Noradrenaline up-regulates volume-regulated chloride current by PKA-independent cAMP/exchange protein activated by cAMP pathway in human atrial myocytes.

Background And Purpose: Adrenergic regulation of cell volume-regulated chloride current (I ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of I in human atrial myocytes.

Experimental Approach: Conventional whole-cell patch voltage-clamp techniques were used to record membrane current in human atrial myocytes. I was evoked by hyposmotic bath solution (0.6 times isosmotic, 0.6 T).

Key Results: I was augmented by noradrenaline (1 μM) during cell swelling in 0.6 T but not under isosmotic (1 T) conditions. Up-regulation of I in 0.6 T was blocked by the β-adrenoceptor antagonist propranolol (2 μM), but not by the α -adrenoceptor antagonist prazosin (2 μM). This β-adrenergic response involved cAMP but was independent of PKA; the protein kinase inhibitor H-89 (2 μM) or PKI (10 μM in pipette solution) failed to prevent I up-regulation by noradrenaline. Moreover, the PI3K/PKB inhibitor LY294002 (50 μM) and the PKG inhibitor KT5823 (10 μM) did not affect noradrenaline-induced increases in I . Interestingly, the exchange protein directly activated by cAMP (Epac) agonist 8-pCPT-2'-O-Me-cAMP (50 μM) also up-regulated I , and the noradrenaline-induced increase of I in 0.6 T was reversed or prevented by the Epac inhibitor ESI-09 (10 μM).

Conclusion And Implications: These data show that I evoked by cell swelling of human atrial myocytes is up-regulated by noradrenaline via a PKA-independent cAMP/Epac pathway in human atrial myocytes. cAMP/Epac-induced I is expected to shorten action potential duration during human atrial myocytes swelling and may be involved in abnormal cardiac electrical activity during cardiac pathologies that evoke β-adrenoceptor signalling.