Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase.
Nitric oxide (NO)-induced relaxation is associated with increased levels of cGMP in vascular smooth muscle cells. However, the mechanism by which cGMP causes relaxation is unknown. This study tested the hypothesis that activation of Ca-sensitive K (KCa) channels, mediated by a cGMP-dependent protein kinase, is responsible for the relaxation occurring in response to cGMP. In rat pulmonary artery rings, cGMP-dependent, but not cGMP-independent, relaxation was inhibited by tetraethylammonium, a classical K-channel blocker, and charybdotoxin, an inhibitor of KCa channels. Increasing extracellular K concentration also inhibited cGMP-dependent relaxation, without reducing vascular smooth muscle cGMP levels. In whole-cell patch-clamp experiments, NO and cGMP increased whole-cell K current by activating KCa channels. This effect was mimicked by intracellular administration of (Sp)-guanosine cyclic 3',5'-phosphorothioate, a preferential cGMP-dependent protein kinase activator. Okadaic acid, a phosphatase inhibitor, enhanced whole-cell K current, consistent with an important role for channel phosphorylation in the activation of NO-responsive KCa channels. Thus NO and cGMP relax vascular smooth muscle by a cGMP-dependent protein kinase-dependent activation of K channels. This suggests that the final common pathway shared by NO and the nitrovasodilators is cGMP-dependent K-channel activation.
Archer
S L
SL
Cardiovascular Section (111C), Veterans Affairs Medical Center, Minneapolis, MN 55417.
Huang
J M
JM
Hampl
V
V
Nelson
D P
DP
Shultz
P J
PJ
Weir
E K
EK
D000818:Animals; D018999:Charybdotoxin; D006152:Cyclic GMP / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000494:pharmacology; D008297:Male; D008839:Microelectrodes; D009569:Nitric Oxide / Q000494:pharmacology*; D019319:Okadaic Acid; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011651:Pulmonary Artery / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*
D004988:Ethers, Cyclic; D015221:Potassium Channels; D000644:Quaternary Ammonium Compounds; D012604:Scorpion Venoms; D013873:Thionucleotides; D018999:Charybdotoxin; D019319:Okadaic Acid; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; C027917:tetramethylammonium; D006152:Cyclic GMP