Affiliation:
1. Department of Surgery, University of Chicago Medical Center and Pritzker School of Medicine, Chicago, Illinois; and
2. Division of Neurosurgery, Keenan Research Centre and the Li Ka Shing Knowledge Institute of St. Michael's Hospital and Department of Surgery, University of Toronto, Ontario, Canada
Abstract
Object
The L-type Ca++ channel antagonists like nimodipine have limited efficacy against vasospasm after subarachnoid hemorrhage (SAH). The authors tested the hypothesis that this is because SAH alters these channels, rendering them less responsible for contraction.
Methods
Basilar artery smooth muscle cells were isolated 4, 7, and 21 days after SAH in dogs, and Ca++ channel currents were recorded in 10-mmol/L barium. Proteins for α1 subunits of L-type Ca++ channels were measured by immunoblotting and isometric tension recordings done on rings of the basilar artery.
Results
High voltage–activated (HVA) Ca++ channel currents were significantly decreased and low voltage–activated (LVA) currents increased during vasospasm 4, 7, and 21 days after SAH (p < 0.05). Vasospasm was associated with a significant decrease in the number of cells with negligible LVA current while the number of cells in which the LVA current formed greater than 50% of the maximal current increased (p < 0.01). Window currents through LVA and HVA channels were significantly reduced. All changes correlated with the severity of vasospasm. There was an increase in protein for Cav3.1 and Cav3.3 α1 subunits that comprise T-type Ca++ channels, a decrease in L-type (Cav1.2 and Cav1.3) and an increase in R-type (Cav2.3) Ca++ channel α1 subunits. Functionally, however, isometric tension studies showed vasospastic arteries still relaxed with nimodipine.
Conclusions
Voltage-dependent Ca++ channels are altered in cerebral arteries after SAH. While decreased L-type channels may account for the lack of efficacy of nimodipine clinically, there may be other reasons such as inadequate dose, effect of nimodipine on other cellular targets, and mechanisms of vasospasm other than smooth muscle contraction mediated by activation of L-type Ca++ channels.
Publisher
Journal of Neurosurgery Publishing Group (JNSPG)
Subject
Genetics,Animal Science and Zoology
Cited by
25 articles.
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