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Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes.

Alvin ZV, Laurence GG, Coleman BR, Zhao A, Hajj-Moussa M, Haddad GE - Med. Sci. Monit. (2011)

Bottom Line: Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham.Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner.Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA.

ABSTRACT

Background: Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes.

Material/methods: Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively.

Results: Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes.

Conclusions: Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

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Related in: MedlinePlus

Effects of IGF-1 (10−8 M) on the activation level of Akt in untreated (white bars) vs. captopril-treated (black bars) of sham and hypertrophied hearts. Data are expressed as the ratio of phosphorylated over total protein normalized to control untreated hearts. The inset shows representative western blot of total and phosphorylated Akt. The data are presented as average ±SEM with n=3 (from different heart samples). * P<0.05 Sham vs. Shunt; Δ P<0.05 Captopril-treated vs. Untreated.
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f7-medscimonit-17-7-br165: Effects of IGF-1 (10−8 M) on the activation level of Akt in untreated (white bars) vs. captopril-treated (black bars) of sham and hypertrophied hearts. Data are expressed as the ratio of phosphorylated over total protein normalized to control untreated hearts. The inset shows representative western blot of total and phosphorylated Akt. The data are presented as average ±SEM with n=3 (from different heart samples). * P<0.05 Sham vs. Shunt; Δ P<0.05 Captopril-treated vs. Untreated.

Mentions: Akt is a known PI3-kinase downstream effector whose activation level is dependent on PI3-K activity. Thus, we performed western blot analysis in order to assess the level of activation of the PI3-K/Akt pathway in sham and shunt hearts that have been treated with captopril versus untreated. The activation level of Akt was expressed as the ratio of phosphorylated Akt over total Akt protein expression. We found that the basal activation level of Akt in hypertrophied heart was significantly higher than in the sham ones (normal 1.00±0.21 versus hypertrophied 2.54±0.33; p<0.01), as shown in Figure 7. Treatment with captopril did not have an effect on the activity level of Akt in the normal cardiomyocytes; however it significantly down-regulated the Akt activation level in the hypertrophied cardiomyocytes toward sham levels (hypertrophied 2.54±0.33 versus captopril-treated 1.68±0.17; p<0.01).


Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes.

Alvin ZV, Laurence GG, Coleman BR, Zhao A, Hajj-Moussa M, Haddad GE - Med. Sci. Monit. (2011)

Effects of IGF-1 (10−8 M) on the activation level of Akt in untreated (white bars) vs. captopril-treated (black bars) of sham and hypertrophied hearts. Data are expressed as the ratio of phosphorylated over total protein normalized to control untreated hearts. The inset shows representative western blot of total and phosphorylated Akt. The data are presented as average ±SEM with n=3 (from different heart samples). * P<0.05 Sham vs. Shunt; Δ P<0.05 Captopril-treated vs. Untreated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3539556&req=5

f7-medscimonit-17-7-br165: Effects of IGF-1 (10−8 M) on the activation level of Akt in untreated (white bars) vs. captopril-treated (black bars) of sham and hypertrophied hearts. Data are expressed as the ratio of phosphorylated over total protein normalized to control untreated hearts. The inset shows representative western blot of total and phosphorylated Akt. The data are presented as average ±SEM with n=3 (from different heart samples). * P<0.05 Sham vs. Shunt; Δ P<0.05 Captopril-treated vs. Untreated.
Mentions: Akt is a known PI3-kinase downstream effector whose activation level is dependent on PI3-K activity. Thus, we performed western blot analysis in order to assess the level of activation of the PI3-K/Akt pathway in sham and shunt hearts that have been treated with captopril versus untreated. The activation level of Akt was expressed as the ratio of phosphorylated Akt over total Akt protein expression. We found that the basal activation level of Akt in hypertrophied heart was significantly higher than in the sham ones (normal 1.00±0.21 versus hypertrophied 2.54±0.33; p<0.01), as shown in Figure 7. Treatment with captopril did not have an effect on the activity level of Akt in the normal cardiomyocytes; however it significantly down-regulated the Akt activation level in the hypertrophied cardiomyocytes toward sham levels (hypertrophied 2.54±0.33 versus captopril-treated 1.68±0.17; p<0.01).

Bottom Line: Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham.Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner.Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA.

ABSTRACT

Background: Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes.

Material/methods: Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively.

Results: Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10-6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes.

Conclusions: Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

Show MeSH
Related in: MedlinePlus