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Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects Of International Journal of Molecular Sciences Hypothesis Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland Anastasios Lymperopoulos * , Jordana I. Borges, Natalie Cora and Anastasiya Sizova Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA; [email protected] (J.I.B.); [email protected] (N.C.); [email protected] (A.S.) * Correspondence: [email protected]; Tel.: +1-954-262-1338; Fax: +1-954-262-2278 Abstract: Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non- diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents Citation: Lymperopoulos, A.; Borges, in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious J.I.; Cora, N.; Sizova, A. question arising from all these studies is, of course, which molecular/pharmacological mechanisms Sympatholytic Mechanisms for the underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant Hypothesis for Dapagliflozin’s Effects isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed in the Adrenal Gland. Int. J. Mol. Sci. over the past few years and tested in cell and animal models and prominent among those is the 2021, 22, 7684. https://doi.org/ potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is 10.3390/ijms22147684 known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting Academic Editor: Hisamitsu Ishihara the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we Received: 24 June 2021 propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically Accepted: 16 July 2021 of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire Published: 19 July 2021 amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects published maps and institutional affil- that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood iations. glucose-lowering effects. Keywords: adrenal medulla; catecholamine; dapagliflozin; free fatty acid; g protein-coupled receptor kinase-2; heart failure; SGLT2 inhibitor; sympathetic neuron; sympatholysis; signal transduction Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and 1. Introduction conditions of the Creative Commons Sodium-glucose co-transporter-2 (SGLT2) inhibitors, also known as gliflozins, are Attribution (CC BY) license (https:// drugs that inhibit this secondary active symporter isoform in the kidney to block reabsorp- creativecommons.org/licenses/by/ tion of glucose from the renal filtrate back into the renal tubule cell and ultimately into the 4.0/). Int. J. Mol. Sci. 2021, 22, 7684. https://doi.org/10.3390/ijms22147684 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 22 Int. J. Mol. Sci. 20212021,, 22,, 7684x FOR PEER REVIEW 22 of 1011 blood.into the Thus, blood. they Thus, lower they blood lower glucose blood glucose levels and levels cause and glucosuria cause glucosuria [1]. They [1]. were They devel- were opeddeveloped for type for 2 type diabetes 2 diabetes mellitus mellitus (T2DM) (T2D treatment,M) treatment, but they but are they now are well-established now well-estab- to alsolished exert to also cardiovascular exert cardiovascular benefits in benefits T2DM patientsin T2DM [2 patients,3]. Several [2,3]. medications Several medications of this class of havethis class been have approved been approved or are currently or are undercurrently development, under development, the most prominentthe most prominent of which beingof which canagliflozin being canagliflozin (Figure1), (Figure the first 1), member the first ofmember this class of this to be class FDA-approved to be FDA-approved in 2013, dapagliflozinin 2013, dapagliflozin (Figure1 (Figure), which 1), is which also used is also (together used (together with insulin) with insulin) for T1DM for T1DM treatment, treat- empagliflozinment, empagliflozin (Figure 1(Figure), which 1), has which the highest has the selectivity highest selectivity for SGLT2 vs.for SGLT1SGLT2 amongvs. SGLT1 the agentsamong in the this agents class, in ertugliflozin, this class, ertugliflozin, and sotagliflozin, and sotagliflozin, which is essentially which is a essentially non-specific a dualnon- SGLT1/2specific dual inhibitor. SGLT1/2 There inhibitor. are additional There are agents additional approved agents and approved marketed and outside marketed the out- US, such as ipragliflozin, luseogliflozin, remogliflozin, and tofogliflozin. side the US, such as ipragliflozin, luseogliflozin, remogliflozin, and tofogliflozin. Figure 1. Structures of the three SGLT2 inhibitors currently carrying FDA-approved cardiovascular indications.Figure 1. Structures The parts of of the the three molecule SGLT2 that inhibitors constitute cu therrently pharmacophore carrying FDA-approved are designated cardiovascular as circled by orangeindications. lines. The parts of the molecule that constitute the pharmacophore are designated as circled by orange lines. 1.1. Chemistry & Structure-Activity Relationships of SGLT2 Inhibitors 1.1. ChemistryAs far as the& Structure-Activity drug class’ chemistry Relationships and structure–activity of SGLT2 Inhibitors relationships are concerned, the pharmacophoreAs far as the (phlorizin) drug class’ is chemistry a β-D-glucoside and stru firstcture–activity isolated from relationships the bark of are the concerned, apple tree. Developmentthe pharmacophore of these (phlorizin) drugs was is baseda β-D-glucoside on this natural first compound.isolated from Phlorizin the barkconsists of the apple of a glucosetree. Development moiety linked of tothese a system drugs of was two based phenyl on rings this natural (the “aglycone” compound. part) Phlorizin connected consists via an ethyleneof a glucose bridge moiety [4]. Aslinked glucosides to a system are readily of two brokenphenyl down rings (the (hydrolyzed) “aglycone” by part) gastrointestinal connected glucosidases,via an ethylene phlorizin bridge was [4]. a As poor glucosides drug candidate, are readily and thus broken served down only as(hydrolyzed) the lead compound by gas- fortrointestinal the development glucosidases, of gliflozins. phlorizin The design was a of poor these drug drugs candidate, mainly involved and thus the served replacement only ofas thethe O-glucosidelead compound in phlorizin for the with development a C-glucoside of (Figuregliflozins.1), which The design made them of these both drugs metabolically mainly stableinvolved (protected the replacement against hydrolysis) of the O-glucoside and more selective in phlorizin for SGLT2 with vs. a SGLT1C-glucoside [5]. The (Figure structural 1), differenceswhich made among them theboth three metabolically most common stable SGLT2 (protected inhibitors against (dapagliflozin, hydrolysis) empagliflozin, and more se- andlective canagliflozin) for SGLT2 vs. are SGLT1 relatively [5].subtle The structur (Figureal1). differences The basic among difference the isthree that most canagliflozin common hasSGLT2 a thienyl inhibitors moiety (dapagliflozin, bridging the two empagliflozin, phenyl rings ofand the canagliflozin) pharmacophore are aglycone, relatively whereas subtle dapagliflozin(Figure 1). The and basic empagliflozin difference have is that a methylene canagliflozin group has instead a thienyl (Figure moiety1). The bridging latter two the also two containphenyl arings chlorine of the substitution pharmacophore on their aglycone, phenyl rings, whereas whose dapagliflozin electronegativity and empagliflozin (i.e., “pulling” electronhave a methylene pairs from group the aromatic insteadπ (Figurering electron 1). The cloud) latter further two
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