156707 significantly decreased the degree of basilar artery vasospasm (placebo: -47 +/- 5% reduction [mean +/- SE] versus PD156707: -28 +/- 7%, p < 0.05, unpaired t-test). There was, however, significant vasospasm when comparing within groups (paired t-test, placebo: p < 0.0001, PD156707: p < 0.005). Mean plasma PD156707 levels (322 +/- 123 ng/ml) were adequate to block responses of endothelin-1 on endothelin A receptors in vitro although CSF levels (11 +/- 7 ng/ml) were substantially lower. Infusion of PD156707 into the basilar artery on day 7 caused a small but significant 10 +/- 3% (paired t-test, p < 0.01) increase in diameter compared to placebo (3 +/- 3% increase, p = 0.32). This infusion also was associated with a substantial increase in CSF drug levels to 19 +/- 9 mg/ml. These results suggest that endothelin A receptors mediate some of the vasospasm that occurs after SAH in dogs and that blockade of these receptors may be a beneficial treatment for vasospasm.
authors.affiliation: Department of Surgery, University of Chicago Medical Center, Illinois, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Macdonald
authors.forename: L
authors.initials: L
authors.lastname: Johns
authors.forename: G
authors.initials: G
authors.lastname: Lin
authors.forename: L S
authors.initials: LS
authors.lastname: Marton
authors.forename: H
authors.initials: H
authors.lastname: Hallak
authors.forename: F
authors.initials: F
authors.lastname: Marcoux
authors.forename: A
authors.initials: A
authors.lastname: Kowalczuk
mesh_terms: D000818:Animals; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use*; D004285:Dogs; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control*; D011897:Random Allocation; D013345:Subarachnoid Hemorrhage / Q000209:etiology*; D013997:Time Factors
chemical_list: D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; C093321:PD 156707