Evidence both L-type and non-L-type voltage-dependent calcium channels contribute to cerebral artery vasospasm following loss of NO in the rat.
We recently found block of NO synthase in rat middle cerebral artery caused spasm, associated with depolarizing oscillations in membrane potential (E(m)) similar in form but faster in frequency (circa 1 Hz) to vasomotion. T-type voltage-gated Ca(2+) channels contribute to cerebral myogenic tone and vasomotion, so we investigated the significance of T-type and other ion channels for membrane potential oscillations underlying arterial spasm. Smooth muscle cell membrane potential (E(m)) and tension were measured simultaneously in rat middle cerebral artery. NO synthase blockade caused temporally coupled depolarizing oscillations in cerebrovascular E(m) with associated vasoconstriction. Both events were accentuated by block of smooth muscle BK(Ca). Block of T-type channels or inhibition of Na(+)/K(+)-ATPase abolished the oscillations in E(m) and reduced vasoconstriction. Oscillations in E(m) were either attenuated or accentuated by reducing [Ca(2+)](o) or block of K(V), respectively. TRAM-34 attenuated oscillations in both E(m) and tone, apparently independent of effects against K(Ca)3.1. Thus, rapid depolarizing oscillations in E(m) and tone observed after endothelial function has been disrupted reflect input from T-type calcium channels in addition to L-type channels, while other depolarizing currents appear to be unimportant. These data suggest that combined block of T and L-type channels may represent an effective approach to reverse cerebral vasospasm.
McNeish
A J
AJ
Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
Jimenez Altayo
Francesc
F
Garland
C J
CJ
D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D020768:Middle Cerebral Artery / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects
D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase