Brain ‘Ouabain’ Mediates Sympathetic Hyperactivity in Congestive Heart Failure

Abstract

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 α 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.