(Hypertension. 2001;37:34.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Synergistic Antihypertensive Effects of Nifedipine on Endothelium
Concurrent Release of NO and Scavenging of Superoxide
From the Department of Chemistry and Biochemistry (V.B., L.K., T.M.), Ohio University, Athens, Ohio, and Institute of Cardiovascular Research (R.M.-P.), Bayer AG, Wuppertal, Germany. Dr Kalinowski is on sabbatical leave from the Department of Biochemistry, Medical University of Gdansk, and the Laboratory of Cellular and Molecular Nephrology, Medical Research Center of the Polish Academy of Science, Gdansk, Poland.
Correspondence to Prof Tadeusz Malinski, PhD, Department of Chemistry and Biochemistry, Ohio University, Athens, Ohio 45701-2979. E-mail malinski{at}ohio.edu
Recent
studies have suggested that part of the vasorelaxation caused by
nifedipine, a 1,4-dihydropyridine
Ca2+ antagonist, depends on the
endothelium. To study the effect of
endothelium-dependent vasorelaxation, the release of NO
and superoxide
(O2-) in the
presence of nifedipine in isolated cultured rabbit
endothelial cells was measured. Highly sensitive
electrochemical microsensors were placed onto the cell membrane, and
the kinetics of NO and
O2- were measured
simultaneously with time resolutions of 0.1 and 0.05 ms,
respectively. Nifedipine at its therapeutical
concentrations stimulated NO release and scavenged
O2- in
endothelial cells. The linear relationship between NO
concentration and nifedipine concentration was observed in
the range between 0.01 and 1 nmol/L. NO concentration reached a
maximum of 200±10 nmol/L at 1.2 nmol/L of nifedipine. The
NO concentration was 
50% and 30% of the concentration measured in
the presence of receptor-dependent (acetylcholine) and the
receptor-independent (Ca2+ ionophore A23187)
NO synthase (eNOS) agonists, respectively. NO release stimulated by
eNOS agonists was followed by the generation of the NO scavenger
superoxide. The concentration of
O2- was
significantly lower after stimulation with nifedipine (peak
5±0.5 nmol/L) than after stimulation with acetylcholine (15±1 nmol/L)
and Ca2+ ionophore (25±1 nmol/L). The
average rate of NO release by nifedipine is relatively slow
(17 nmol/L per second). This is in sharp contrast to the fast rate of
NO release by acetylcholine and Ca2+
ionophore (40 and 300 nmol/L per second, respectively). These
experiments show that nifedipine, apart from its well-known
Ca2+ antagonistic properties in
vascular smooth muscle cells, stimulates the release of significant
concentration of NO in endothelium and also preserves
NO concentration. Both these effects may be beneficial in the treatment
of hypertension.
Key Words: nifedipine • endothelium • nitric oxide • superoxide
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