Neurovascular protection in voltage-gated proton channel Hv1 knock-out rats
after ischemic stroke: interaction with Na+ /H+ exchanger-1 antagonism.
Authors Li W, Ward R, Dong G, Ergul A, O'Connor P
Submitted By Weiguo Li on 8/2/2019
Status Published
Journal Physiological reports
Year 2019
Date Published
Volume : Pages 7 : e14142
PubMed Reference 31250553
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.

Investigators with authorship
Weiguo LiMedical University of South Carolina