© 1995 American Heart Association, Inc.
Articles |
Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure
From the Hypertension Unit, Division of Cardiology, University of Ottawa (Canada) Heart Institute.
Correspondence to Frans H.H. Leenen, MD, PhD, FRCPC, Hypertension Unit, H360, University of Ottawa Heart Institute, 1053 Carling Ave, Ottawa, Ontario, Canada, K1Y 4E9. E-mail fleenen@ohi-net.heartinst.on.ca.
Abstract In congestive heart failure (CHF),
endogenous compounds with ouabainlike activity (OLA) may
contribute to the maintenance of the circulatory homeostasis by
peripheral as well as central effects. In the present
study, we assessed changes in peripheral (plasma and left
ventricle) and central (pituitary, hypothalamus, pons, and cortex) OLA
in two animal models of CHF and determined whether brain OLA mediates
sympathetic hyperactivity in CHF. Cardiomyopathic
hamsters with their controls were studied at 9 months of age for tissue
OLA. Rats were studied 4 weeks after acute coronary artery
ligation for tissue OLA and sympathetic activity. In both models, left
ventricular end-diastolic pressure was
markedly increased. CHF was associated with significant increases in
both plasma and tissue OLA in both models. In the brain, the most
marked (twofold to threefold) increases occurred in the hypothalamus.
In vitro, all OLA measured could be blocked by antibody Fab fragments
(Digibind). Conscious rats with CHF showed elevated plasma
catecholamines and enhanced responses of mean
arterial pressure (MAP), heart rate (HR), and renal
sympathetic nerve activity (RSNA) to air stress and to
intracerebroventricular (ICV) injection
of the 
2-adrenergic receptor agonist guanabenz compared
with sham-operated rats. ICV administration of the Fab fragments
did not change resting RSNA or responses to air stress at 1 hour.
However, 18 hours after injection of the Fab fragments, resting RSNA
levels had significantly decreased compared with the control values,
and plasma catecholamine levels had decreased to control
values. Moreover, the magnitudes of the increases or decreases in MAP,
HR, and RSNA to air stress or ICV guanabenz had markedly decreased as
well and were now similar to those observed in sham-operated
control animals. The present results show that the development of
CHF in two animal models is associated with marked increases in both
peripheral and brain OLA. Brain OLA appears to mediate the
increase in resting sympathetic tone and enhanced
sympathoexcitatory responses to stress.
Key Words: ouabain • brain • heart • heart failure • sympathetic activity
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