Ovariectomy provokes inflammatory and cardiovascular effects of endotoxemia in rats: Dissimilar benefits of hormonal supplements

Toxicol Appl Pharmacol. 2020 Apr 15:393:114928. doi: 10.1016/j.taap.2020.114928. Epub 2020 Feb 21.

Abstract

The female gender is protected against immunological complications of endotoxemia. Here we investigated whether gonadal hormone depletion by ovariectomy (OVX) uncovers inflammatory and cardiovascular effects of endotoxemia and whether these effects are reversed by hormone replacement therapies. Changes in inflammatory cytokines, blood pressure (BP), left ventricular (LV) function, and cardiac autonomic activity caused by lipopolysaccharide (LPS) in conscious female rats with different hormonal states were determined. In contrast to no effects in sham-operated females, treatment of OVX rats with LPS (i) decreased BP, (ii) increased spectral low-frequency/high-frequency ratio of HRV, denoting enhanced cardiac sympathetic dominance, (iii) attenuated reflex tachycardic responses to sodium nitroprusside, and (iv) increased systolic contractility (dP/dtmax). The developed hypotension was (i) fully eliminated in estrogen (E2)-pretreated OVX rats, (ii) partially counteracted after selective activation of estrogen receptor-α (PPT) or β (DPN). All estrogenic compounds abrogated LPS enhancement of cardiac sympathetic drive. However, PPT was more successful than E2 or DPN in compromising LPS depression in baroreflex activity and elevation in dP/dtmax. Molecular studies showed that PPT was most effective in attenuating the upregulated myocardial expressions of NF-κB and iNOS in endotoxic OVX rats. Myocardial expression of the defensive HSP70 was comparably increased by all estrogenic products. Except for improved cardiac spectral activity, none of these functional or molecular entities was affected by medroxyprogesterone acetate (MPA). Overall, our data suggest diverse therapeutic advantages for gonadal hormones in the worsened endotoxic complications in rats with surgical menopause, with probably more favorable role for ERα agonism within this context.

Keywords: Cardiovascular; Cytokines; Endotoxemia; Estrogen receptors; Hormone replacement; Ovariectomy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Baroreflex / drug effects
  • Blood Pressure
  • Cardiovascular Diseases / drug therapy*
  • Cardiovascular Diseases / etiology*
  • Cytokines
  • Endotoxemia / chemically induced
  • Endotoxemia / complications*
  • Endotoxemia / drug therapy*
  • Estradiol / therapeutic use
  • Estrogen Receptor alpha / agonists
  • Estrogen Replacement Therapy / adverse effects
  • Estrogen Replacement Therapy / methods*
  • Female
  • Heart Rate / drug effects
  • Inflammation / drug therapy*
  • Inflammation / etiology*
  • Lipopolysaccharides
  • Medroxyprogesterone Acetate / therapeutic use
  • Ovariectomy / adverse effects*
  • Rats
  • Rats, Wistar
  • Selective Estrogen Receptor Modulators / therapeutic use
  • Ventricular Function, Left / drug effects

Substances

  • Cytokines
  • Estrogen Receptor alpha
  • Lipopolysaccharides
  • Selective Estrogen Receptor Modulators
  • Estradiol
  • Medroxyprogesterone Acetate