The guanylyl cyclase activator YC-1 directly inhibits the voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.
We investigated the effects of YC-1, an activator of soluble guanylyl cyclase (sGC), on voltage-dependent K+ (Kv) channels in smooth muscle cells from freshly isolated rabbit coronary arteries by using the whole-cell patch clamp technique. YC-1 inhibited the Kv current in a dose-dependent fashion with an apparent K(d) of 9.67 microM. It accelerated the decay rate of Kv channel inactivation without altering the kinetics of current activation. The rate constants of association and dissociation for YC-1 were 0.36 +/- 0.01 microM(-1) x s(-1) and 3.44 +/- 0.22 s(-1), respectively. YC-1 did not have a significant effect on the steady-state activation and inactivation curves. The recovery time constant from inactivation was decreased in the presence of YC-1, and application of train pulses (1 or 2 Hz) caused a progressive increase in the YC-1 blockade, indicating that YC-1-induced inhibition of Kv currents is use-dependent. Pretreatment with Bay 41-2272 (also a sGC activator), ODQ (a sGC inhibitor), or Rp-8-Br-PET-cGMPs (a protein kinase G inhibitor) did not affect the basal Kv current and also did not significantly alter the inhibitory effect of YC-1. From these results, we suggest that YC-1 directly inhibits the Kv current independently of sGC activation and in a state-, time-, and use-dependent fashion.
Park
Won Sun
WS
National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, FIRST Mitochondrial Research Group, Biomarker Medical Research Center, Inje University, Korea.
Ko
Jae-Hong
JH
Ko
Eun A
EA
Son
Youn Kyoung
YK
Hong
Da Hye
DH
Jung
In Duk
ID
Park
Yeong-Min
YM
Choi
Tae-Hoon
TH
Kim
Nari
N
Han
Jin
J
D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D011817:Rabbits
D020536:Enzyme Activators; D007191:Indazoles; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D006162:Guanylate Cyclase