Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

Ziolo, Mark T.; Katoh, Hideki; Bers, Donald M.

doi:10.1161/hc4901.100379

Cited by 77 publications

(51 citation statements)

References 42 publications

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“…Several early studies reported that activation of NOS with increased NO production tends to decrease contractility via cGMP-dependent or cGMP- independent mechanisms (3,6,7,12,17,43). Moreover, as recently reviewed, analysis of the phenotypes of mice genetically deficient in one or more isoforms of NOS further supports the conclusion that NO signaling tends to attenuate contractility under basal conditions (28).…”

Section: Discussionmentioning

confidence: 87%

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Jung¹,

Kubo²,

Wilson³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Modulation of contractility by myocytederived arginase in normal and hypertrophied feline myocardium. Am J Physiol Heart Circ Physiol 290: H1756 -H1762, 2006. First published December 3, 2005 doi:10.1152/ajpheart.01104.2005.-L-Arginine, the sole substrate for the nitric oxide (NO) synthase (NOS) enzyme in producing NO, is also a substrate for arginase. We examined normal feline hearts and hearts with compensated left ventricular (LV) hypertrophy (LVH) produced by ascending aorta banding. Using Western blot analysis, we examined the abundance of arginase isozymes in crude homogenates and isolated cardiac myocytes obtained from the LVs of normal and LVH hearts. We examined the functional significance of myocyte arginase via measurement of shortening and intracellular calcium in isolated myocytes in the presence and absence of boronoethyl chloride (BEC), a specific pharmacological inhibitor of arginase. Both arginase I and II were detected in crude myocardial homogenates, but only arginase I was present in isolated cardiac myocytes. Arginase I was downregulated in LVH compared with normal. Inhibition of arginase with BEC reduced fractional shortening, maximal rate of shortening (ϩdL/dt) and relengthening (ϪdL/dt), and the peak of the free cytosolic calcium transient in normal myocytes but did not affect these parameters in LVH myocytes. These negative inotropic actions of arginase inhibition were associated with increases in cGMP generation. These studies indicate that only arginase I is present in cardiac myocytes where it tends to limit NO and cGMP production with the effect of supporting basal contractility. In experimental LVH induced by pressure overload, our studies demonstrate reduced arginase I expression and reduced functional significance, allowing greater arginine substrate availability for NO/cGMP signaling.arginase; hypertrophy; nitric oxide; guanosine 3Ј,5Ј-cyclic monophosphate; calcium AS IN THE VASCULATURE, nitric oxide (NO) synthase (NOS) regulates the generation of NO in cardiac myocytes by deaminating the amino acid substrate L-arginine to produce NO and citrulline. NO modulates cardiac contractility via activation of soluble guanylyl cyclase, inducing increases in cGMP. In turn, cGMP modulates contractility via the activation of certain phosphodiesterases, activation of protein kinase G, and by direct stimulation of calcium cycling proteins. On the other hand, there are reports that NO can alter contractility independent of cGMP by direct nitrosylation or acetylation of various channels and calcium cycling proteins.In the normal myocardium, the acute effects of increases in NO are bimodal, with a positive inotropic effect at low amounts of NO exposure but a negative one at higher amounts (28). NO donors have been shown to exhibit weak to moderate negative inotropic effects in nondiseased preparations (8,25,34). On the other hand, in pathological states, there is increasing evidence that upregulation of NOS and/or increased production of NO improves left ventricular (LV) performance and myocyt...

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Section: Discussionmentioning

confidence: 87%

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Jung¹,

Kubo²,

Wilson³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, a coherent hypothesis detailing the role of specific NOS isoforms and the locus of action of NO in heart failure has not yet emerged. Some studies indicate that cytokine-induced NOS2 and NO production cause suppression of myocyte Ca 2ϩ transients (35)(36)(37)(38). However, it has more recently been shown that constitutive NOS isoforms contribute to the heart failure phenotype.…”

Section: Discussionmentioning

confidence: 99%

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

Steppan

Ryoo

Schuleri

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Cardiac myocytes contain two constitutive NO synthase (NOS) isoforms with distinct spatial locations, which allows for isoformspecific regulation. One regulatory mechanism for NOS is substrate (L-arginine) bioavailability. We tested the hypothesis that arginase (Arg), which metabolizes L-arginine, constrains NOS activity in the cardiac myocyte in an isoform-specific manner. Arg activity was detected in both rat heart homogenates and isolated myocytes. Although both Arg I and II mRNA and protein were present in whole heart, Arg II alone was found in isolated myocytes. Arg inhibition with S-(2-boronoethyl)-L-cysteine (BEC) augmented Ca 2؉ -dependent NOS activity and NO production in myocytes, which did not depend on extracellular L-arginine. Arg II coimmunoprecipited with NOS1 but not NOS3. Isolation of myocyte mitochondrial fractions in combination with immuno-electron microscopy demonstrates that Arg II is confined primarily to the mitochondria. Because NOS1 positively modulates myocardial contractility, we determined whether Arg inhibition would increase basal myocardial contractility. Consistent with our hypothesis, Arg inhibition increased basal contractility in isolated myocytes by a NOS-dependent mechanism. Both the Arg inhibitors N-hydroxynor-L-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N G -nitro-L-arginine methyl ester and S-methyl-L-thiocitrulline, respectively. Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice. We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain. These findings have implications for therapy in pathophysiologic states such as aging and heart failure in which myocardial NO signaling is disrupted. mitochondria ͉ L-arginine pools ͉ spatial confinement

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“…Additionally, the lack of effect of low SIN-1 in PLB −/− myocytes may indicate that these positive effects are mediated via PLB-dependent mechanisms. However, the effects of low SIN-1 on other excitation-contraction coupling proteins cannot be completely ruled out, as peroxynitrite has been shown to have effects on other excitation-contraction coupling proteins [35][36][37][38][39]. Further, SIN-1 has a complex chemistry that could potentially lead to the formation of other reactive nitrogen species.…”

Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

“…NOS1 is considered a physiological regulator of cardiac function and is also thought to increase myocardial contractility [41]. Conversely, high SIN-1 may be mimicking the peroxynitrite production of NOS2, which is considered to be a pathophysiological regulator of cardiac function by reducing β-adrenergic responsiveness [3,36]. During many pathophysiological conditions of the myocardium, nitric oxide production is increased with NOS2 expression [3,42] and superoxide production is increased through NADPH oxidase and/or xanthine oxidoreductase [8,9], leading to supraphysiological peroxynitrite production and cardiac dysfunction.…”

Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

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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Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

Cited by 77 publications

References 42 publications

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism

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

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