Activation of the cGMP-dependent protein kinase mimics the stimulatory effect of nitric oxide and cGMP on calcium-gated potassium channels.
Nitric oxide (NO) is an endogenous vasodilator and inhaled NO is a promising therapeutic agent for the treatment of pulmonary hypertension. However, NO's mechanism of action is not completely understood. Previous studies have shown that NO increases intracellular levels of cyclic guanosine 3',5'-monophosphate (cGMP) and that leads to activation of calcium-gated potassium channels in vascular smooth muscle cells. Resulting cell membrane hyperpolarization causes vasorelaxation. The potassium channel activation by NO is inhibited by a blockade of cyclic nucleotide-dependent protein kinases, suggesting a key role of these enzymes in NO-induced vasodilation. To further examine this mechanism, we tested the hypothesis that pharmacological stimulation of the cGMP-dependent protein kinase will simulate the activating effect of NO on potassium channels. Indeed, we found that (Sp)-guanosine cyclic 3',5'-phosphorothioate (1 microM), a selective activator of the cGMP-dependent protein kinase, dramatically increased potassium currents measured by the whole-cell patch clamp technique in freshly dispersed pulmonary artery smooth muscle cells. These currents were inhibited by an inhibitor of calcium-gated potassium channels, charybdotoxin. Our results support the hypothesis that the effect of NO on potassium channels is mediated by the cGMP-dependent protein kinase.
Hampl
V
V
Department of Medicine, University of Minnesota, Minneapolis, USA.
Huang
J M
JM
Weir
E K
EK
Archer
S L
SL
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D015220:Calcium Channels; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP