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Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system.

El-Bassossy HM, Watson ML - J Transl Med (2015)

Bottom Line: IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation.However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. helbassossy@kau.edu.sa.

ABSTRACT

Background: We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR.

Methods: IR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT1) were assessed by immunofluorescence.

Results: IR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT1 receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.

Conclusions: XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

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Related in: MedlinePlus

Effect of allopurinol (Allo) administration (20 mg.kg−1.day−1) in the last 4 weeks on serum levels of uric acid (a) and xanthine oxidase activity (b) in rats with high fructose high fat (for 12 weeks) -induced insulin resistance (IR). Data are presented as mean ± standard error of 8 animals in each group. *P < 0.05, compared with the corresponding control group values; #P < 0.05, ##P < 0.01, compared with the corresponding IR group values; by one way ANOVA and Newman Keuls’ post hoc test.
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Fig1: Effect of allopurinol (Allo) administration (20 mg.kg−1.day−1) in the last 4 weeks on serum levels of uric acid (a) and xanthine oxidase activity (b) in rats with high fructose high fat (for 12 weeks) -induced insulin resistance (IR). Data are presented as mean ± standard error of 8 animals in each group. *P < 0.05, compared with the corresponding control group values; #P < 0.05, ##P < 0.01, compared with the corresponding IR group values; by one way ANOVA and Newman Keuls’ post hoc test.

Mentions: High fructose high fat diet administration was associated by a significant elevation in serum uric acid level compared to control (p < 0.05, Figure 1a) while allopurinol administration significantly inhibited the developed hyperuricemia (p < 0.01, Figure 1a). The serum XO activity tended to increase in rats fed on high fructose high fat diet while allopurinol administration significantly inhibited serum XO activity compared to the high fructose high fat diet fed group (p < 0.05, Figure 1b).Figure 1


Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system.

El-Bassossy HM, Watson ML - J Transl Med (2015)

Effect of allopurinol (Allo) administration (20 mg.kg−1.day−1) in the last 4 weeks on serum levels of uric acid (a) and xanthine oxidase activity (b) in rats with high fructose high fat (for 12 weeks) -induced insulin resistance (IR). Data are presented as mean ± standard error of 8 animals in each group. *P < 0.05, compared with the corresponding control group values; #P < 0.05, ##P < 0.01, compared with the corresponding IR group values; by one way ANOVA and Newman Keuls’ post hoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4355989&req=5

Fig1: Effect of allopurinol (Allo) administration (20 mg.kg−1.day−1) in the last 4 weeks on serum levels of uric acid (a) and xanthine oxidase activity (b) in rats with high fructose high fat (for 12 weeks) -induced insulin resistance (IR). Data are presented as mean ± standard error of 8 animals in each group. *P < 0.05, compared with the corresponding control group values; #P < 0.05, ##P < 0.01, compared with the corresponding IR group values; by one way ANOVA and Newman Keuls’ post hoc test.
Mentions: High fructose high fat diet administration was associated by a significant elevation in serum uric acid level compared to control (p < 0.05, Figure 1a) while allopurinol administration significantly inhibited the developed hyperuricemia (p < 0.01, Figure 1a). The serum XO activity tended to increase in rats fed on high fructose high fat diet while allopurinol administration significantly inhibited serum XO activity compared to the high fructose high fat diet fed group (p < 0.05, Figure 1b).Figure 1

Bottom Line: IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation.However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. helbassossy@kau.edu.sa.

ABSTRACT

Background: We have previously shown that hyperuricemia plays an important role in the vascular complications of insulin resistance (IR). Here we investigated the effect of xanthine oxidase (XO) inhibition on the cardiac complications of IR.

Methods: IR was induced in rats by a high fructose high fat diet for 12 weeks. Allopurinol, a standard XO inhibitor, was administered in the last 4 weeks before cardiac hemodynamics and electrocardiography, serum glucose, insulin, tumor necrosis factor alpha (TNFα), 8-isoprostane, uric acid, lactate dehydrogenase (LDH) and XO activity were measured. Expression of cardiac angiotensin II (AngII) and angiotensin receptor 1 (AT1) were assessed by immunofluorescence.

Results: IR animals had significant hyperuricemia which was inhibited by allopurinol administration. IR was associated with impaired ventricular relaxation (reflected by a decreased diastolic pressure increment and prolonged diastolic duration) and XO inhibition greatly attenuated impaired relaxation. IR was accompanied by cardiac ischemia (reflected by increased QTc and T peak trend intervals) while XO inhibition alleviated the ECG abnormalities. When subjected to isoproterenol-induced ischemia, IR hearts were less resistant (reflected by larger ST height depression and higher LDH level) while XO inhibition alleviated the accompanying ischemia. In addition, XO inhibition prevented the elevation of serum 8-isoprostane and TNFα, and blocked elevated AngII and AT1 receptor expression in the heart tissue of IR animals. However, XO inhibition did not affect the developed hyperinsulinemia or dyslipidemia.

Conclusions: XO inhibition alleviates cardiac ischemia and impaired relaxation in IR through the inhibition of low grade inflammation and the angiotensin system.

Show MeSH
Related in: MedlinePlus