Hypoxia reduces K Ca channel activity by inducing Ca 2+ spark uncoupling in cerebral artery smooth muscle cells

Large‐conductance Ca 2+ ‐activated potassium (K Ca ) channels have been implicated in mediating hypoxic dilation of cerebral arteries, but this is controversial. In arterial myocytes, K Ca channel activity is controlled by localized Ca 2+ transients, termed Ca 2+ sparks. Although O 2 regulation of whole‐cell K Ca currents or single K Ca channels has been studied, hypoxic regulation of Ca 2+ sparks and K Ca channels activated by Ca 2+ sparks has not been investigated. Our data show that in voltage‐clamped (−40 mV) cerebral artery myocytes, hypoxia (O 2 from 150 to 20 mmHg) decreased Ca 2+ spark‐induced transient K Ca current frequency from 0.76±0.18 to 0.39±0.12 Hz and reduced amplitude from 20±2 to 16±2 pA. Hypoxia did not alter Ca 2+ spark amplitude, but reduced the percentage of Ca 2+ sparks that activated a transient K Ca current from 90 to 70%. Consistent with this finding, in inside‐out patches at −40 mV hypoxia reduced K Ca channel apparent Ca 2+ sensitivity and increased the K d for Ca 2+ from 17 to 30μM. In contrast, hypoxia did not change global intracellular Ca 2+ concentration in voltage‐clamped myocytes, SR Ca 2+ load or mitochondrial membrane potential. In summary, data indicate that hypoxia induces Ca 2+ spark uncoupling through a mechanism that is independent of cytosolic factors. Data also suggest that K Ca channel inhibition would oppose, rather than contribute to, the hypoxic vasodilation.