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Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca²⁺ current

Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio

Submitted 29 October 2007 ; accepted in final form 16 January 2008

Signaling via endothelial nitric oxide synthase (NOS3) limits the heart's response to β-adrenergic (β-AR) stimulation, which may be protective against arrhythmias. However, mechanistic data are limited. Therefore, we performed simultaneous measurements of action potential (AP, using patch clamp), Ca²⁺ transients (fluo 4), and myocyte shortening (edge detection). L-type Ca²⁺ current (I_Ca) was directly measured by the whole cell ruptured patch-clamp technique. Myocytes were isolated from wild-type (WT) and NOS3 knockout (NOS3^–/–) mice. NOS3^–/– myocytes exhibited a larger incidence of β-AR (isoproterenol, 1 µM)-induced early afterdepolarizations (EADs) and spontaneous activity (defined as aftercontractions). We also examined I_Ca, a major trigger for EADs. NOS3^–/– myocytes had a significantly larger β-AR-stimulated increase in I_Ca compared with WT myocytes. In addition, NOS3^–/– myocytes had a larger response to β-AR stimulation compared with WT myocytes in Ca²⁺ transient amplitude, shortening amplitude, and AP duration (APD). We observed similar effects with specific NOS3 inhibition [L-N⁵-(1-iminoethyl)-ornithine (L-NIO), 10 µM] in WT myocytes as with NOS3 knockout. Specifically, L-NIO further increased isoproterenol-stimulated EADs and aftercontractions. L-NIO also further increased the isoproterenol-stimulated I_Ca, Ca²⁺ transient amplitude, shortening amplitude, and APD (all P < 0.05 vs isoproterenol alone). L-NIO had no effect in NOS3^–/– myocytes. These results indicate that NOS3 signaling inhibits the β-AR response by reducing I_Ca and protects against arrhythmias. This mechanism may play an important role in heart failure, where arrhythmias are increased and NOS3 expression is decreased.

endothelial nitric oxide synthase; cardiac myocytes; early afterdepolarizations; action potential

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