| First Author | Wang H | Year | 2008 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 294 |
| Issue | 3 | Pages | H1473-80 |
| PubMed ID | 18203845 | Mgi Jnum | J:132621 |
| Mgi Id | MGI:3776367 | Doi | 10.1152/ajpheart.01249.2007 |
| Citation | Wang H, et al. (2008) Endothelial nitric oxide synthase decreases {beta}-adrenergic responsiveness via inhibition of the L-type Ca2+ current. Am J Physiol Heart Circ Physiol 294(3):H1473-80 |
| abstractText | Signaling via endothelial nitric oxide synthase (NOS3) limits the heart's response to beta-adrenergic (beta-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), Ca(2+) transients (fluo 4), and myocyte shortening (edge detection). L-type Ca(2+) 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 beta-AR (isoproterenol, 1 muM)-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 beta-AR-stimulated increase in I(Ca) compared with WT myocytes. In addition, NOS3(-/-) myocytes had a larger response to beta-AR stimulation compared with WT myocytes in Ca(2+) transient amplitude, shortening amplitude, and AP duration (APD). We observed similar effects with specific NOS3 inhibition [l-N(5)-(1-iminoethyl)-ornithine (l-NIO), 10 muM] 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), Ca(2+) 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 beta-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. |
