Copyright © 2006, European Society of Cardiology
Are myocardial eNOS and nNOS involved in the β-adrenergic and muscarinic regulation of inotropy? A systematic investigation
Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
* Corresponding author. Tel.: +44 1865 220132; fax: +44 1865 768844. Email address: barbara.casadei{at}cardiov.ox.ac.uk
Objective The role of constitutive nitric oxide (NO) production in the regulation of β-adrenergic and muscarinic responses remains controversial. Conflicting data in left ventricular (LV) myocytes from eNOS knockout mice (eNOS– / –) have been ascribed to inconsistent experimental conditions (i.e., differences in the choice of controls, age of the mice, myocytes' stimulation frequency, and in the level of β-adrenergic stimulation); however, the recent identification of a neuronal-like NO synthase (nNOS) in the LV myocardium has raised the possibility that this isoform may be involved in the modulation of β-adrenergic and muscarinic responses.
Methods To address these issues we recorded sarcomere shortening at 35 °C under basal conditions, in the presence of isoproterenol (ISO, 10–100 nmol/L) and of ISO plus carbamylcholine (CCh, 1 µmol/L) in LV myocytes isolated from eNOS– / – and nNOS– / – mice, their wild type littermates (eNOS+/+ and nNOS+/+) or C57BL/6J mice. eNOS– / – and control myocytes were studied at 1 and 3 Hz, in the presence of 10 and 100 nmol/L ISO, and responses were compared between young (3 months) and old (
12 months) mice.
Results Contraction did not differ between young eNOS– / – and eNOS+/+ mice at all stages of the experimental protocol, either at 1 or 3 Hz or in response to 10 or 100 nmol/L ISO. However, myocytes from old eNOS– / – mice showed a reduced inotropic response to ISO compared with age-matched eNOS+/+ mice (P=0.02). Similarly, there was a significant difference in the ISO response between eNOS+/+ and C57BL/6J myocytes (P<0.01), suggesting that experimental variables such as age and the choice of control animals may have contributed to the inconsistency in the results reported in the literature. In contrast, nNOS– / – myocytes showed greater contraction and slower relaxation at all stages of the experimental protocol (P=0.0003 and P=0.01 vs. nNOS+/+ myocytes).
Conclusions Constitutive eNOS expression in murine LV myocytes is not essential for the muscarinic-mediated inhibition of β-adrenergic signalling and does not appear to play a significant role in the regulation of basal and β-adrenergic myocardial contraction. Our data suggest that nNOS is the myocardial constitutive isoform responsible for the NO-mediated autocrine regulation of myocardial inotropy and relaxation.
KEYWORDS Nitric oxide; β-Adrenergic; Cholinergic; Inotropy; Autocrine; nNOS; eNOS; Age; Wild type controls
1 These authors have contributed equally to this work.
Time for primary review 32 days
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