Evidence for a Digitalis-Like Substance in the Hypothalamopituitary Axis in Rats: Implications in the Central Cardiovascular Regulation Associated with an Excess Intake of Sodium

Abstract

The origin and the physiological role of an endogenous digitalis-like substance were investigated by measuring both the digoxin-like substance by a digoxin radioimmunoassay (RIA) and the inhibitory activity on the ouabain sensitive Na+, K+-ATPase in rats. The digitalis-like substance was in high concentration in the pituitary, and in decreasing concentration in the hypothalamus, adrenal and the other organs as measured by RIA using an antibody raised from a goat. However, the adrenal showed the highest content of digitalis-like substance as measured by the antibody raised from a rabbit. The plasma level markedly decreased during a 2-week sodium-loading, and the adrenal content decreased markedly on hypophysectomy as measured with the rabbit-antibody. Therefore, the substance measured with the rabbit-antibody must be one of ACTH-dependent adrenal steroids. The inhibitory activity on the Na+, K+-ATPase was high in he pituitary gland, and was decreased in order of the adrenal, hypothalamus and other organs. The 2-week sodium-loading increased both the content in the pituitary gland and the output in the urine, and decreased the hypothalamic content. Immunohistochemical staining of the hypothalamus with the antibody revealed that the immunoreactivity is restricted to the neurons of the paraventricualr nucleus, supraoptic nucleus, magnocellular accessary nuclei and extended their fibers reaching to the inner layer of the median eminence. To determine the role of the substance in the brain, the crude extract dissolved in artificial cerebrospinal fluid was injected into the lateral ventricle; vasopressor responses, tachycardia and hyperactivity of the splanchinic nerve lasting for more than 30 min were recorded, which resembled the responses to ouabain injected similarly. Electrical lesions of the anteroventral third ventricle significantly attenuated the DOCA-salt hypertension and decreased the urinary output of the digitalis-like activity. These results suggest that the digitalis-like substance could be produced in the hypothalamus and secreted from the pituitary gland in a fashon similar to vasopressin secretion, and that the turnover is increased in the hypothalamus with sodium-loading. The substance could also play a physiological role on the central cardiovascular regulation to increase blood pressure particularly when sodium is loaded. © 1987, The Japanese Circulation Society. All rights reserved.