Positive and negative inotropic effects of NO donors in atrial and ventricular fibres of the frog heart

Chesnais, J. M.; Fischmeister, Rodolphe; Méry, Pierre‐François

doi:10.1111/j.1469-7793.1999.0449p.x

Cited by 38 publications

(44 citation statements)

References 46 publications

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“…Many studies have demonstrated the positive effect of low concentrations of the nitric oxide/ superoxide donor SIN-1 and of peroxynitrite on basal myocardial contractility [16][17][18]. We confirmed these results in isolated murine cardiomyocytes, in that 10 μmol/L SIN-1 induced an increase in basal [Ca 2+ ] i transient amplitude and myocyte shortening (Fig.…”

Section: Low Sin-1 (10 μMol/l) and Myocyte Contractilitysupporting

confidence: 87%

“…There are many studies which demonstrate a concentration-dependent biphasic effect of peroxynitrite on basal myocardial contractility, but the majority of these studies did not address these effects on β-adrenergic responsiveness [10][11][12][13][14][15][16][17][18]26,28]. In our study, SIN-1 (source of peroxynitrite) had a biphasic effect on murine cardiomyocyte contractility that was not only dependent on concentration, but also on the contractile state of the cardiomyocyte.…”

Section: Discussionmentioning

confidence: 60%

“…For instance, numerous studies have shown high concentrations of peroxynitrite to be detrimental to myocardial contractility [10][11][12][13][14][15], while at low concentrations peroxynitrite appears to act as a positive inotropic agent [16][17][18]. However, the majority of these studies examined effects on basal contractility and did not address the effects of peroxynitrite as they relate to β-adrenergic responsiveness.…”

Section: Introductionmentioning

confidence: 99%

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Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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Section: Low Sin-1 (10 μMol/l) and Myocyte Contractilitysupporting

confidence: 87%

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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“…In addition, investigators also demonstrated that the NO donor-induced contractile enhance ment in frog [33] and rodent [34] cardiomyocytes was mediated through a cGMP-independent mechanism. The exact nature of this response remains to be elucidated.…”

Section: Phosphodiesterases and Cyclic Nucleotide Signalingmentioning

confidence: 99%

“…In the coronary vasculature, cAMP and cGMP promote vasodilation that may indirectly affect cardiac performance [52,53] . In addition, the above-mentioned cGMP-independent positive inotropic effects of NO in cardiomyocytes [33,34] might be achieved through direct S-nitrosylation of the excitation-contraction coupling elements, such as the L-type calcium channels [34,54] and RyR [34,55] (Figure 1). …”

Section: Phosphodiesterases and Cyclic Nucleotide Signalingmentioning

confidence: 99%

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Rao

2008

Acta Pharmacol Sin

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Phosphodiesterases (PDEs) are enzymes that degrade cellular cAMP and cGMP and are thus essential for regulating the cyclic nucleotides. At least 11 families of PDEs have been identified, each with a distinctive structure, activity, expression, and tissue distribution. The PDE type-3, -4, and -5 (PDE3, PDE4, PDE5) are localized to specific regions of the cardiomyocyte, such as the sarcoplasmic reticulum and Z-disc, where they are likely to influence cAMP/cGMP signaling to the end effectors of contractility. Several PDE inhibitors exhibit remarkable hemodynamic and inotropic properties that may be valuable to clinical practice. In particular, PDE3 inhibitors have potent cardiotonic effects that can be used for short-term inotropic support, especially in situations where adrenergic stimulation is insufficient. Most relevant to this review, PDE inhibitors have also been found to have cytoprotective effects in the heart. For example, PDE3 inhibitors have been shown to be cardioprotective when given before ischemic attack, whereas PDE5 inhibitors, which include three widely used erectile dysfunction drugs (sildenafil, vardenafil and tadalafil), can induce remarkable cardioprotection when administered either prior to ischemia or upon reperfusion. This article provides an overview of the current laboratory and clinical evidence, as well as the cellular mechanisms by which the inhibitors of PDE3, PDE4 and PDE5 exert their beneficial effects on normal and ischemic hearts. It seems that PDE inhibitors hold great promise as clinically applicable agents that can improve cardiac performance and cell survival under critical situations, such as ischemic heart attack, cardiopulmonary bypass surgery, and heart failure.

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Cyclic AMP and cyclic GMP independent stimulation of ventricular calcium current by peroxynitrite donors in guinea pig myocytes

Malan

Levi

Alloatti

et al. 2003

Journal Cellular Physiology

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We investigated the potential involvement of peroxynitrite (ONOO(-)) in the modulation of calcium current (I(Ca)) in guinea pig ventricular myocytes with the whole-cell patch clamp technique and with cyclic AMP (cAMP) measurements. Because of the short half-life of ONOO(-) at physiological pH, we induced an increase in its intracellular levels by using donors of the precursors, nitric oxide (NO) and superoxide anion (O(2) (-)). High concentrations of NO donors, SpermineNONOate (sp/NO, 300 microM) or SNAP (300 microM) increased basal I(Ca) (50.3 +/- 4.6%, n = 7 and 46.2 +/- 5.0%, n = 13). The superoxide anion donor Pyrogallol (100 microM) also stimulated basal I(Ca) (44.6 +/- 2.8%, n = 11). At lower concentration sp/NO (10 nM) and Pyrogallol (1 microM), although separately ineffective on I(Ca), enhanced the current if applied together (33.5 +/- 0.7%, n = 7). The simultaneous donor of O(2) (-) and NO, SIN-1 (500 microM), also stimulated basal I(Ca) (22.8 +/- 2.1%, n = 13). In the presence of saturating cyclic GMP (cGMP, 50 microM) in the patch pipette or of extracellular dibutyryl cGMP (dbcGMP, 100 microM), I(Ca) was still increased by SIN-1 (32.0 +/- 6.1%, n = 4 and 30.0 +/- 5.4%, n = 8). Both Manganese(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP, 100 microM) a ONOO(-) scavenger, and superoxide dismutase (SOD) (150 U/ml) reversed the stimulatory effect of SIN-1 on I(Ca) (respectively -0.6 +/- 4.1%, n = 4 and 3.6 +/- 4.3%, n = 4). Intracellular cAMP level was unaltered by SIN-1, while it was enhanced by blocking the NO-cGMP pathway with the NO synthase inhibitor L-NMMA. These results suggest that peroxynitrite donors increase cardiac calcium current without the involvement of cAMP and cGMP.

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Positive and negative inotropic effects of NO donors in atrial and ventricular fibres of the frog heart

Cited by 38 publications

References 46 publications

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

Cyclic AMP and cyclic GMP independent stimulation of ventricular calcium current by peroxynitrite donors in guinea pig myocytes

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