Cardiac and Medullary Neuroinflammatory Pathways Trigger Androgenic Incitement of Cardiovascular Sequels of Endotoxemia in Rats

Abstract

Inconsistent reports are available on the role of testosterone in end organ damage caused by endotoxemia. Here, pharmacologic, surgical, and molecular studies were employed to assess the testosterone modulation of cardiovascular and autonomic derangements caused by endotoxemia and the role of peripheral and central inflammatory pathways in this interaction. Studies were performed in conscious male rats pre‐instrumented with femoral indwelling catheters for hemodynamic monitoring and subjected to castration or pharmacologic interventions that interrupt the biosynthetic cascade of testosterone. Compared to the effects of lipopolysaccharide (LPS, 10 mg/kg i.v.) in sham operated rats, 2‐week castration significantly reduced the LPS‐evoked: (i) falls in blood pressure, (ii) decreases in time‐ and frequency domain indices of heart rate variability (HRV), (iii) shifts in cardiac sympathovagal balance towards parasympathetic dominance as evidenced by decreases in low‐frequency to high‐frequency ratio of spectral powers, and (iii) increases in protein expressions of toll‐like receptor 4 and monocyte chemoattractant protein‐1 in the heart as well as in medullary neurons of the nucleus tractus solitarius and rostral ventrolateral medulla. The favorable influences of castration on inflammatory and cardiovascular abnormalities of endotoxemia were replicated in intact rats pretreated with degarelix (gonadotropin‐releasing hormone receptor blocker) or finasteride (5α‐reductase inhibitor), but not formestane (aromatase inhibitor). The data signifies the importance of testosterone and its biosynthetic enzymes in cardiovascular and autonomic insults induced by the endotoxic inflammatory response. Clinically, the interruption of testosterone biosynthesis could offer a potential therapeutic strategy for endotoxemia.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grants No. 14895)