Carvedilol ameliorates dexamethasone-induced myocardial injury in rats independent of its action on the α1-adrenergic receptor

Figures

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  Fig. 1. Timeline of drugs and vehicle administration

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  Fig. 2. Changes in mortality rate %, heart weight normalized to tibial length and blood markers of cardiac injury. Graphical presentation of mortality rate % (a), heart weight normalized to tibial length (HW/TL) (b), serum level of cardiac troponin I (cTnI) (c) and creatine kinase–myoglobin (CK–MB) (d). Control: Rats received vehicle for 7 days. Dexa: Rats received dexamethasone (10 mg/kg, S.C.) for 7 days. CARV: Rats received carvedilol (10 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. PH.EPH: Rats received phenylephrine (1 mg/kg, I.P.) then dexamethasone 2.5 hours later for 7 days. CARV+PH.EPH: Rats received phenylephrine then carvedilol 30 minutes later then dexamethasone 2 hours later for 7 days. PROP: Rats received propranolol (30 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post-test for selected pairs. Values are expressed as mean ± S.E.M. n = 9 for the control and CARV groups. n = 7 for the Dexa group. n = 4 for the PH.EPH, CARV+PH.EPH and PROP groups. Blood samples of each group were randomly pooled in three pools. * P < 0.05 vs control; # P < 0.05 vs Dexa; @ P < 0.05 vs CARV

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  Fig. 3. Changes in the cardiac levels of diacylglycerol (DAG), malondialdehyde (MDA) and Akt kinase activity. Graphical presentation of the DAG (a), MDA (b) and Akt kinase activity (c). Control: Rats received vehicle for 7 days. Dexa: Rats received dexamethasone (10 mg/kg, S.C.) for 7 days. CARV: Rats received carvedilol (10 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. PH.EPH: Rats received phenylephrine (1 mg/kg, I.P.) then dexamethasone 2.5 hours later for 7 days. CARV+PH.EPH: Rats received phenylephrine then carvedilol 30 minutes later then dexamethasone 2 hours later for 7 days. PROP: Rats received propranolol (30 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post-test for selected pairs. Values are expressed as mean ± S.E.M. n = 9 for the control and CARV groups. n = 7 for the Dexa group. n = 4 for the PH.EPH, CARV+PH.EPH and PROP groups. Samples of each group were randomly pooled in three pools. * P < 0.05 vs control; # P < 0.05 vs Dexa; @ P < 0.05 vs CARV

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  Fig. 4. Changes in the cardiac levels of profibrotic signals. Graphical presentation of transforming growth factor-β (a), SMAD3 (b) and alpha smooth muscle actin (α-SMA) (C). Control: Rats received vehicle for 7 days. Dexa: Rats received dexamethasone (10 mg/kg, S.C.) for 7 days. CARV: Rats received carvedilol (10 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. PH.EPH: Rats received phenylephrine (1 mg/kg, I.P.) then dexamethasone 2.5 hours later for 7 days. CARV+PH.EPH: Rats received phenylephrine then carvedilol 30 minutes later then dexamethasone 2 hours later for 7 days. PROP: Rats received propranolol (30 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post-test for selected pairs. Values are expressed as mean ± S.E.M. n = 9 for the control and CARV groups. n = 7 for the Dexa group. n = 4 for the PH.EPH, CARV+PH.EPH and PROP groups. Samples of each group were randomly pooled in three pools. * P < 0.05 vs control; # P < 0.05 vs Dexa; @ P < 0.05 vs CARV

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  Fig. 5. Histopathological changes in the cardiac ventricles stained with hematoxylin and eosin (H&E) stain (×400). I-VI: Representative photomicrographs of ventricular tissues. O: Central oval vesicular nuclei of the cardiac myocytes; Arrows: Small blood capillaries; N: elongated nuclei of interstitial cells; S: Abnormal interstitial separations; Arrowheads: Hyper-eosinophilia; *: Cytoplasmic vacuolation; P: Peripheral small dark nuclei; E: Extravasated blood cells; Curved arrows: Distortion of cardiac muscle striations. Control: Rats received vehicle for 7 days. Dexa: Rats received dexamethasone (10 mg/kg, S.C.) for 7 days. CARV: Rats received carvedilol (10 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. PH.EPH: Rats received phenylephrine (1 mg/kg, I.P.) then dexamethasone 2.5 hours later for 7 days. CARV+PH.EPH: Rats received phenylephrine then carvedilol 30 minutes later then dexamethasone 2 hours later for 7 days. PROP: Rats received propranolol (30 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days

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  Fig. 6. Changes in collagen deposits in the cardiac ventricles stained with Sirius red (×100). A–F: Representative photomicrographs of ventricular tissues. G: Graphical presentation of the fibrosis area percentage. Control: Rats received vehicle for 7 days. Dexa: Rats received dexamethasone (10 mg/kg, S.C.) for 7 days. CARV: Rats received carvedilol (10 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. PH.EPH: Rats received phenylephrine (1 mg/kg, I.P.) then dexamethasone 2.5 hours later for 7 days. CARV+PH.EPH: Rats received phenylephrine then carvedilol 30 minutes later then dexamethasone 2 hours later for 7 days. PROP: Rats received propranolol (30 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post-test for selected pairs. Values are expressed as mean ± S.E.M. n = 3

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  Fig. 7. Changes in cardiac β-arrestin2 level. A–F: Representative photomicrographs of immuno-stained ventricular tissues (×100). G: Graphical presentation of the β-arrestin2 level percentage. Control: Rats received vehicle for 7 days. Dexa: Rats received dexamethasone (10 mg/kg, S.C.) for 7 days. CARV: Rats received carvedilol (10 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. PH.EPH: Rats received phenylephrine (1 mg/kg, I.P.) then dexamethasone 2.5 hours later for 7 days. CARV+PH.EPH: Rats received phenylephrine then carvedilol 30 minutes later then dexamethasone 2 hours later for 7 days. PROP: Rats received propranolol (30 mg/kg, I.P.) then dexamethasone 2 hours later for 7 days. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post-test for selected pairs. Values are expressed as mean ± S.E.M. n = 3. * P < 0.05 vs control; # P < 0.05 vs Dexa; @ P < 0.05 vs CARV