Alteration in voltage-dependent calcium channels in dog basilar artery after subarachnoid hemorrhage

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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 Ca(v)3.1 and Ca(v)3.3 α₁ subunits that comprise T-type Ca++ channels, a decrease in L-type (Ca(v)1.2 and Ca(v)1.3) and an increase in R-type (Ca(v)2.3) 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.

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