Affiliation:
1. From the University Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.
Abstract
Background
—
Evidence indicates that myocardial NO production can modulate contractility, but the source of NO remains uncertain. Here, we investigated the role of a type 1 NO synthase isoform (NOS1), which has been recently localized to the cardiac sarcoplasmic reticulum, in the regulation of basal and β-adrenergic myocardial contraction.
Methods and Results
—
Contraction was assessed in left ventricular myocytes isolated from mice with NOS1 gene disruption (NOS1
−/−
mice) and their littermate controls (NOS1
+/+
mice) at 3 stimulation frequencies (1, 3, and 6 Hz) in basal conditions and during β-adrenergic stimulation with isoproterenol (2 nmol/L). In addition, we examined the effects of acute specific inhibition of NOS1 with vinyl-
l
-
N
-5-(1-imino-3-butenyl)-
l
-ornithine (L-VNIO, 500 μmol/L). NOS1
−/−
myocytes exhibited greater contraction at all frequencies (percent cell shortening at 6 Hz, 10.7±0.92% in NOS1
−/−
myocytes versus 7.21±0.8% in NOS1
+/+
myocytes;
P
<0.05) with a flat frequency-contraction relationship. Time to 50% relaxation was increased in NOS1
−/−
myocytes at all frequencies (at 6 Hz, 26.53±1.4 ms in NOS1
−/−
myocytes versus 21.27±1.3 ms in NOS1
+/+
myocytes;
P
<0.05). L-VNIO prolonged time to 50% relaxation at all frequencies (at 6 Hz, 21.28±1.7 ms in NOS1
+/+
myocytes versus 26.45±1.4 ms in NOS1
+/+
+L-VNIO myocytes;
P
<0.05) but did not significantly increase basal contraction. However, both NOS1
−/−
myocytes and NOS1
+/+
myocytes treated with L-VNIO showed a greatly enhanced contraction in response to β-adrenergic stimulation (percent increase in contraction at 6 Hz, 25.2±10.8 in NOS1
+/+
myocytes, 68.2±11.2 in NOS1
−/−
myocytes, and 65.1±13.2 in NOS1
+/+
+L-VNIO myocytes;
P
<0.05).
Conclusions
—
NOS1 disruption enhances basal contraction and the inotropic response to β-adrenergic stimulation in murine ventricular myocytes. These findings indicate that cardiac NOS1-derived NO plays a significant role in the autocrine regulation of myocardial contractility.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
136 articles.
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