Ryanodine receptors regulate arterial diameter and wall Ca2+ in cerebral arteries of rat via Ca2+-dependent K+ channels

摘要

class="enumerated" style="list-style-type:decimal">The effects of inhibitors of ryanodine-sensitive calcium release (RyR) channels in the sarcoplasmic reticulum (SR) and Ca²⁺-dependent potassium (KCa) channels on the membrane potential, intracellular [Ca²⁺], and diameters of small pressurized (60 mmHg) cerebral arteries (100–200 μm) were studied using digital fluorescence video imaging of arterial diameter and wall [Ca²⁺], combined with microelectrode measurements of arterial membrane potential.Ryanodine (10 μm), an inhibitor of RyR channels, depolarized by 9 mV, increased intracellular [Ca²⁺] by 46 nm and constricted pressurized (to 60 mmHg) arteries with myogenic tone by 44 μm (∼22 %). Iberiotoxin (100 nm), a blocker of KCa channels, under the same conditions, depolarized the arteries by 10 mV, increased arterial wall calcium by 51 nm, and constricted by 37 μm (∼19 %). The effects of ryanodine and iberiotoxin were not additive and were blocked by inhibitors of voltage-dependent Ca²⁺ channels.Caffeine (10 mm), an activator of RyR channels, transiently increased arterial wall [Ca²⁺] by 136 ± 9 nm in control arteries and by 158 ± 12 nm in the presence of iberiotoxin. Caffeine was relatively ineffective in the presence of ryanodine, increasing [calcium] by 18 ± 5 nm.In the presence of blockers of voltage-dependent Ca²⁺ channels (nimodipine, diltiazem), ryanodine and inhibitors of the SR calcium ATPase (thapsigargin, cyclopiazonic acid) were without effect on arterial wall [Ca²⁺] and diameter.These results suggest that local Ca²⁺ release originating from RyR channels (Ca²⁺ sparks) in the SR of arterial smooth muscle regulates myogenic tone in cerebral arteries solely through activation of KCa channels, which regulate membrane potential through tonic hyperpolarization, thus limiting Ca²⁺ entry through L-type voltage-dependent Ca²⁺ channels. KCa channels therefore act as a negative feedback control element regulating arterial diameter through a reduction in global intracellular free [Ca²⁺].