Inducible nitric oxide synthase depresses cardiac contractile function in Zucker diabetic fatty rats

Song, Dongzhe; Kuo, Kuo‐Hsing; Yao, Reina; Hutchings, Simon; Pang, Catherine C.Y.

doi:10.1016/j.ejphar.2007.09.043

Cited by 20 publications

(13 citation statements)

References 36 publications

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“…The levels of iNOS mRNA tended to be higher in resistance PA from obese rats but differences did not reach statistical significance due to the high variability within our experimental samples. However the protein iNOS expression was significantly higher in obese resistance PA than in lean resistance PA. iNOS upregulation has also been found in other tissues such as the aorta, the visceral adipose tissue and the heart in the Zucker obese rats and other models of insulin resistance [40,42,43]. There are a large number of studies showing that increased expression of iNOS induced by lipopolysaccharide (LPS) is accompanied by endothelial dysfunction, as opposed to the present study.…”

Section: Discussionmentioning

confidence: 47%

“…Moreover, iNOS has been directly related to cardiac contractile dysfunction [40] and in vascular complications derived from insulin resistance [41,42]. We found that the contractile response to 5-HT was increased by the non selective NO synthase inhibitor L-NAME much more effectively in the obese than in the lean rats, suggesting that increased NO synthesis was responsible for the vascular hyporesponsiveness in the obese rats.…”

Section: Discussionmentioning

confidence: 75%

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Pulmonary arterial dysfunction in insulin resistant obese Zucker rats

et al. 2011

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BackgroundInsulin resistance and obesity are strongly associated with systemic cardiovascular diseases. Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension. The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat.MethodsLarge and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording. mRNA and protein expression was measured by RT-PCR or Western blot, respectively. KV currents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique.ResultsRight ventricular wall thickness was similar in obese and lean Zucker rats. Lung BMPR2, KV1.5 and 5-HT2A receptor mRNA and protein expression and KV current density were also similar in the two rat strains. In conductance and resistance pulmonary arteries, the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung eNOS expression revealed a preserved endothelial function. However, in resistance (but not in conductance) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents (hypoxia, phenylephrine and 5-HT) was observed. The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the iNOS inhibitor 1400W.ConclusionsIn contrast to rat models of type 1 diabetes or other mice models of insulin resistance, the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of iNOS.

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Section: Discussionmentioning

confidence: 47%

Section: Discussionmentioning

confidence: 75%

Pulmonary arterial dysfunction in insulin resistant obese Zucker rats

et al. 2011

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“…Interestingly, ablation of these cardiac abnormalities by Akt2 knockout was accompanied by increased SERCA expression and phospholamban phosphorylation, suggesting a role of SERCA2a-phospholamban mediated intracellular Ca 2+ cycling in Akt2 knockout-induced beneficial effect under iNOS inhibition. It is commonly accepted that enhanced iNOS expression, which occurs in metabolic diseases such as diabetes, may lead to increased production of NO and thus reactive intermediate peroxynitrite (ONOO − ), leading to cardiac geometric and contractile defects (Soliman et al , 2008; Song et al , 2008). Observations from our present study favor a role of iNOS in the regulation of insulin signaling and cardiac function, thus prompting to a role of “double-edged sword“ for iNOS in insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

Akt2 knockout mitigates chronic iNOS inhibition-induced cardiomyocyte atrophy and contractile dysfunction despite persistent insulin resistance

Roe

Ren

2011

Toxicology Letters

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Increased levels of inducible nitric oxide synthase (iNOS) during cardiac stress such as ischemia-reperfusion, sepsis and hypertension may display both beneficial and detrimental roles in cardiac contractile performance. However, the precise role of iNOS in the maintenance of cardiac contractile function remains elusive. This study was designed to determine the impact of chronic iNOS inhibition on cardiac contractile function and the underlying mechanism involved with a special focus on the NO downstream signaling molecule Akt. Male C57 or Akt2 knockout [Akt2(−/−)] mice were injected with the specific iNOS inhibitor 1400W (2 mg/kg/d) or saline for 7 days. Both 1400W and Akt2 knockout dampened glucose and insulin tolerance without additive effects. Treatment of 1400W decreased heart and liver weights as well as cardiomyocyte cross-sectional area in C57 but not Akt2 knockout mice. 1400W but not Akt2 knockout compromised cardiomyocyte mechanical properties including decreased peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening duration, reduced intracellular Ca2+ release and decay rate, the effects of which were ablated or attenuated by Akt2 knockout. Akt2 knockout but not 1400W increased the levels of intracellular Ca2+ regulatory proteins including SERCA2a and phospholamban phosphorylation. 1400W reduced the level of anti-apoptotic protein Bcl-2, the effect of which was unaffected by Akt2 knockout. Neither 1400W nor Akt2 knockout significantly affected ER stress, autophagy, the post-insulin receptor signaling Akt, GSK3β and AMPK, as well as the stress signaling IΚB, JNK, ERK and p38 with the exception of elevated IΚB phosphorylation with jointed effect of 1400W and Akt2 knockout. Taken together, these data indicated that an essential role of iNOS in the maintenance of cardiac morphology and function possibly through an Akt2-dependent mechanism.

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“…Additionally, our NO data also indicate a pro‐inflammatory and pro‐oxidant state already in young ZDF rats because both plasma NO and iNOS expression were significantly increased. Other studies have reported augmented cytokines levels in ZDF rats (46) that appear to be accompanied by an upregulation of heart iNOS expression, which is related to inflammation and impaired cardiac function (47). Although we did not measure plasma cytokine in ZDF rats, our data suggest a pro‐inflammatory condition derived from the increase in hepatic iNOS expression and plasma NO.…”

Section: Discussionmentioning

confidence: 99%

Postprandial Insulin Resistance in Zucker Diabetic Fatty Rats is Associated with Parasympathetic‐Nitric Oxide Axis Deficiencies

Afonso

Fernandes

Santos

et al. 2012

J Neuroendocrinology

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The Zucker diabetic fatty (ZDF) rat is an obesity and type 2 diabetes model. Progression to diabetes is well characterised in ZDF rats, but only in the fasted state. We evaluated the mechanisms underlying postprandial insulin resistance in young ZDF rats. We tested the hypothesis that the overall postprandial action of insulin is affected in ZDF rats as a result of impairment of the hepatic parasympathetic-nitric oxide (PSN-NO) axis and/or glutathione (GSH), resulting in decreased indirect (PSN-NO axis) and direct actions of insulin. Nine-week-old male ZDF rats and lean Zucker rats (LZR, controls) were used. The action of insulin was assessed in the fed state before and after parasympathetic antagonism atropine. Basal hepatic NO and GSH were measured, as well as NO synthase (NOS) and γ-glutamyl-cysteine synthethase (GCS) activity and expression. ZDF rats presented postprandial hyperglycaemia (ZDF, 201.4 ± 12.9 mg/dl; LZR, 107.7 ± 4.3 mg/dl), but not insulinopaenia (ZDF, 5.9 ± 0.8 ng/ml; LZR, 1.5 ± 0.3 ng/ml). Total postprandial insulin resistance was observed (ZDF, 78.6 ± 7.5 mg glucose/kg; LZR, 289.2 ± 24.7 mg glucose/kg), with a decrease in both the direct action of insulin (ZDF, 54.8 ± 7.0 mg glucose/kg; LZR, 173.3 ± 20.5 mg glucose/kg) and the PSN-NO axis (ZDF, 24.5 ± 3.9 mg glucose/kg; LZR, 115.9 ± 19.4 mg glucose/kg). Hepatic NO (ZDF, 117.2 ± 11.4 μmol/g tissue; LZR, 164.6 ± 4.9 μmol/g tissue) and GSH (ZDF, 4.9 ± 0.3 μmol/g; LZR, 5.9 ± 0.2 μmol/g) were also compromised as a result of decreased NOS and GCS activity, respectively. These results suggest a compromise of the mechanism responsible for potentiating insulin action after a meal in ZDF rats. We show that defective PSN-NO axis and GSH synthesis, together with an impaired direct action of insulin, appears to contribute to postprandial insulin resistance in this model.

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Inducible nitric oxide synthase depresses cardiac contractile function in Zucker diabetic fatty rats

Cited by 20 publications

References 36 publications

Pulmonary arterial dysfunction in insulin resistant obese Zucker rats

Pulmonary arterial dysfunction in insulin resistant obese Zucker rats

Akt2 knockout mitigates chronic iNOS inhibition-induced cardiomyocyte atrophy and contractile dysfunction despite persistent insulin resistance

Postprandial Insulin Resistance in Zucker Diabetic Fatty Rats is Associated with Parasympathetic‐Nitric Oxide Axis Deficiencies

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