Effectiveness in the inhibition of dapagliflozin and canagliflozin on M-type K+ current and α-methylglucoside-induced current in pituitary tumor (GH3) and pheochromocytoma PC12 cells

So, Edmund Cheung; Liu, Ping Yen; Wu, Sheng‐Nan

doi:10.1016/j.ejphar.2020.173141

Cited by 4 publications

(4 citation statements)

References 57 publications

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“…Moreover, in the continued presence of KYNA, further application of either linopirdine, bisoprolol, or dapagliflorizin was able to decrease KYNA-enhanced probability of K M -channel openings significantly. Bisoprolol and dapagliflorizin were previously reported to inhibit I K(M) amplitude [32,38].…”

Section: Effect Of Kyna On M-type K + Channel (K M ) Channels Recorded From Gh 3 Cellsmentioning

confidence: 99%

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Lin

Fang

et al. 2021

IJMS

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Kynurenic acid (KYNA, 4-oxoquinoline-2-carboxylic acid), an intermediate of the tryptophan metabolism, has been recognized to exert different neuroactive actions; however, the need of how it or its aminoalkylated amide derivative N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide (KYNA-A4) exerts any effects on ion currents in excitable cells remains largely unmet. In this study, the investigations of how KYNA and other structurally similar KYNA derivatives have any adjustments on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were performed by patch-clamp technique. KYNA or KYNA-A4 increased the amplitude of M-type K+ current (IK(M)) and concomitantly enhanced the activation time course of the current. The EC50 value required for KYNA- or KYNA-A4 -stimulated IK(M) was yielded to be 18.1 or 6.4 μM, respectively. The presence of KYNA or KYNA-A4 shifted the relationship of normalized IK(M)-conductance versus membrane potential to more depolarized potential with no change in the gating charge of the current. The voltage-dependent hysteretic area of IK(M) elicited by long-lasting triangular ramp pulse was observed in GH3 cells and that was increased during exposure to KYNA or KYNA-A4. In cell-attached current recordings, addition of KYNA raised the open probability of M-type K+ channels, along with increased mean open time of the channel. Cell exposure to KYNA or KYNA-A4 mildly inhibited delayed-rectifying K+ current; however, neither erg-mediated K+ current, hyperpolarization-activated cation current, nor voltage-gated Na+ current in GH3 cells was changed by KYNA or KYNA-A4. Under whole-cell, current-clamp recordings, exposure to KYNA or KYNA-A4 diminished the frequency of spontaneous action potentials; moreover, their reduction in firing frequency was attenuated by linopirdine, yet not by iberiotoxin or apamin. In hippocampal mHippoE-14 neurons, the addition of KYNA also increased the IK(M) amplitude effectively. Taken together, the actions presented herein would be one of the noticeable mechanisms through which they modulate functional activities of excitable cells occurring in vivo.

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Section: Effect Of Kyna On M-type K + Channel (K M ) Channels Recorded From Gh 3 Cellsmentioning

confidence: 99%

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Lin

Fang

et al. 2021

IJMS

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“…These findings strongly suggest that dapagliflozin can downregulate TH, thereby inhibiting catecholamine biosynthesis, in tissues [ 62 ]. On the other hand, both SGLT1 and -2 have been shown to be present in adrenal gland tissue and, specifically, in adrenal chromaffin cells [ 63 , 64 ]. Taken together, all these findings combined promoted us to hypothesize that dapagliflozin (and potentially other SGLT2 inhibitors, as well) downregulates adrenal GRK2 expression and activity, thereby reducing both synthesis and secretion of catecholamines from the adrenal medulla [ 65 ].…”

Section: Research Hypothesis: Dapagliflozin Attenuates Adrenal Catecholamine Productionmentioning

confidence: 99%

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Lymperopoulos

Borges

Cora

et al. 2021

IJMS

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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 in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is 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 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 propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire 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 evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

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“…Both GLP-1RAs and sodium-glucose cotransporter 2 inhibitors (SGLT2is) might confer cardioprotective effects in this clinical setting [ 87 ]. Intriguingly, the latter are also shown to effectively inhibit SGLT activity and I K(M) electrical current in pheochromocytoma cell lines; the subsequent perturbance of membrane excitability in these cells might have functional implications [ 88 ]. However, SGLT2is should be used with caution in insulin-deficient patients due to risk of euglycemic DKA [ 82 ].…”

Section: Presentation Prognosis and Management Of Secondary Diabetes ...mentioning

confidence: 99%

Secondary diabetes mellitus in pheochromocytomas and paragangliomas

Moustaki,

Paschou,

Vakali

et al. 2023

Endocrine

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Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.

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Effectiveness in the inhibition of dapagliflozin and canagliflozin on M-type K+ current and α-methylglucoside-induced current in pituitary tumor (GH3) and pheochromocytoma PC12 cells

Cited by 4 publications

References 57 publications

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Secondary diabetes mellitus in pheochromocytomas and paragangliomas

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