Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats after ischemic stroke: interaction with Na+/H+ exchanger-1 antagonism

Weiguo Li, Rebecca Ward, Guangkuo Dong, Adviye Ergul, Paul O'Connor

Research output: Contribution to journalArticle

Abstract

Experimental studies have demonstrated protective effects of NHE-1 inhibition on cardiac function; however, clinical trials utilizing NHE-1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase-derived reactive oxygen species (ROS) from microglial cells have been shown to contribute to injury following stroke. We have recently demonstrated that NHE-1 inhibition enhances ROS in macrophages in a Hv1-dependent manner. As Hv1 protein is highly expressed in microglia, we hypothesized that “NHE-1 inhibition may augment neurovascular injury by activating Hv1,” providing a potential mechanism for the deleterious effects of NHE-1. The goal of this study was to determine whether neurovascular injury and functional outcomes after experimental stroke differed in wild-type and Hv1 mutant Dahl salt-sensitive rats treated with an NHE-1 inhibitor. Stroke was induced using both transient and permanent of middle cerebral artery occlusion (MCAO). Animals received vehicle or NHE-1 inhibitor KR32568 (2 mg/kg, iv) either 30 min after the start of MCAO or were pretreated (2 mg/kg, iv, day) for 3 days and then subjected to MCAO. Our data indicate that Hv1 deletion confers both neuronal and vascular protection after ischemia. In contrast to our hypothesis, inhibition of NHE-1 provided further protection from ischemic stroke, and the beneficial effects of both pre- and post-treatment with KR32568 were similar in wild-type and Hv1−/− rats. These data indicate that Hv1 activation is unlikely to be responsible for the increased incidence of cerebrovascular events observed in the heart disease patients after NHE-1 inhibition treatment.

Original languageEnglish (US)
Article numbere14142
JournalPhysiological reports
Volume7
Issue number13
DOIs
StatePublished - Jul 2019

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Keywords

  • Ischemic stroke
  • NHE inhibitor
  • neurovascular protection
  • voltage-gated proton channel

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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