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

Authors: Li, Weiguo  Ward, Rebecca  Dong, Guangkuo  Ergul, Adviye  O'Connor, Paul 
Citation: Li W, etal., Physiol Rep. 2019 Aug;7(13):e14142. doi: 10.14814/phy2.14142.
Pubmed: (View Article at PubMed) PMID:31250553
DOI: Full-text: DOI:10.14814/phy2.14142

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.

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CRRD Object Information
CRRD ID: 14985213
Created: 2019-10-09
Species: All species
Last Modified: 2019-10-09
Status: ACTIVE



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