An inhibitor of nitric oxide synthase does not increase contraction or β-adrenoceptor sensitivity of ventricular myocytes from failing human heart

Harding, Siân E.; Davies, C. S. L.; Money-Kyrle, Andrew; Poole‐Wilson, Philip A.

doi:10.1016/s0008-6363(98)00188-6

Cited by 27 publications

(13 citation statements)

References 21 publications

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“…That is, when there was no effect of NOS2 inhibition on the ISO response, a large response to ␤-AR stimulation was already seen in the trabeculae and isolated cardiac myocytes (failing and nonfailing human hearts). In the minority of HF cases in which NOS2 is not expressed, the ISO response was similar to what we observed in trabeculae and myocytes isolated from nonfailing human heart ( Figures 3 and 4 and similar to previous studies in nonfailing trabeculae and myocytes 15,18,23 ). Thus, we conclude that NOS2 expression is a key element in the ␤-AR hyporesponsiveness associated with human HF.…”

Section: Responsiveness In Human Hfsupporting

confidence: 90%

“…22 In addition, it has been found that nonspecific NOS inhibition had no effect on the ISO response in myocytes isolated from failing human hearts. 23 We show here that specific NOS2 inhibition greatly enhanced the response to ␤-AR stimulation in trabeculae from failing human hearts (Figure 1). We also show that specific NOS2 inhibition in isolated cardiac myocytes from failing human hearts restored the ␤-AR response (Figure 2).…”

Section: Effects Of Nos2 Inhibition On ␤-Ar Response In Human Hfmentioning

confidence: 67%

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Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

et al. 2004

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Background-Human heart failure (HF) usually exhibits blunted response to ␤-adrenergic receptor (AR) stimulation.Here, we examined whether expression of nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of inotropic reserve in human HF. Methods and Results-Failing human hearts were obtained at transplantation. Contraction and [Ca 2ϩ ] i measurements were performed in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle, isoproterenol (ISO), a ␤-AR agonist, led to small inotropic and lusitropic responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL dramatically increased the ISO-induced inotropy and lusitropy, such that the ISOϩAG response in HF approached that seen with ISO alone in nonfailing human myocytes or muscles. Ca 2ϩ transient data directly paralleled these results, indicating that altered cellular Ca 2ϩ handling is responsible. In nonfailing human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also had no effect in 30% of failing hearts, but in these myocytes and muscles, the ISO response alone was similar to that of nonfailing hearts. In line with these functional findings, NOS2 protein expression measured by Western blotting was induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no effect on contractility and Ca 2ϩ transients. Conclusions-NOS2 expression strongly limited ISO-induced increases in contraction, twitch ⌬[Ca 2ϩ ] i , and lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus, the ␤-AR hyporesponsiveness in human HF is mediated in large part by NO (or related congeners) produced within cardiac myocytes via NOS2.

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Section: Responsiveness In Human Hfsupporting

confidence: 90%

Section: Effects Of Nos2 Inhibition On ␤-Ar Response In Human Hfmentioning

confidence: 67%

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

et al. 2004

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“…These data are consistent with the lack of effect of NOS inhibition on the response of isolated failing human cardiomyocytes to pacing. 31 …”

Section: No and The Myocardial Ffr In The Human Heartmentioning

confidence: 99%

Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo

et al. 2001

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Background-Nitric oxide (NO) exerts autocrine/paracrine effects on cardiac function, including alterations of the inotropic state. In vitro studies suggest that NO modulates the myocardial force-frequency relationship. Basal left ventricular (LV) contractility is depressed and the force-frequency relationship is blunted in human heart failure, and it is speculated that an increase in NO production is involved. Methods and Results-We compared the effects of intracoronary NO synthase inhibition with N G -monomethyl-L-arginine (L-NMMA; 25 mol/min) on basal LV function and the response to incremental atrial pacing in patients with dilated cardiomyopathy (nϭ11; mean age, 51 years) and in control subjects with atypical chest pain and normal cardiac function (nϭ7; mean age, 54 years). In controls, L-NMMA significantly reduced basal LV dP/dt max (from 1826 to 1578 mm Hg/s; PϽ0.002), but had no effect on heart rate, mean aortic pressure, or right atrial pressure. Pacing-induced increases in LV dP/dt max were unaltered by L-NMMA. In patients with dilated cardiomyopathy, L-NMMA had no effect on baseline LV dP/dt max (from 1313 to 1337 mm Hg/s; PϭNS). The blunted pacing-induced rise in LV dP/dt max in these patients was unaltered by L-NMMA. Conclusion-Endogenous NO has a small baseline positive inotropic effect in the normal human heart, which is lost in heart failure patients. NO does not significantly influence the force-frequency relationship in either the normal or failing human heart in vivo. Because this study was performed in patients with moderate heart failure, whether the findings apply to subjects with more severe heart failure requires further investigation.

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“…Unlike the ␤-adrenergic response, the positive forcefrequency relationship that is blunted in CHF patients is also insensitive to NOS inhibitors, 35 as is the shortening amplitude of isolated cardiomyocytes from HF patients when increasing pacing rate from 0.2 to 1 Hz. 112 Clearly, additional patho- …”

mentioning

confidence: 99%

Nitric Oxide and Cardiac Function

Massion¹,

Feron²,

Dessy³

et al. 2003

Circulation Research

519

230

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Abstract-Nitric oxide (NO) is produced from virtually all cell types composing the myocardium and regulates cardiac function through both vascular-dependent and -independent effects. The former include regulation of coronary vessel tone, thrombogenicity, and proliferative and inflammatory properties as well as cellular cross-talk supporting angiogenesis. The latter comprise the direct effects of NO on several aspects of cardiomyocyte contractility, from the fine regulation of excitation-contraction coupling to modulation of (presynaptic and postsynaptic) autonomic signaling and mitochondrial respiration. This multifaceted involvement of NO in cardiac physiology is supported by a tight molecular regulation of the three NO synthases, from cellular spatial confinement to posttranslational allosteric modulation by specific interacting proteins, acting in concert to restrict the influence of NO to a particular intracellular target in a stimulus-specific manner. Loss of this specificity, such as produced on excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves), may result in profound cellular disturbances leading to heart failure. Future therapeutic manipulations of cardiac NO synthesis will necessarily draw on additional characterization of the cellular and molecular determinants for the net effect of this versatile radical on the cardiomyocyte biology. (Circ Res. 2003;93:388-398.)Key Words: nitric oxide Ⅲ contractile function Ⅲ cardiomyocytes Ⅲ endothelium Ⅲ heart failure A s the prototypical endothelium-derived relaxing factor, nitric oxide (NO) is a primary determinant of blood vessel tone and thrombogenicity. Applied to heart tissue, these functions alone largely justify the growing interest for NO as a regulator of cardiac function. However, the recognition that all three isoforms of nitric oxide synthase (NOS) are expressed in cardiomyocytes themselves has raised several intriguing questions regarding the signaling role of NO in the heart.The modulatory effects of NO on contractile function are undoubtedly complex. [1][2][3][4] Perhaps this is expected when one considers the versatility of NO biochemistry, the multiplicity of its intracellular targets (with sometimes opposite contractile influences), as well as the diversity of its cellular sources within the myocardium. However, subcellular targeting of NO, driven in a stimulus-specific manner, ensures coordinate regulation of cardiac function. Mouse models genetically deficient or overexpressing one or several of the three NOS isoforms helped to clarify the role of endogenously produced NO (versus exogenous NO from pharmacologic sources) in normal or diseased hearts despite several unanswered questions. In the following paragraphs, we attempt to revisit the major paradigms on the influence of NO on several parameters of cardiac contraction with the hindsight of recent knowledge from genetic or molecular characterization of NOS regulation. Cellular Regulation of NOSTwo major posttranslational modes of regulation of en...

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An inhibitor of nitric oxide synthase does not increase contraction or β-adrenoceptor sensitivity of ventricular myocytes from failing human heart

Abstract: These results do not suggest a functional role for tonic NO production in the frequency-dependent depression of contraction or beta-adrenoceptor desensitisation in myocytes from failing human ventricle.

Cited by 27 publications

References 21 publications

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo

Nitric Oxide and Cardiac Function

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An inhibitor of nitric oxide synthase does not increase contraction or β-adrenoceptor sensitivity of ventricular myocytes from failing human heart

Abstract: These results do not suggest a functional role for tonic NO production in the frequency-dependent depression of contraction or beta-adrenoceptor desensitisation in myocytes from failing human ventricle.

Cited by 27 publications

References 21 publications

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca 2+ Transients

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca 2+ Transients

Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo

Nitric Oxide and Cardiac Function

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Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted β-Adrenergic Response in Failing Human Hearts by Decreasing Ca ²⁺ Transients