Nitric oxide regulates the calcium current in isolated human atrial myocytes.
Cardiac Ca2+ current (ICa) 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 ICa 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 ICa in isolated human atrial myocytes. An extracellular application of SIN-1 produced a profound stimulatory effect on basal ICa at concentrations > 1 pM. Indeed, 10 pM SIN-1 induced a approximately 35% increase in ICa. The stimulatory effect of SIN-1 was maximal at 1 nM (approximately 2-fold increase in ICa) and was comparable with the effect of a saturating concentration (1 microM) of isoprenaline, a beta-adrenergic agonist. Increasing the concentration of SIN-1 to 1-100 microM 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 ICa. Because, in frog heart, the stimulatory effect of SIN-1 on ICa 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 ICa in human. Milrinone (10 microM) induced a strong stimulation of ICa (approximately 150%), demonstrating that cGI-PDE controls the amplitude of basal ICa in this tissue. In the presence of milrinone, SIN-1 (0.1-1 nM) had no stimulatory effect on ICa, suggesting that the effects of SIN-1 and MIL were not additive. We conclude that NO may stimulate ICa in human atrial myocytes via inhibition of the cGI-PDE.
Kirstein
M
M
Laboratoire de Cardiologie Cellulaire et Moléculaire, Institut National de la Santé et de la Recherche Médicale CJF 92-11, Université de Paris-Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
Rivet-Bastide
M
M
Hatem
S
S
Bénardeau
A
A
Mercadier
J J
JJ
Fischmeister
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001001:Anura; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D006325:Heart Atria; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D020105:Milrinone; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011728:Pyridones / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology*
D015220:Calcium Channels; D011728:Pyridones; D014665:Vasodilator Agents; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006152:Cyclic GMP; D020105:Milrinone; D007545:Isoproterenol