Effects of Ouabain on Insulin Release, Adenosine 3',5'-Monophosphate and Guanine 3',5'-Monophosphate in Pancreatic Islets*

Gagerman, E; Hellman, Bo; Täljedal, Inge‐Bert

doi:10.1210/endo-104-4-1000

Cited by 16 publications

(6 citation statements)

References 28 publications

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“…In the presence of the AC activator forskolin, ouabain further elevated atrial cAMP production. These findings are similar to those that ouabain increases intracellular cAMP production in the intestinal mucosa, pancreatic islets, and brain by stimulating AC [ 13 17 18 ].…”

Section: Discussionsupporting

confidence: 89%

cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria

Peng

Zhang

et al. 2016

Korean J Physiol Pharmacol

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Adenosine 3',5'-cyclic monophosphate (cAMP) participates in the regulation of numerous cellular functions, including the Na+-K+-ATPase (sodium pump). Ouabain, used in the treatment of several heart diseases, is known to increase cAMP levels but its effects on the atrium are not understood. The aim of the present study was to examine the effect of ouabain on the regulation of atrial cAMP production and its roles in atrial endothelin-1 (ET-1) secretion in isolated perfused beating rabbit atria. Our results showed that ouabain (3.0 µmol/L) significantly increased atrial dynamics and cAMP levels during recovery period. The ouabain-increased atrial dynamics was blocked by KB-R7943 (3.0 µmol/L), an inhibitor for reverse mode of Na+-Ca2+ exchangers (NCX), but did not by L-type Ca2+ channel blocker nifedipine (1.0 µmol/L) or protein kinase A (PKA) selective inhibitor H-89 (3.0 µmol/L). Ouabain also enhanced atrial intracellular cAMP production in response to forskolin and theophyline (100.0 µmol/L), an inhibitor of phosphodiesterase, potentiated the ouabain-induced increase in cAMP. Ouabain and 8-Bromo-cAMP (0.5 µmol/L) markedly increased atrial ET-1 secretion, which was blocked by H-89 and by PD98059 (30 µmol/L), an inhibitor of extracellular-signal-regulated kinase (ERK) without changing ouabain-induced atrial dynamics. Our results demonstrated that ouabain increases atrial cAMP levels and promotes atrial ET-1 secretion via the mitogen-activated protein kinase (MAPK)/ERK signaling pathway. These findings may explain the development of cardiac hypertrophy in response to digitalis-like compounds.

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Section: Discussionsupporting

confidence: 89%

cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria

Peng

Zhang

et al. 2016

Korean J Physiol Pharmacol

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“…Such a cAMP rise has been reported in different tissues, including dog renal cortex (53), goldfish intestinal mucosa (2), mouse pancreatic islets (21), murine epithelioid and fibroblastic cell lines (34), rat brain (38), and rat renal collecting tubule cells in culture (28). In each of these reported studies, the concentration of ouabain was likely enough to inhibit Na-K-ATPase to a degree where cytoplasmic sodium increased.…”

Section: Discussionmentioning

confidence: 85%

Ouabain-induced stimulation of sodium-hydrogen exchange in rat optic nerve astrocytes

Mandal¹,

Delamere²,

Shahidullah³

2008

American Journal of Physiology-Cell Physiology

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Sodium-dependent transporters are inhibited indirectly by the Na-K-ATPase inhibitor ouabain. Here we report stimulation of sodium-hydrogen exchange (NHE) in ouabain-treated cells. BCECF was used to measure cytoplasmic pH in cultured rat optic nerve astrocytes. Ammonium chloride was applied to acid load the cells. On removal of ammonium chloride, cytoplasmic pH fell abruptly, then gradually recovered toward baseline. Ouabain (1 microM) did not change cell sodium content, but the rate of pH recovery increased by 68%. Ouabain speeded pH recovery both in the presence and absence of bicarbonate. In bicarbonate-free medium, dimethylamiloride, an NHE inhibitor, eliminated the effect of 1 microM ouabain on pH recovery. Western blot analysis showed an NHE1 immunoreactive band but not NHE2, NHE3, or NHE4. Immunoprecipitation studies showed phosphorylation of NHE1 in cells treated with 1 microM ouabain. Ouabain evoked an increase of cAMP, and the effect of 1 microM ouabain on pH recovery was abolished by H-89, a protein kinase A inhibitor. 8-Bromoadenosine-cAMP increased the pH recovery rate, and this recovery was not further increased by ouabain. Although 1 microM ouabain did not alter cytoplasmic calcium concentration, it stimulated calcium entry after store depletion, a response abolished by 2-APB. Ouabain-induced stimulation of pH recovery was suppressed by inhibitors of capacitative calcium entry, SKF-96365, and 2-APB, as well as the cytoplasmic calcium chelator BAPTA. The cAMP increase in ouabain-treated cells was abolished by BAPTA and 2-APB. Taken together, the results are consistent with increased capacitative calcium entry and subsequent cAMP-PKA-dependent stimulation of NHE1 in ouabain-treated cells.

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“…The late stimulatory effect was prominent at low and intermediate glucose, but did not occur at high glucose concentrations. Others have found that at nonstimulatory glucose concentrations ouabain either stimulated insulin release (27)(28)(29)(30)(31) or did not affect it (32,33) and no effects were seen with high glucose concentrations (27,(29)(30)(31).…”

Section: Resultsmentioning

confidence: 99%

Evidence for the Involvement of Na/Ca Exchange in Glucose-induced Insulin Release from Rat Pancreatic Islets

Siegel¹,

Wollheim²,

Renold³

et al. 1980

J. Clin. Invest.

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A B S T R A C T Glucose-induced inhibition of Ca++extrusion from the j8-cell may contribute to the rise in cytosol Ca++ that leads to insulin release. To study whether interference with Na/Ca exchange is involved in this inhibition the effects of glucose were compared to those of ouabain. This substance inhibits Na/K ATPase, decreases the transmembrane Na+ gradient in islets, and thus interferes with Na/Ca exchange. Collagenase isolated rat islets were maintained for 2 d in tissue culture with a trace amount of 45Ca++. Insulin release and 45Ca++ efflux were then measured during perifusion. In Ca++-deprived. medium (to avoid changes in tissue specific radioactivity) 16.7 mM glucose inhibited 45Ca++ efflux. Initially 1 mM ouabain inhibited 45Ca++ efflux in a similar fashion, the onset being even faster than that of glucose. The effects of 16.7 mM glucose and ouabain were not additive, indicating that both substances may interfere with Na/Ca exchange. In the presence of Ca++, 16.7 mM glucose induced biphasic insulin release. Ouabain alone caused a gradual increase of insulin release. Again, the effects of ouabain and 16.7 mM glucose were not additive. In contrast, at a submaximal glucose concentration (7 mM) ouabain enhanced both phases of release. An important role for Na/Ca exchange is suggested from experiments in which Ca++ was removed at the time of glucose-stimulation (16.7 mM). The resulting marked inhibition of insulin release was completely overcome during first phase by ouabain added at the time of Ca++ removal; second phase was restored to 60%. This could be due to the rapid inhibitory action ofouabain on Ca++ efflux thereby preventing loss of cellular calcium critical

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Effects of Ouabain on Insulin Release, Adenosine 3',5'-Monophosphate and Guanine 3',5'-Monophosphate in Pancreatic Islets*

Cited by 16 publications

References 28 publications

cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria

cAMP induction by ouabain promotes endothelin-1 secretion via MAPK/ERK signaling in beating rabbit atria

Ouabain-induced stimulation of sodium-hydrogen exchange in rat optic nerve astrocytes

Evidence for the Involvement of Na/Ca Exchange in Glucose-induced Insulin Release from Rat Pancreatic Islets

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