HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/H1473    most recent 01249.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Wang, H. Articles by Ziolo, M. T. PubMed PubMed Citation Articles by Wang, H. Articles by Ziolo, M. T.

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

This article has been cited by other articles:

				H. Wang, M. J. Kohr, C. J. Traynham, D. G. Wheeler, P. M. L. Janssen, and M. T. Ziolo Neuronal nitric oxide synthase signaling within cardiac myocytes targets phospholamban Am J Physiol Cell Physiol, June 1, 2008; 294(6): C1566 - C1575. [Abstract] [Full Text] [PDF]