C. Communal et al., NOREPINEPHRINE STIMULATES APOPTOSIS IN ADULT-RAT VENTRICULAR MYOCYTESBY ACTIVATION OF THE BETA-ADRENERGIC PATHWAY, Circulation, 98(13), 1998, pp. 1329-1334
Citations number
48
Categorie Soggetti
Peripheal Vascular Diseas",Hematology,"Cardiac & Cardiovascular System
Background-Myocardial sympathetic activity is increased in heart failu
re. We tested the hypothesis that norepinephrine (NE) stimulates apopt
osis in adult rat ventricular myocytes in vitro. Methods and Results-M
yocytes were exposed to NE alone (10 mu mol/L), NE+propranolol (2 mu m
ol/L), NE+prazosin (0.1 mu mol/L), or isoproterenol (ISO, 10 mu mol/L)
for 24 hours. NE and ISO decreased the number of viable myocytes by a
pproximate to 35%. This effect was completely blocked by the beta-adre
nergic antagonist propranolol but was not affected by the alpha(1)-adr
energic antagonist prazosin. NE increased DNA laddering on agarose gel
electrophoresis and increased the percentage of cells that were stain
ed by terminal deoxynucleotidyl transferase-mediated nick end-labeling
from 5.8+/-1.0% to 21.0+/-2.3% (P<0.01; n=4). NE likewise increased t
he percentage of apoptotic cells with hypodiploid DNA content as asses
sed by flow cytometry from 7.8+/-0.7% to 16.7+/-2.2% (P<0.01; n=6), an
d this effect was abolished by propranolol but not prazosin. ISO and f
orskolin (10 mu mol/L) mimicked the effect of NE, increasing the perce
ntage of apoptotic cells to 14.7+/-1.9% and 14.4+/-2.2%, respectively.
NE-stimulated apoptosis was abolished by the protein kinase A inhibit
or H-89 (20 mu mol/L) or the voltage-dependent calcium channel blocker
s diltiazem and nifedipine, Conclusions-NE, acting via the beta-adrene
rgic pathway, stimulates apoptosis in adult rat cardiac myocytes in vi
tro. This effect is mediated by protein kinase A and requires calcium
entry via voltage-dependent calcium channels. NE-stimulated apoptosis
of cardiac myocytes may contribute to the progression of myocardial fa
ilure.