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

Abstract

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.

Influence of Platelet Aggregation Modulators on Cyclic AMP Production in Human Thrombocytes

“…Ouab is responsible for the increase of free cytosolic Ca 2+ in platelets 10 -an event, leading to their activation, as well as for the increase of cAMP in other cell types. [14][15][16] Ouab may cause cell membrane depolarization, mediated by an increase of cAMP content, and this effect of Ouab is augmented in the presence of theophylline. 21 In contrast, cAMP regulates Ouab sensitive Na(+)/K(+)-ATPase activity in SH-SY5Y human neuroblastoma cells.…”

“…12 Wort treatment of Aspergillus parasiticus D8D3 increased intracellular cAMP levels up to 25-fold. 13 Ouab has been shown to increase cAMP levels in rat optic nerve astrocytes 14 , rat brain 15 , and cultured renal papillary-collecting tubule cells 16 .…”