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Activators of the PKA and PKG pathways attenuate RhoA-mediated suppression of the K_DR current in cerebral arteries

Department of Physiology and Biophysics, University of Calgary, Alberta, Canada

Submitted 16 November 2006 ; accepted in final form 30 January 2007

This study tested whether activation of protein kinase A (PKA) and G (PKG) pathways would attenuate the ability of RhoA to suppress the delayed rectifier K⁺ (K_DR) current and limit agonist-induced depolarization and constriction. Smooth muscle cells from rat cerebral arteries were enzymatically isolated, and whole cell K_DR currents were monitored with conventional patch-clamp electrophysiology. The K_DR current averaged 21.2 ± 2.3 pA/pF (mean ± SE) at +40 mV and was potently inhibited by UTP. Current suppression was eliminated in the presence of C3 exoenzyme, confirming that this modulation is dependent on RhoA. Activation of PKA (dibutyryl-cAMP, forskolin) or PKG (dibutyryl-cGMP, sodium nitroprusside, nitric oxide) similarly abolished the ability of UTP to suppress K_DR and did so without effect on baseline current. Using pressure myography techniques, we stripped cerebral arteries of endothelium and preconstricted them with UTP; these were subsequently shown to hyperpolarize and dilate to both forskolin and sodium nitroprusside. An increase in K_V channel activity was found to partly underlie these associated changes, as constriction to 4-aminopyridine (K_DR channel blocker) was greater after PKA or PKG activation. We conclude from our electrophysiological and functional observations that the PKA and PKG pathways attenuate the ability of UTP to depolarize and constrict cerebral arteries in part by minimizing the RhoA-mediated suppression of the K_DR current.

cyclic nucleotides; pyrimidine nucleotides; Rho signaling; smooth muscle

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