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¹ Loyola University Chicago, Stritch School of Medicine, Department of Physiology, Maywood, IL 60153, USA

This study determined the effects of ₁-adrenergic receptor (₁-AR) stimulation by phenylephrine (PE) on L-type Ca²⁺ current (I_Ca,L) in cat atrial myocytes. PE (10 µM) reversibly increased I_Ca,L (51.3%; n = 40) and shifted peak I_Ca,L activation voltage by –10 mV. PE-induced stimulation of I_Ca,L was blocked by each of 1 µM prazocin, 10 µM L-NIO, 10 µM W-7, 10 µM ODQ, 2 µM H-89 or 10 µM LY294002, and was unaffected by 10 µM chelerythrine or incubating cells in pertussis toxin (PTX). PE-induced stimulation of I_Ca,L also was inhibited by each of 10 µM ryanodine or 5 µM thapsigargin, by blocking IP₃ receptors with 2 µM 2-APB or 10 µM xestospongin C or by intracellular dialysis of heparin. In field-stimulated cells, PE increased intracellular NO (NO_i) production. PE-induced NO_i release was inhibited by each of 1 µM prazocin, 10 µM L-NIO, 10 µM W-7, 10 µM LY294002, 2 µM H-89, 10 µM ryanodine, 5 µM thapsigargin, 2 µM 2-APB or 10 µM xestospongin C, and unchanged by PTX. PE (10 µM) increased phosphorylation of Akt, which was inhibited by LY294002. Confocal microscopy showed that PE stimulated NO_i release from subsarcolemmal sites and this was prevented by 2 mM methyl-ß-cyclodextrin, an agent that disrupts caveolae formation. PE also increased local, subsarcolemmal SR Ca²⁺ release via IP₃-dependent signalling. Electron micrographs of atrial myocytes show peripheral SR cisternae in close proximity to clusters of caveolae. We conclude that in cat atrial myocytes PE acts via ₁-ARs coupled to PTX-insensitive G-protein to release NO_i, which in turn stimulates I_Ca,L. PE-induced NO_i release requires stimulation of both PI-3K/Akt and IP₃-dependent Ca²⁺ signalling. NO stimulates I_Ca,L via cGMP-mediated cAMP-dependent PKA signalling. IP₃-dependent Ca²⁺ signalling may enhance local SR Ca²⁺ release required to activate Ca²⁺-dependent eNOS/NO_i production from subsarcolemmal caveolae sites.

(Received 5 May 2005; accepted after revision 7 June 2005; first published online 9 June 2005)
Corresponding author S. L. Lipsius: Department of Physiology, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA. Email: slipsiu{at}lumc.edu

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