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

Harm J. Knot, Nicholas B. Standen * and Mark T. Nelson

1. The effects of inhibitors of ryanodine-sensitive calcium release (RyR) channels in the sarcoplasmic reticulum (SR) and Ca²⁺-dependent potassium (K_Ca) 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.

2. 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 K_Ca 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.

3. 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.

4. 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.

5. 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 K_Ca channels, which regulate membrane potential through tonic hyperpolarization, thus limiting Ca²⁺ entry through L-type voltage-dependent Ca²⁺ channels. K_Ca channels therefore act as a negative feedback control element regulating arterial diameter through a reduction in global intracellular free [Ca²⁺].

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