Modulation of cardiac contraction, relaxation and rate by the endothelial nitric oxide synthase (eNOS): lessons from genetically modified mice

Abstract

The modulatory role of endothelial nitric oxide synthase (eNOS) on heart contraction, relaxation and rate is examined in light of recent studies using genetic deletion or overexpression in mice under specific conditions. Unstressed eNOS‐/‐ hearts in basal conditions exhibit a normal inotropic and lusitropic function, with either decreased or unchanged heart rate. Under stimulation with catecholamines, eNOS‐/‐ mice predominantly show a potentiation in their β‐adrenergic inotropic and lusitropic responsiveness. A similar phenotype is observed in β3‐adrenoceptor deficient mice, pointing to a key role of this receptor subtype for eNOS coupling. The effect of eNOS on the muscarinic cholinergic modulation of cardiac function probably operates in conjunction with other NO‐independent mechanisms, the persistence of which may explain the apparent dispensability of this isoform for the effect of acetylcholine in some eNOS‐/‐ mouse strains. eNOS‐/‐ hearts submitted to short term ischaemia‐reperfusion exhibit variable alterations in systolic and diastolic function and infarct size, while those submitted to myocardial infarction present a worsened ventricular remodelling, increased 1 month mortality and loss of benefit from ACE inhibitor or angiotensin II type I receptor antagonist therapy. Although non‐conditional eNOS gene deletion may engender phenotypic adaptations (e.g. ventricular hypertrophy resulting from chronic hypertension, or upregulation of the other NOS isoforms) potentially confounding the interpretation of comparative studies, the use of eNOS‐/‐ mice has undoubtedly advanced (and will probably continue to improve) our understanding of the complex role of eNOS (in conjunction with the other NOSs) in the regulation of cardiac function. The challenge is now to confirm the emerging paradigms in human cardiac physiology and hopefully translate them into therapy.

Longitudinal Age-Related Changes in 24-Hour Total Heart Beats and Premature Beats and Their Relationship in Healthy Elderly Subjects

“…The increase in THB with age in healthy elderly subjects may derive from the decrease in cardiac output and total blood volume and respiratory dysfunction with aging, as well as from age-related changes in norepinephrine metabolism at the neuroeffector gaps in the sinus node and norepinephrine spillover from the synapses in heart and other organs to circulatory blood with age, 6,16,19,20) or from a decline in vagal activity due to a decrease in nitric oxide and muscarinic receptors with age. [21][22][23] If this HR change was due to the former, that is, cardiopulmonary dysfunction with age, it would increase more in the daytime than in the nighttime. However, the increases in HRs with age in the daytime have been shown to be comparable to those in the nighttime, as our previous study on the same subject showed.…”

Voluntary physical activity alterations in endothelial nitric oxide synthase knockout mice

“…In addition, eNOSϪ/Ϫ mice demonstrate no changes in basal coronary flow (15), and in basal conditions they have normal cardiac hemodynamics (56) as well as inotropic and lusitropic responses (11). Under conditions of ␤-adrenergic stimulation, eNOSϪ/Ϫ hearts even demonstrate augmented inotropy (2,35). All these data are evidence against a possible contribution of impaired cardiac function to the decreased voluntary physical activity in the absence of eNOS.…”

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

“…NOS1 signaling has been found to potentiate the response to ␤-AR stimulation (4). The observed effects of NOS3 signaling on the ␤-AR response are the opposite of NOS1 (30), that is, studies have shown that NOS3 signaling depresses the functional response to ␤-AR stimulation. For example, mice with specific knockout of NOS3 (NOS3 Ϫ/Ϫ ) have an increased response to ␤-AR stimulation (4,11,19,20,47).…”