Pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut reduces atrial fibrillation susceptibility in obese spontaneously hypertensive rats

Benedikt Linz; Mathias Hohl; Ricardo Mishima; Arnela Saljic; Dennis H Lau; Thomas Jespersen; Ulrich Schotten; Prashanthan Sanders; Dominik Linz

doi:10.1016/j.ijcha.2020.100534

Pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut reduces atrial fibrillation susceptibility in obese spontaneously hypertensive rats

Int J Cardiol Heart Vasc. 2020 May 20:28:100534. doi: 10.1016/j.ijcha.2020.100534. eCollection 2020 Jun.

Authors

Benedikt Linz^{1

2}, Mathias Hohl¹, Ricardo Mishima³, Arnela Saljic², Dennis H Lau³, Thomas Jespersen², Ulrich Schotten⁴, Prashanthan Sanders³, Dominik Linz^{1

3

4}

Affiliations

¹ Klinik für Innere Medizin III, Universität des Saarlandes, 66421 Homburg/Saar, Germany.
² Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia.
⁴ University Maastricht, Cardiovascular Research Institute Maastricht (CARIM), the Netherlands.

Abstract

Background: Increased sodium uptake has been shown to contribute to hypertension and cardiac end-organ damage. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. Whether a reduction in intestinal sodium absorption can prevent the development of an atrial arrhythmogenic substrate in hypertension is unknown.

Methods: Eight-week-old obese spontaneously hypertensive rats (SHR-ob) were treated for six weeks with the gut-specific NHE3-inhibitor SAR (1-(β-D-glucopyranosyl)-3-{3-[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroiso-chinolin-4-yl]phenyl}urea, 1 mg/kg/d in chow, SHR-ob SAR, n = 7) and compared to aged-matched placebo-treated SHR-ob (SHR-ob PLAC, n = 8). Cardiac magnetic resonance imaging was performed at the end of the treatment period to assess atrial emptying function. Afterwards, local conduction disturbances and inducible atrial fibrillation (AF) duration were determined and histological analysis to quantify atrial fibrosis amount were performed.

Results: Inhibition of intestinal NHE3 by SAR increased fecal sodium excretion, resulted in marked changes in feces electrolyte concentrations and water content, reduced blood pressure and preserved atrial emptying function (active total percent emptying: SHR-ob SAR: 0.47 ± 0.05% vs. SHR-ob PLAC: 0.38 ± 0.007, p < 0.0001). Atrial fibrosis content was lower (21.4 ± 2.5% vs. 36.7 ± 1.2%, p < 0.0001) and areas of slow conduction were smaller (2.5 ± 0.09% vs. 5.3 ± 0.2%, p < 0.0001) in SHR-ob SAR compared to SHR-ob PLAC. Left atrial burst stimulation resulted in shorter inducible AF-durations in SHR-ob SAR compared to SHR-ob PLAC.

Conclusions: Reduction of intestinal sodium absorption and subsequent changes in feces milieu by pharmacological NHE3 inhibition in the gut preserved atrial emptying function and reduced AF susceptibility. Whether pharmacological NHE3 inhibition in the gut prevents AF in humans warrants further study.

Keywords: Atrial fibrillation; Intestinal sodium absorption; Salt; Sodium-proton-exchanger Subtype 3 (NHE 3).