Abstract
Isoflurane activates protein kinase A (PKA) in vascular smooth muscle cells (VSMCs), which in turn activates ATP-sensitive potassium (K(ATP)) channels and causes vasodilation. The present study was undertaken to examine whether advanced age influences the effect of isoflurane on K(ATP) channel activity in cultured VSMCs. We used VSMCs obtained from 12- to 15-week-old (adult) and 24- to 25-month-old (aged) male Wistar rats. Electrophysiological experiments were performed using cell-attached and inside-out patch-clamp techniques to monitor the K(ATP) channel activity. Application of isoflurane or forskolin to the bath solution in cell-attached recordings induced a significant increase in K(ATP) channel activity in the VSMCs from the adult group. However, K(ATP) channel opening induced by isoflurane, but not forskolin, was significantly suppressed by aging. On the other hand, cell-free recordings showed similar pharmacologic sensitivity to the K(ATP) channel opener pinacidil, inward rectification, and unitary conductance (40–45 pS) between groups. In addition, direct K(ATP) channel activation by c-PKA in the inside-out patches was similar in both groups. Furthermore, increasing PKA activation in cell-attached patches by CPT-cAMP restored isoflurane's effects in the aged group. These results suggest that aging decreases isoflurane-induced PKA activation, resulting in attenuation of K(ATP) channel opening.
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