742 | VOLUME 60 | NUMBER 4 | APRIL 2007 www.neurosurgery-online.com EXPERIMENTAL STUDIES AUGMENTATION OF CEREBRAL BLOOD FLOW AND REVERSAL OF ENDOTHELIN-1-INDUCED V ASOSPASM: A COMPARISON OF INTRACAROTID NICARDIPINE AND VERAPAMIL OBJECTIVE: Local intra-arterial infusions of verapamil and nicardipine have been used to treat human cerebral vasospasm. Only a few reports of early clinical experience with these medications are currently available, and limited data are available regarding their cerebral physiological activity. We assessed the efficacy of intracarotid administration of verapamil and nicardipine on augmenting cerebral blood flow of New Zealand White rabbits and compared the ability of these drugs with reverse topical endothelin (ET)-1- triggered vasospasm. METHODS: In the first group of New Zealand white rabbits, cerebral blood flow (laser Doppler) and systemic hemodynamic measurements were recorded at baseline and with increasing intracarotid doses of verapamil and nicardipine. In the second group, topical ET-1 (10 -4 mol/L) was applied in an acutely implanted cranial window. Dose responses to nonspecific reversal of ET-1-induced vasospasm were evaluated with intra- arterially administered nicardipine and verapamil. RESULTS: The dose-response studies revealed that intracarotid administration of nicardip- ine, compared with verapamil, was more effective in augmenting cerebral blood flow. Topical ET-1-induced vasospasm was completely reversed by nicardipine and partially reversed by verapamil. CONCLUSION: This study suggests that intra-arterially administered nicardipine is a more potent cerebral vasodilator and is superior to verapamil for treating ET-1-induced experimental cerebral vasospasm and supports further investigation of these agents in subarachnoid hemorrhage-induced vasospasm. KEY WORDS: Endothelin-1, Intra-arterial, Intracarotid, Nicardipine, Vasospasm, Verapamil Neurosurgery 60:742–749, 2007 DOI: 10.1227/01.NEU.0000255404.30904.CE www.neurosurgery-online.com Sean D. Lavine, M.D. Departments of Radiology and Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, New York Mei Wang, M.P.H. Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York Joshua J. Etu, B.A. Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York Philip M. Meyers, M.D. Departments of Radiology and Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, New York Shailendra Joshi, M.D. Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York Reprint requests: Shailendra Joshi, M.D., Department of Anesthesiology, P&S P Box 46, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032. Email: sj121@columbia.edu Received, June 2, 2006. Accepted, December 5, 2006. C alcium channel blockers have an impor- tant role in the clinical management of aneurysmal subarachnoid hemorrhage (SAH). Vasospasm affects up to 70% of people who experience SAH, leading to death in 25% of patients and significant disability in 50% of the survivors (7, 8). Several prospective, ran- domized trials have demonstrated improved neurological outcomes in the patients treated with oral nimodipine (19, 20). In recent years, both verapamil and nicardipine have been administrated intra-arterially for treating cere- bral vasospasm after SAH (1, 4). However, no studies have compared the cerebrovascular effects of these drugs when administered by the intra-arterial route. Verapamil and nicardipine are frequently used for treating hypertension. Both increase cerebral blood flow (CBF) if administered by the intra-arterial route in humans (12, 13). It is generally thought that intravenous nicardip- ine has a preferentially greater effect on CBF compared with verapamil. Vasodilator effects of systemically administered verapamil occur at doses that cause cardiovascular depression. In contrast, nicardipine has a more selective effect on the vascular smooth muscles (5). Intra-arterial bolus injections of medication result in free drug concentrations that are 5- to 25-fold greater than those suggested by pro- tein-binding parameters (9). Intravenous nicardipine is 95% protein bound, whereas, in