In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 96, No. 1 ( 2005-01-07), p. 64-72
Abstract:
Sarcolemmal Ca 2+ entry is a vital step for contraction of cardiomyocytes, but Ca 2+ overload is harmful and may trigger arrhythmias and/or apoptosis. To maintain the amount of Ca 2+ entry within an appropriate range, cardiomyocytes have feedback systems that tightly regulate ion channel activities in response to the changes in intracellular Ca 2+ concentration ([Ca 2+ ] i ), thereby regulating Ca 2+ entry. In guinea pig ventricular myocytes, Ca 2+ ionophore, A23187, induced suppression of the L-type Ca 2+ 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 Ca 2+ -sensitivity on I Ks . Ca 2+ -induced I Ks enhancement and resultant APD shortening potentially act as a physiological regulatory mechanism of Ca 2+ recycling, because they were observed at a physiological range of [Ca 2+ ] i in cardiac myocytes and are induced by physiologically relevant Ca 2+ loading, such as digitalis application and rise in extracellular Ca 2+ concentration.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/01.RES.0000151846.19788.E0
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2005
detail.hit.zdb_id:
1467838-X
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