Ropivacaine inhibits pressure-induced lung endothelial hyperpermeability in models of acute hypertension

Life Sci. 2019 Apr 1;222:22-28. doi: 10.1016/j.lfs.2019.02.053. Epub 2019 Feb 26.

Abstract

Aims: Increases in hydrostatic pressure results in endothelial hyperpermeability via eNOS-dependent pathways. Ropivacaine is known to inhibit eNOS activation and to attenuate lung injury. Herein, we sought to determine if ropivacaine regulates pressure-induced lung endothelial hyperpermeability.

Main methods: The effects of ropivacaine on lung permeability were assessed in two models of acute hypertension (AH): the isolated perfused lung preparation where acute increases in left atrial pressure model the hemodynamic changes of severe hypertension, and an animal model of AH induced by norepinephrine. In the IPL model, whole lung filtration coefficient (Kf) was used as the index of lung permeability; pulmonary artery pressure (Ppa), pulmonary capillary pressures (Ppc), and zonal characteristics (ZC) were measured to assess the effects of ropivacaine on hemodynamics and their relationship to Kf2/Kf1. In vivo, ropivacaine effects were investigated on indices of pulmonary edema (changes in PaO2, lung wet-to-dry ratio), changes in plasma volume and nitric oxide (NO) production.

Key findings: Ropivacaine provided robust protection from pressure-dependent barrier failure; it inhibited pressure-induced increases in Kf without affecting Ppa, Ppc or ZC. In vivo, ropivacaine prevented pressure-induced lung edema and associated hyperpermeability as evidence by maintaining PaO2, lung wet-to-dry ratio and plasma volume in levels similar to sham rats. Ropivacaine inhibited pressure-induced NO production as evidenced by decreased lung nitro-tyrosine content when compared to hypertensive lungs.

Significance: Collectively these data show that ropivacaine inhibits pressure-induced lung endothelial hyperpermeability and suggest that ropivacaine may be a clinically useful agent to prevent endothelial hyperpermeability when pulmonary pressure is acutely increased.

Keywords: Local anesthetics; Mechanotransduction; Pulmonary edema and filtration coefficient; Vascular barrier.

MeSH terms

  • Acute Disease
  • Anesthetics, Local / pharmacology
  • Anesthetics, Local / therapeutic use
  • Animals
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology*
  • Disease Models, Animal*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Hypertension / drug therapy
  • Hypertension / metabolism*
  • Hypertension / physiopathology
  • Lung / blood supply
  • Lung / drug effects
  • Lung / metabolism
  • Lung Injury / drug therapy
  • Lung Injury / metabolism
  • Lung Injury / physiopathology
  • Pulmonary Edema / drug therapy
  • Pulmonary Edema / metabolism*
  • Pulmonary Edema / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Ropivacaine / pharmacology
  • Ropivacaine / therapeutic use*

Substances

  • Anesthetics, Local
  • Ropivacaine