title: Role of nitric oxide in Ca2+ sensitivity of the slowly activating delayed rectifier K+ current in cardiac myocytes.
abstract: Sarcolemmal Ca2+ entry is a vital step for contraction of cardiomyocytes, but Ca2+ overload is harmful and may trigger arrhythmias and/or apoptosis. To maintain the amount of Ca2+ entry within an appropriate range, cardiomyocytes have feedback systems that tightly regulate ion channel activities in response to the changes in intracellular Ca2+ concentration ([Ca2+]i), thereby regulating Ca2+ entry. In guinea pig ventricular myocytes, Ca2+ ionophore, A23187, induced suppression of the L-type Ca2+ currents (I(Ca,L)) and enhancement of the slowly activating delayed rectifier K(+) currents (I(Ks)). At a low stimulation rate, I(Ca,L) suppression and I(Ks) enhancement contributed to the A23187-induced APD shortening with a similar magnitude, whereas at a high stimulation rate, I(Ks) enhancement dominantly contributed to APD shortening. I(Ks) enhancement induced by A23187 was attributable to actions of nitric oxide (NO), because they were inhibited by an inhibitor of NO synthase (NOS) and by a NO scavenger. A23187-induced alterations of APD and I(Ks) were strongly suppressed by a NOS3 inhibitor, but barely affected by a NOS1 inhibitor, suggesting that NOS3 was responsible for NO release in this phenomenon. Inhibition of calmodulin (CaM), but not Akt, blocked the enhancement of I(Ks) by A23187. Thus, CaM-dependent NOS3 activation confers the selective Ca2+-sensitivity on I(Ks). Ca2+-induced I(Ks) enhancement and resultant APD shortening potentially act as a physiological regulatory mechanism of Ca2+ recycling, because they were observed at a physiological range of [Ca2+]i in cardiac myocytes and are induced by physiologically relevant Ca2+ loading, such as digitalis application and rise in extracellular Ca2+ concentration.
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Chang-Xi
authors.initials: CX
authors.lastname: Bai
authors.forename: Iyuki
authors.initials: I
authors.lastname: Namekata
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
authors.forename: Koki
authors.initials: K
authors.lastname: Shigenobu
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000200:Action Potentials; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002839:Chromans / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D004558:Electric Stimulation; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D017136:Ion Transport / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D015737:Nisoldipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002147:Calmodulin; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D007476:Ionophores; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D009569:Nitric Oxide; D000001:Calcimycin; D015737:Nisoldipine; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D011188:Potassium; D002118:Calcium