Mineralocorticoids act centrally to regulate blood-borne tumor necrosis factor-alpha in normal rats.
Excessive mineralocorticoid receptor (MR) stimulation induces neurohumoral excitation and cardiac and vascular fibrosis. In heart failure (HF) rats, with excessive neurohumoral drive, central infusion of the MR antagonist spironolactone (SL) decreases blood-borne TNF-alpha. This study aimed to determine whether DOCA, a precursor of aldosterone, acts centrally to stimulate TNF-alpha production in normal rats. DOCA (5 mg sc daily for 8 days) induced a progressive increase in TNF-alpha beginning on day 3 and increased tissue TNF-alpha in hypothalamus, pituitary, and heart but not in other brain and peripheral tissues harvested on day 9. A continuous intracerebroventricular infusion of SL (100 ng/h) blocked the plasma TNF-alpha response. Oral SL (1 mg/kg) blocked the plasma and tissue TNF-alpha responses. Thus DOCA increases TNF-alpha in brain, heart, and blood in normal rats. Activation of brain MR appears to account for the increase in plasma TNF-alpha. These findings have important implications for the understanding of pathophysiological states (e.g., HF, hypertension) characterized by high circulating levels of aldosterone.
Francis
Joseph
J
Department of Internal Medicine,University of Iowa, Iowa City, Iowa 52242, USA.
Beltz
Terry
T
Johnson
Alan Kim
AK
Felder
Robert B
RB
D000818:Animals; D001066:Appetite; D003900:Desoxycorticosterone / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013148:Spironolactone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha; D013148:Spironolactone; D003900:Desoxycorticosterone