Showing papers by "Barbara Casadei published in 2007"

Cardiomyocytes as effectors of nitric oxide signalling.

Abstract: Nitric oxide (NO) generated constitutively within the heart has long been known to influence myocardial function; however, the precise nature of these effects has been controversial – at least in part – because of the experimental use of non-isoform-selective inhibitors of NO synthases (NOS) and unwarranted extrapolation from results obtained with NO donors. Recent studies using NOS-selective inhibitors and genetically modified models are beginning to redress the balance. It is well established that agonist-stimulated release of NO from eNOS in the coronary endothelium exerts paracrine effects on cardiomyocytes, predominantly affecting the timing of relaxation as well as myocardial oxygen consumption. A significant recent advance has been the finding that both eNOS and nNOS are constitutively expressed in distinct subcellular locations within cardiomyocytes. The relative autocrine role of these isoforms in the cardiomyocyte remains to be fully clarified but evidence suggests that the autocrine effects of nNOS may include the modulation of basal inotropy and relaxation, β-adrenergic responsiveness, and the force-frequency relationship. Myocardial eNOS, on the other hand, may be involved in mediating the inotropic response to sustained stretch. These effects may change significantly in the diseased heart where the expression, activity and/or coupling of NOS isoforms to downstream effectors may be altered. In this article, we review the current understanding of this important but complex field, focussing particularly on contractile function and on recent advances in knowledge regarding the autocrine functions of nNOS-derived NO.

Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation–contraction coupling

Abstract: Nitric oxide (NO) is a highly reactive, free radical signalling molecule that is constitutively released in cardiomyocytes by both the endothelial and neuronal isoforms of nitric oxide synthase (eNOS and nNOS, respectively). There are increasing data indicating that NO modulates various proteins involved in excitation-contraction coupling (ECC), and here we discuss the evidence that NO may modulate the function of the ryanodine receptor Ca(2+) release channel (RyR2) on the cardiac sarcoplasmic reticulum (SR). Both constitutive isoforms of NOS have been shown to co-immunoprecipitate with RyR2, suggesting that the channel may be a target protein for NO. eNOS gene deletion has been shown to abolish the increase in spontaneous Ca(2+) spark frequency in cardiomyocytes exposed to sustained stretch, whereas the effect of nNOS-derived NO on RyR2 function remains to be investigated. Single channel studies have been performed with RyR2 reconstituted in planar lipid bilayers and exposed to various NO donors and, under these conditions, NO appears to have a dose-dependent, stimulatory effect on channel open probability (P(open)). We discuss whether NO has a direct effect on RyR2 via covalent S-nitrosylation of reactive thiol residues within the protein, or whether there are downstream effects via cyclic nucleotides, phosphodiesterases, and protein kinases. Finally, we consider whether the proposed migration of nNOS from the SR to the sarcolemma in the failing heart may have consequences for the nitrosative vs. oxidative balance at the level of the RyR2, and whether this may contribute to an increased diastolic Ca(2+) leak, depleted SR Ca(2+) store, and reduced contractility in heart failure.