ArticleCardiovascular research2020
Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1.
Article in Cardiovascular research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Revising NHE-1: From Cardiac Homeostasis to Heart Failure and Future Drug Development.Cell biochemistry and function · 2026Review
- Influence of Soluble Guanylate Cyclase on Cardiac, Vascular, and Renal Structure and Function: A Physiopathological Insight.International journal of molecular sciences · 2025Review
- Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia.Cardiovascular diabetology · 2025Article
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation.Nature cardiovascular research · 2023Article
- Protease XIV abolishes NHE inhibition by empagliflozin in cardiac cells.Frontiers in physiology · 2023Article
- Acidic environments trigger intracellular H+-sensing FAK proteins to re-balance sarcolemmal acid-base transporters and auto-regulate cardiomyocyte pH.Cardiovascular research · 2022Article
- The Remaining Conundrum of the Role of the NaReviews in cardiovascular medicine · 2022Review
- The HVCN1 voltage-gated proton channel contributes to pH regulation in canine ventricular myocytes.The Journal of physiology · 2022Article
- The role of activation of two different sGC binding sites by NO-dependent and NO-independent mechanisms in the regulation of SACs in rat ventricular cardiomyocytes.Physiological reports · 2022Article
- SGLT2 inhibitors and the cardiac Na+/H+ exchanger-1: the plot thickens.Cardiovascular research · 2021Article
- Decreased Brain pH and Pathophysiology in Schizophrenia.International journal of molecular sciences · 2021Review
- Two Motors and One Spring: Hypothetic Roles of Non-Muscle Myosin II and Submembrane Actin-Based Cytoskeleton in Cell Volume Sensing.International journal of molecular sciences · 2021Review
- Treatment with a DC-SIGN ligand reduces macrophage polarization and diastolic dysfunction in the aging female but not male mouse hearts.GeroScience · 2021Article
- Myocardial Impact of NHE1 Regulation by Sildenafil.Frontiers in cardiovascular medicine · 2021Review
- Nitric oxide fine-tunes NHE1 to control cardiomyocyte pH.Cardiovascular research · 2020Article
- Cardiomyocyte NaFrontiers in cardiovascular medicine · 2020Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
aimsWhen activated, Na+/H+ exchanger-1 (NHE1) produces some of the largest ionic fluxes in the heart. NHE1-dependent H+ extrusion and Na+ entry strongly modulate cardiac physiology through the direct effects of pH on proteins and by influencing intracellular Ca2+ handling. To attain an appropriate level of activation, cardiac NHE1 must respond to myocyte-derived cues. Among physiologically important cues is nitric oxide (NO), which regulates a myriad of cardiac functions, but its actions on NHE1 are unclear. METHODS AND
resultsNHE1 activity was measured using pH-sensitive cSNARF1 fluorescence after acid-loading adult ventricular myocytes by an ammonium prepulse solution manoeuvre. NO signalling was manipulated by knockout of its major constitutive synthase nNOS, adenoviral nNOS gene delivery, nNOS inhibition, and application of NO-donors. NHE1 flux was found to be activated by low [NO], but inhibited at high [NO]. These responses involved cGMP-dependent signalling, rather than S-nitros(yl)ation. Stronger cGMP signals, that can inhibit phosphodiesterase enzymes, allowed [cAMP] to rise, as demonstrated by a FRET-based sensor. Inferring from the actions of membrane-permeant analogues, cGMP was determined to activate NHE1, whereas cAMP was inhibitory, which explains the biphasic regulation by NO. Activation of NHE1-dependent Na+ influx by low [NO] also increased the frequency of spontaneous Ca2+ waves, whereas high [NO] suppressed these aberrant forms of Ca2+ signalling.
conclusionsPhysiological levels of NO stimulation increase NHE1 activity, which boosts pH control during acid-disturbances and results in Na+-driven cellular Ca2+ loading. These responses are positively inotropic but also increase the likelihood of aberrant Ca2+ signals, and hence arrhythmia. Stronger NO signals inhibit NHE1, leading to a reversal of the aforementioned effects, ostensibly as a potential cardioprotective intervention to curtail NHE1 overdrive.
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