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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

IK voltage relationship for normal cardiomyocytes and volume-overload induced hypertrophied cardiomyocytes. The inset in each graph shows the respective representative current responses at +30 mV for IK. Data are presented as average current density ±SEM with n=5–10. * P<0.05 sham vs. shunt.
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f1-medscimonit-17-7-br165: IK voltage relationship for normal cardiomyocytes and volume-overload induced hypertrophied cardiomyocytes. The inset in each graph shows the respective representative current responses at +30 mV for IK. Data are presented as average current density ±SEM with n=5–10. * P<0.05 sham vs. shunt.

Mentions: Hypertrophied myocytes as compared to normal myocytes showed significant decrease in the basal current density levels of the delayed outward rectifier potassium channel IK (hypertrophied 3.6±0.1 pA/pF vs. normal 5.7±0.7 pA/pF; P<0.05, n=4) and slope conductance gK (hypertrophied 66.7±8.1 nS/pF vs. normal 114.6±11.2 nS/pF; P<0.05) (Figure 1). Superfusion with ANG II (10−6 M) did not affect IK current density (control 4.1±0.4 pA/pF vs. ANG II 5.0±0.4 pA/pF; n=5) nor its slope conductance in normal cardiomyocytes (57.8±15.4 nS/pF vs. 61.3±26.8 nS/pF) (Figure 2A). In the presence of ANG II, the PI3-K inhibitor, LY294002 (10−6 M), had no effect on the sham IK current density. However, the ANG II effects on IK channels of hypertrophied cardiomyocytes caused an increase in IK current density (control 2.1±0.4 pF/pA vs. ANG II 2.9±0.5 pA/pF; P<0.05, n=4) and gK (nS/pF) (control 37.6±15.8 vs. ANG II 44.6±15.4; p<0.05) (Figure 2B). Interestingly, addition of LY294002 (10−6 M) abrogated the ANG II effect on IK in the hypertrophied cardiomyocytes (1.7±0.4 pA/pF; P<0.05, n=5) and its slope conductance, gK (nS/pF) (44.6±15.4 vs. 35.2±14.4; P<0.05).


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)

IK voltage relationship for normal cardiomyocytes and volume-overload induced hypertrophied cardiomyocytes. The inset in each graph shows the respective representative current responses at +30 mV for IK. Data are presented as average current density ±SEM with n=5–10. * P<0.05 sham vs. shunt.
© Copyright Policy
Related In: Results  -  Collection

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

f1-medscimonit-17-7-br165: IK voltage relationship for normal cardiomyocytes and volume-overload induced hypertrophied cardiomyocytes. The inset in each graph shows the respective representative current responses at +30 mV for IK. Data are presented as average current density ±SEM with n=5–10. * P<0.05 sham vs. shunt.
Mentions: Hypertrophied myocytes as compared to normal myocytes showed significant decrease in the basal current density levels of the delayed outward rectifier potassium channel IK (hypertrophied 3.6±0.1 pA/pF vs. normal 5.7±0.7 pA/pF; P<0.05, n=4) and slope conductance gK (hypertrophied 66.7±8.1 nS/pF vs. normal 114.6±11.2 nS/pF; P<0.05) (Figure 1). Superfusion with ANG II (10−6 M) did not affect IK current density (control 4.1±0.4 pA/pF vs. ANG II 5.0±0.4 pA/pF; n=5) nor its slope conductance in normal cardiomyocytes (57.8±15.4 nS/pF vs. 61.3±26.8 nS/pF) (Figure 2A). In the presence of ANG II, the PI3-K inhibitor, LY294002 (10−6 M), had no effect on the sham IK current density. However, the ANG II effects on IK channels of hypertrophied cardiomyocytes caused an increase in IK current density (control 2.1±0.4 pF/pA vs. ANG II 2.9±0.5 pA/pF; P<0.05, n=4) and gK (nS/pF) (control 37.6±15.8 vs. ANG II 44.6±15.4; p<0.05) (Figure 2B). Interestingly, addition of LY294002 (10−6 M) abrogated the ANG II effect on IK in the hypertrophied cardiomyocytes (1.7±0.4 pA/pF; P<0.05, n=5) and its slope conductance, gK (nS/pF) (44.6±15.4 vs. 35.2±14.4; P<0.05).

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