PKA and PKG regulate RhoA‐mediated suppression of K DR current in cerebral arteries

This study tested whether protein kinase A (PKA) & G (PKG) could attenuate the ability of RhoA to 1) suppress the delayed rectifier K + (K DR ) current and 2) depolarize and constrict cerebral arteries. Myocytes from rat cerebral arteries were enzymatically isolated and whole cell K DR currents monitored using conventional patch clamp electrophysiology. At +40 mV, the KDR current averaged 21.2+2.3 pA/pF (mean+SE) and the 4‐aminopyridine sensitive component was potently inhibited by uridine triphosphate (UTP; 30 uM). Consistent with past observations, K DR suppression was blocked by the RhoA inhibitor C3 exoenzyme (10 mg/ml in the patch pipette). The activation of PKA (dibutyryl cAMP, 200 nM; forskolin; 1uM) or PKG (dibutyryl‐cGMP, 100 nM; sodium nitroprusside, 20 uM) abolished ability of UTP to suppress K DR . Using pressure myography techniques, cerebral arteries (preconstricted with UTP and stripped of endothelium) were subsequently shown to dilate and hyperpolarize to forskolin. Increased K DR activity was found to underlie this dilation/hyperpolarization as the constriction to 4‐AP (5mM; an open pore K DR channel blocker) was greater following PKA activation. We conclude from our electrophysiological and functional observations that PKA and likely PKG attenuate the ability of UTP to depolarize and constrict cerebral arteries by minimizing the RhoA‐mediated suppression of K DR . Supported by CIHR and AHFMR.