(Circulation. 1996;93:2068-2079.)
© 1996 American Heart Association, Inc.
Articles |
Endothelin-1 Is Involved in Norepinephrine-Induced Ventricular Hypertrophy In Vivo
Acute Effects of Bosentan, an Orally Active, Mixed Endothelin ETA and ETB Receptor Antagonist
From the National Heart and Lung Institute, Imperial College, London (S.K., K.R.B., P.H.S., P.A.P.-W.); Royal Brompton Hospital, London (S.K., P.A.P.-W.); and the Institute of Molecular Medicine, John Radcliffe Hospital, Oxford (J.D.F.), England.
Correspondence to Dr Samer Kaddoura, Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College, London SW3 6LY, England, UK. E-mail s.kaddoura@ic.ac.uk.
Background Endothelin-1 (ET-1) has potent effects on cell growth and induces hypertrophy of cultured ventricular myocytes. Catecholamines increase expression of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in catecholamine-induced hypertrophy in vivo by studying the effects of continuous norepinephrine infusion on physical and molecular markers of ventricular hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute effects of bosentan, an orally active ETA and ETB receptor antagonist.
Methods and Results Seventy male Sprague-Dawley
rats (175 to 200 g) were divided into four groups: (1)
sham-operated rats, (2) norepinephrine-infused rats
(600
µg·kg-1·h-1
by subcutaneous osmotic pump, up to 7 days), (3) sham-operated rats
given bosentan, and (4) norepinephrine-infused rats
given bosentan. Bosentan (100 mg/kg once daily) was administered by
gavage for 6 days starting 1 day before operation.
Norepinephrine caused increases in absolute
ventricular weight and ratios of ventricular
weight to body weight and ventricular RNA to protein.
Ventricular expression of mRNAs for atrial
natriuretic factor, skeletal 
-actin, and
ß-myosin heavy chain, which in adult rat ventricle are indicators
of hypertrophy, also increased. Ventricular
expression of ET-1 mRNA was elevated in the norepinephrine
group at 1, 2, and 3 days. By 5 days, this had fallen to control
levels. In lung, kidney, and skeletal muscle,
norepinephrine did not significantly increase expression of
ET-1 mRNA. Bosentan attenuated norepinephrine-induced
increases in ventricular weight, ratio of RNA to protein,
and expression of skeletal -actin mRNA and ß-myosin heavy
chain mRNA at 5 days, but it did not attenuate increased
ventricular expression of atrial natriuretic
factor mRNA.
Conclusions These data suggest that endogenous ET-1 plays a direct role in mediating norepinephrine-induced ventricular hypertrophy in vivo.
Key Words: endothelin • hypertrophy • RNA • norepinephrine • bosentan
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