NITRIC-OXIDE REGULATES THE CALCIUM CURRENT IN ISOLATED HUMAN ATRIAL MYOCYTES

被引:164
作者
KIRSTEIN, M
RIVETBASTIDE, M
HATEM, S
BENARDEAU, A
MERCADIER, JJ
FISCHMEISTER, R
机构
[1] UNIV PARIS SUD,FAC PHARM,INSERM,CJF 9211,CARDIOL CELLULAIRE & MOLEC LAB,F-92296 CHATENAY MALABRY,FRANCE
[2] UNIV PARIS SUD,HOP MARIE LANNELONGUE,CARDIOL MOLEC & CELLULAIRE LAB,CNRS,URA 1159,F-92350 LE PLESSIS ROBINS,FRANCE
关键词
HUMAN CARDIAC MYOCYTES; CALCIUM CHANNEL CURRENT; NITRIC OXIDE; CGMP; CGMP-INHIBITED PHOSPHODIESTERASE;
D O I
10.1172/JCI117729
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Cardiac Ca2+ current (I-Ca) was shown to be regulated by cGMP in a number of different species. Recently, we found that the NO-donor SIN-1 (3-morpholino-sydnonimine) exerts a dual regulation of I-Ca in frog ventricular myocytes via an accumulation of cGMP. To examine whether NO also regulates Ca2+ channels in human heart, we investigated the effects of SIN-1 on I-Ca in isolated human atrial myocytes. An extracellular application of SIN-1 produced a profound stimulatory effect on basal I-Ca at concentrations > 1 pM. Indeed, 10 pM SIN-1 induced a approximate to 35% increase in I-Ca. The stimulatory effect of SIN-1 was maximal at 1 nM (approximate to 2-fold increase in I-Ca) and was comparable with the effect of a saturating concentration (1 mu M) of isoprenaline, a beta-adrenergic agonist. Increasing the concentration of SIN-1 to 1-100 mu M reduced the stimulatory effect in two thirds of the cells. The stimulatory effect of SIN-1 was not mimicked by SIN-1C, the cleavage product of SIN-1 produced after liberation of NO. This suggests that NO mediates the effects of SIN-1 on I-CA. Because, in frog heart, the stimulatory effect of SIN-1 on I-Ca was found to be due to cGMP-induced inhibition of cGMP-inhibited phosphodiesterase (cGI-PDE), we compared the effects of SIN-1 and milrinone, a cGI-PDE selective inhibitor, on I-Ca in human. Milrinone (10 mu M) induced a strong stimulation of I-Ca (approximate to 150%), demonstrating that cGI-PDE controls the amplitude of basal I-Ca in this tissue. In the presence of milrinone, SIN-1 (0.1-1 nM) had no stimulatory effect on I-Ca suggesting that the effects of SIN-1 and MIL were not additive. We conclude that NO may stimulate I-Ca in human atrial myocytes via inhibition of the cGI-PDE.
引用
收藏
页码:794 / 802
页数:9
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