Inhibition of the norepinephrine transporter rescues vascular hyporeactivity to catecholamine in obstructive jaundice

Eur J Pharmacol. 2021 Jun 5:900:174055. doi: 10.1016/j.ejphar.2021.174055. Epub 2021 Mar 26.

Abstract

In patients with obstructive jaundice, the cardiovascular system exhibits hypotension and vascular hyporeactivity. Most norepinephrine is taken up through the neuronal norepinephrine transporter (NET), which is implicated in cardiovascular diseases. A previous study demonstrated that pharmacological NET inhibition could increase resting blood pressure. However, the role of NETs in vascular hyporeactivity induced by obstructive jaundice is poorly understood. This study used the NET inhibitor nisoxetine and a rat model of bile duct ligation (BDL) to investigate whether NET is associated with BDL-induced vascular hyporeactivity. Rats were injected with nisoxetine via the tail vein for 7 consecutive days after BDL. Samples of the superior cervical sympathetic ganglion (SCG) and thoracic aortic rings were processed for investigations. Our results showed that NET expression in the SCG was significantly increased after BDL. Nisoxetine prevented the augmentation of NET expression, increased α1-adrenoceptor activation, and enhanced the weakened contractile responses of thoracic aortic rings after BDL. Our study demonstrates that nisoxetine plays a protective role in BDL-induced vascular hyporeactivity through increased α1-adrenoceptor activation in rats.

Keywords: Bile duct ligation; Norepinephrine; Norepinephrine transporter; Obstructive jaundice; Vascular hyporeactivity; α(1)-adrenoceptor.

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists / pharmacology
  • Animals
  • Bile Ducts
  • Bilirubin / pharmacology
  • Blood Pressure / drug effects
  • Blood Vessels / drug effects*
  • Blood Vessels / physiopathology*
  • Catecholamines*
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / pharmacology
  • Ganglia, Sympathetic / drug effects
  • Jaundice, Obstructive / drug therapy*
  • Jaundice, Obstructive / physiopathology
  • Ligation
  • Male
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Adrenergic alpha-1 Receptor Agonists
  • Catecholamines
  • Norepinephrine Plasma Membrane Transport Proteins
  • Fluoxetine
  • nisoxetine
  • Bilirubin