Abstract
This randomized, blinded study tested the prophylactic effect of PD156707, a nonpeptide competitiveantagonist 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 arterialblood (0.5 ml/kg) into the cisterna magna. Dogs had central venous catheters implanted for continuousinfusion of drug vehicle (n=10) or PD156707 (n=12). Cisternal blood injection was repeatedon day 2. Drug levels were measured in plasma on days 2, 4, 6, and 7 and in cerebrospinal fluid (CSF) ondays 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 (unpairedt-test) groups at each time showed that drug-treated animals had significantly increased heartrate on day 7 compared to day 0 (p<0.005). Comparison of basilar artery diameters at day 7 showedthat 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. Infusionof PD156707 into the basilar artery on day 7 caused a small but significant 10±3% (paired ttest, p<0.01) increase in diameter compared to placebo (3±3% increase, p=0.32). This infusionalso was associated with a substantial increase in CSF drug levels to 19±9 mg/ml. These results suggestthat endothelin A receptors mediate some of the vasospasm that occurs after SAH in dogs and thatblockade of these receptors may be a beneficial treatment for vasospasm.
