Pinacidil inhibits insulin release by increasing K+ outflow from pancreatic B-cells

Lebrun, Philippe; Devreux, Vincent; Hermann, Marcel; Herchuelz, André

doi:10.1016/0014-2999(88)90334-2

Cited by 28 publications

(28 citation statements)

References 6 publications

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“…On the other hand, our pharmacological data also indirectly suggest that, in colonic smooth muscle cells, pinacidil and diazoxide could interfere with membrane K+ channels sharing common properties with the K+ATP channels previously described in other tis sues [13][14][15], This hypothesis is consistent with the recent demonstration that, in pan creatic B-cells, pinacidil and the hyperglycaemic sulfonylurea diazoxide activate such ATP-regulated K+ channels [15,17]. Inci dentally, the failure of TEA to counteract the relaxation response to pinacidil and diazox ide does not necessarily detract from the view that both compounds interact with cer tain K+ channels.…”

Section: Discussionsupporting

confidence: 80%

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

Lebrun¹,

Fontaine²

1990

Pharmacology

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Pinacidil and diazoxide induced concentration-related relaxations of the longitudinal muscle of the mouse distal colon. The relaxing effects of pinacidil and diazoxide were unaffected by tetraethylammonium, but were antagonized by tolbutamide and glibenclamide. Relaxations provoked by nifedipine were not counteracted by the two hypoglycaemic sulfonylureas. It is tempting to suggest that the relaxation response to pinacidil and diazoxide could reflect the ability of both compounds to interfere with membrane K⁺ channels sharing common pharmacological properties with the K⁺_ATP channels recently described in other tissues.

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Section: Discussionsupporting

confidence: 80%

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

Lebrun¹,

Fontaine²

1990

Pharmacology

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“…Although the mechanism of action of these vasodilators is not fully understood, these drugs activate K + channels (74)(75)(76)(77). Vasodilation could be explained by the hyperpolarization that results from K + -channel activation, the subsequent block of Ca 2+ influx, and smooth muscle contraction.…”

Section: Ion Channels and Insulin Secretionmentioning

confidence: 98%

“…Recently, Lebrun et al (77) described experiments with pancreatic islets and 86 Rb-efflux measurements. Pinacidil (500 |xM) did not modify the rate for 86 Rb efflux from islets in the absence of a secretagogue.…”

Section: Ion Channels and Insulin Secretionmentioning

confidence: 98%

Ion Channels and Insulin Secretion

et al. 1990

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We review the role of ion channels in regulating insulin secretion from pancreatic beta-cells. By controlling ion permeability, ion channels at the membrane play a major role in regulating both electrical activity and signal transduction in the beta-cell. A proximal step in the cascade of events required for stimulus-secretion coupling is the closure of ATP-sensitive K+ channels, resulting in cell depolarization. Of particular relevance is the finding that this channel is directly regulated by a metabolite of glucose, which is the primary insulin secretagogue. In addition, this channel, or a closely associated protein, contains the sulfonylurea-binding site. Another K+ channel, the Ca2(+)-activated K+ channel, may be involved in cell repolarization to create homeostasis. Voltage-dependent Ca2+ channels are activated by cell depolarization and regulate Ca2+ influx into the cell. By controlling cytosolic free-Ca2+ levels ([Ca2+]i), these channels play an important role in transducing the initial stimulus to the effector systems that modulate insulin secretion. The link between a rise in [Ca2+]i and the terminal event of exocytosis is the least-understood aspect of stimulus-secretion coupling. However, phosphorylation studies have identified substrate proteins that may correspond to those involved in smooth muscle contraction, suggesting an analogy in the processes of stimulus secretion and excitation contraction. The advent of new methodology, particularly the patch-clamp technique, has fostered a more detailed characterization of the beta-cell ion channels. Furthermore, biochemical and molecular approaches developed for the structural analysis of ion channels in other tissues can now be applied to the isolation and characterization of the beta-cell ion channels. This is of particular significance because there appear to be tissue-specific variations in the different types of ion channels. Given the importance of ion channels in cell physiology, a knowledge of the structure and properties of these channels in the beta-cell is required for understanding the abnormalities of insulin secretion that occur in non-insulin-dependent diabetes mellitus. Ultimately, these studies should also provide new therapeutic approaches to the treatment of this disease.

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“…16 In addition, both pinacidil and cromakalim hyperpolarize the cell membrane and have been shown to inhibit glucose evoked d e p~l a r i z a t i o n '~,~~ and rises in intracellular Ca2+ .16* 475, 476 In vitro studies in rat or mouse pancreatic islets have demonstrated that pinacidil(500 pM) or cromakalim (250-500 pM) may inhibit insulin s e~r e t i o n ,~~,~~~ although other studies have demonstrated cromakalim and nicorandil to be without e f f e~t .~~~,~" Despite indirect evidence in vivo that intravenously administered cromakalim may inhibit insulin release,478 plasma levels of insulin or glucose were largely unaffected by oral or intravenous administration of blood-pressurelowering doses of cromakalim to rats51,477 (see Fig. 14).…”

Section: Pancreasmentioning

confidence: 99%

Potassium channel activator drugs: Mechanism of action, pharmacological properties, and therapeutic potential

Longman¹,

Hamilton

1992

Medicinal Research Reviews

127

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Pinacidil inhibits insulin release by increasing K+ outflow from pancreatic B-cells

Cited by 28 publications

References 6 publications

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

Relaxation Response to Pinacidil and Diazoxide in the Mouse Isolated Distal Colon

Ion Channels and Insulin Secretion

Potassium channel activator drugs: Mechanism of action, pharmacological properties, and therapeutic potential

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