© 1997 American Heart Association, Inc.
Articles |
Direct Inhibition of Expressed Cardiac L-Type Ca2+ Channels by S-Nitrosothiol Nitric Oxide Donors
From the Section of Molecular and Cellular Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Eduardo Marban, MD, PhD, 844 Ross Bldg, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. E-mail marban{at}welchlink.welch.jhu.edu
Abstract NO donors have complex effects on Ca2+
currents in native cardiac cells, with reports of direct stimulation
and indirect cGMP-mediated inhibition or stimulation. To investigate
the molecular basis of these effects, we tested the effects of one
class of NO donors, S-nitrosothiols (RSNOs), on
expressed cardiovascular L-type Ca2+
channels (
1C±ß1a±2 or
1C±ß2a±2) in human
embryonic kidney (HEK293) cells. The RSNO compounds we used were
S-nitroso-N-acetylpenicillamine (SNAP, 5
to 10 nmol/L or 100 to 800 µmol/L),
S-nitrosocysteine (SNC, 100 µmol/L or 1
mmol/L), and S-nitrosoglutathione (GSNO, 1 mmol/L).
Currents were measured using whole-cell patch recordings with 2
to 10 mmol/L Ba2+ as the charge carrier. SNAP reduced
the amplitude of barium currents (IBa) through all the
subunit combinations, with an EC50 of 360 µmol/L for
1C+ß1a channels. SNC or GSNO also
inhibited IBa, albeit less potently. The
inhibitory effect of SNAP was not affected by methylene
blue (10 to 30 µmol/L) or 8-bromo-cGMP (200 to 400
µmol/L). The effects are relatively specific for Ca2+
channels, as expressed cardiac or skeletal muscle Na+
channels, which have a similar overall architecture, were barely
affected by SNAP at concentrations as high as 1 mmol/L. We
conclude that in the HEK293 expression system, the
S-nitrosothiol NO donors inhibit L-type Ca2+
channels by a mechanism independent of cGMP.
Key Words: nitric oxide • Ca2+ channel • Na+ channel • cysteine • oxidation
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