Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Stephan, Damian; Winkler, Marcus; Kühner, Petra; Russ, Ulrich; Quast, Ulrich

doi:10.1007/s00125-006-0307-3

Cited by 56 publications

(48 citation statements)

References 43 publications

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“…In the present study, we observed the effects of Nat at doses of 1, 3, and 9 mg/kg, and the results were in accordance with previously obtained results [7][8][9][10] . Therefore, these results demonstrated that the two SUR2B/ Kir6.1 channel openers showed equivalent effects against CHF in the same experiment and that the drugs with different chemical structures aimed at the same target had similar Antagonism of the KCB, Gli, against the SUR2B/Kir6.1 channel opener, Nat, in vivo SUR2B/Kir6.1 channels are mainly distributed in blood vessels and are closely associated with endothelial func tion [6,14,15] . Our series of experiments using electrophysiological and molecular biological methods confirmed that both Nat and Ipt could open the SUR2B/Kir6.1 channels present on the endothelial cells with high selectivity [16] .…”

Section: Discussionmentioning

confidence: 59%

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Wang

Long

Cui³

et al. 2016

Acta Pharmacol Sin

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Both iptakalim (Ipt) and natakalim (Nat) activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel (K ATP ) subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure (ISO-CHF) in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat (1, 3, 9 mg·kg -1 ·d -1 ) or Ipt (3 mg·kg -1 ·d -1 ) for 60 days significantly improved cardiac dysfunction, reversed cardiac remodeling, significantly attenuated the pathological increases in BNP levels, and improved endothelial dysfunction by adjusting the balance between endothelin and NO systems. The therapeutic effects of Nat were prevented by the selective K ATP blocker glibenclamine (Gli, 50 mg·kg -1 ·d -1 ), confirming that these effects were mediated through activation of the SUR2B/Kir6.1 channel in endothelial cells. The molecular mechanisms underlying the therapeutic effects of Nat were further addressed using proteomic methods. We identified 724 proteins in the plasma of ISO-CHF rats; 55 proteins were related to Nat. These differentially expressed proteins were mainly involved in single-organism processes and the regulation of biological quality relative to CHF, including proteasome (Psm) and ATP protein clusters. We screened out PRKAR2β, GAS6/eNOS/NO and NO/PKG/VASP pathways involved in the amelioration of CHF among the 24 enriched pathways. We further confirmed 6 protein candidates, including PRKAR2β, GAS6 and VASP, which were involved in the endothelial mechanisms, and ATP, TIMP3 and AGT, which contributed to its cardiovascular actions. This study demonstrates a new pharmacological approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells, and that the eNOS/VASP pathways are involved in its signaling mechanisms.

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Section: Discussionmentioning

confidence: 59%

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Wang

Long

Cui³

et al. 2016

Acta Pharmacol Sin

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“…As shown in Fig. 4D, repaglinide (a specific K ATP channel blocker (Stephan et al 2006)) alone significantly increased insulin secretion in the cells with 16.8 mM glucose. In view of the fact that repaglinide at 10 nM could inhibit the K ATP channel by almost 95% in pancreatic cells (Stephan et al 2006), high concentrations of repaglinide at 1 or 10 mM (Fig.…”

Section: Camentioning

confidence: 57%

“…4D, repaglinide (a specific K ATP channel blocker (Stephan et al 2006)) alone significantly increased insulin secretion in the cells with 16.8 mM glucose. In view of the fact that repaglinide at 10 nM could inhibit the K ATP channel by almost 95% in pancreatic cells (Stephan et al 2006), high concentrations of repaglinide at 1 or 10 mM (Fig. 4D) were thus suggested to be obviously enough to totally blockade the K ATP channel as indicated by the result that the repaglinide-stimulated insulin secretion reached a peak at 1 and 10 mM (Fig.…”

Section: Camentioning

confidence: 94%

BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice

Yao

Wang

et al. 2015

Journal of Endocrinology

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Impaired glucose-stimulated insulin secretion (GSIS) and increasing b-cell death are two typical dysfunctions of pancreatic b-cells in individuals that are destined to develop type 2 diabetes, and improvement of b-cell function through GSIS enhancement and/or inhibition of b-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting b-cells from cytokine-or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca 2C channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on b-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored b-cell functions as indicated by the increased plasma insulin level and decrease in the b-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.

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“…Glibenclamide contains both sulfonylurea and benzamido moieties, and it can, therefore, bind to SUR1 in two regions and to SUR2 in one region (Ashcroft & Gribble 2000b). Stephan et al (2006) demonstrated that glibenclamide (10 K9 M) induced complete inhibition of the pancreatic K ATP channel, whereas higher concentrations (10 K7 or 10 K6 M) produced only partial and reversible inhibition of the cardiovascular K ATP channels. These studies clearly revealed that glibenclamide is a non-selective SUR blocker.…”

Section: K8mentioning

confidence: 97%

Ontogeny of sulfonylurea-binding regulatory subunits of KATP channels in the pregnant rat myometrium

Lovasz¹,

Ducza²,

Gáspár³

et al. 2011

Reproduction

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ATP-sensitive potassium channels (K ATP channels) are composed of sulfonylurea receptors (SURs) and potassium inward rectifiers (Kir 6.x ) that assemble to form a large octameric channel. This study was designed to examine the expression and role of sulfonylureabinding regulatory subunits 1 (SUR1 (ABCC8)) and 2 (SUR2 (ABCC9)) of the K ATP channels in the pregnant rat myometrium with particular regard to the contractility. RT-PCR and western blot analyses were performed to detect the presence of SUR1 and SUR2. The SUR1 levels were markedly increased in the early stages of pregnancy. The highest level was detected on day 6 of pregnancy, whereas in the late stages, the levels of SUR1 were significantly decreased. The SUR2 level remained unchanged throughout pregnancy. The SUR non-selective diazoxide and the SUR2-selective pinacidil inhibited oxytocin-induced contractions. Glibenclamide, a K ATP channel blocker, antagonized both pinacidil-and diazoxide-induced relaxations. It was established that SURs are responsible for pharmacological reactivity of K ATP channel openers. We conclude that both SURs are involved in the K ATP channel in the pregnant rat myometrium. It may further be concluded that 'pinacidil-like' K ATP channel openers may be of therapeutic relevance as tocolytic agents in the future.

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Selectivity of repaglinide and glibenclamide for the pancreatic over the cardiovascular KATP channels

Cited by 56 publications

References 43 publications

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice

Ontogeny of sulfonylurea-binding regulatory subunits of KATP channels in the pregnant rat myometrium

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