Comparing the Effects of Carvedilol Enantiomers on Regression of Established Cardiac Hypertrophy Induced by Pressure Overload

Jia Hao; Chan-Hyung Kim

doi:10.5625/lar.2010.26.1.75

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Hao and Kim: Comparing the Effects of Carvedilol Enantiomers on Regression of Established Cardiac Hypertrophy Induced by Pressure Overload

Original Article

Lab. Anim. Res. 2010;26(1):75-82.

Published online: 17 March 2010

DOI: https://doi.org/10.5625/lar.2010.26.1.75

Comparing the Effects of Carvedilol Enantiomers on Regression of Established Cardiac Hypertrophy Induced by Pressure Overload

Jia Hao¹, Chan-Hyung Kim^2,^∗

¹Department of pharmacology, Shantou University Medical College, Shantou, Guangdong, China

²Department of Pharmacology, College of Medicine and BK21 Chungbuk Biomedical Science Center, Chungbuk National University, Cheongju, Korea

^∗Corresponding author: Chan-Hyung Kim, Department of Pharmacology, College of Medicine, Chungbuk National University, 410 Seongbongro, Heungdeok-gu, Cheongju, Chungbuk 361-763, Korea Tel: +82-43-261-2878 Fax: +82-43-272-1603 E-mail: kch@chungbuk.ac.kr

Received 1 November 2009 Revised 17 February 2010 Accepted 17 March 2010

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Pressure overload diseases such as valvular stenosis and systemic hypertension morphologically manifest in patients as cardiac concentric hypertrophy. Preventing cardiac remodeling due to increased pressure overload is important to reduce the morbidity and mortality. A recent clinical study has shown that carvedilol has beneficial effects on the survival rate of patients with heart failure. This may be due to the actions of carvedilol such as β-adrenoceptor blockade and the α¹-adrenergic receptor blockade effects. Therefore, we investigated whether carvedilol can reverse preexisting cardiac hypertrophy and we compared the effects of racemic carvedilol and the carvedilol enantiomers. Cardiac hypertrophy was induced in rats by suprarenal transverse abdominal aortic constriction (AC). Fifteen weeks after AC surgery, concentric hypertrophy was identified in the AC group by performing echocardiography. Low dose S- and SR-carvedilol (2 mg/kg/day), which were orally administered for three weeks, caused significant regression of the cardiac hypertrophy, and this most significantly occurred in the rats that received S-carvedilol. However, R-carvedilol did not reduce cardiac hypertrophy. Regression of cardiac hypertrophy by carvedilol was confirmed on the echocardiograms and electrocardiograms. These results suggest that carvedilol could reverse the development of leftventricular concentric hypertrophy that is induced by pressure overload. S-carvedilol is proposed to be superior to SR-and R-carvedilol as a beneficial treatment for cardiac hypertrophy.

Keywords: Established cardiac hypertrophy, carvedilol, enantiomers, pressure overload

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Figure 1.

Experimental design. Cardiac hypertrophy were confirmed at 15 weeks after abdominal aortic constriction (AC) using echocardiography. Carvedilol was dissolved in 0.5% methylcellulose and oral administered (1 mL/kg) for 3 weeks. Cardiac function, cardiac hypertrophy and electrocardiogram were performed after 18 weeks of abdominal AC.

Figure 2.

Regression of pressure overload induced cardiac hypertrophy in vivo by carvedilol. A. Representative hearts of rats treated with 18 weeks aortic constriction (AC) or 15 weeks AC+carvedilol for 3 weeks. bar=1 mm. B. Heart wet weight was normalized to body weight in each rat as an index of cardiac hypertrophy. Heart weight to body weight ratio was reversed by 2 mg/ kg/d carvedilol in hypertrophied heart induced by aortic constriction (AC). C. Liver weight to body weight ratio. R, R-carvedilol; SR, SR-carvedilol; S, S-carvedilol. ^†,#P<0.001 compared with sham; ∗P<0.001 compared with AC, n≥6.

Figure 3.

Representative M-mode echocardiograms after 3 weeks of carvedilol administration in established cardiac hypertrophy induced by 15 weeks of aortic constriction (AC). Quantitative data are shown in Table 1. Concentric cardiac remodeling was observed in the AC group. The increased wall thickness was reversed by S-carvedilol. R, R-carvedilol; SR, SR-carvedilol; S, S-carvedilol.

Figure 4.

Representative electrocardiograms after 3 weeks of carvedilol administration in established cardiac hypertrophy induced by 15 weeks of aortic constriction (AC). Quantitative data are shown in Table 3. Abnormal ECGs were observed in the AC group and these wave were significantly reversed by S-carvedilol. R, R-carvedilol; SR, SR-carvedilol; S, S-carvedilol.

Table 1.

Echocardiographic changes after pressure overload

15 weeks				18 weeks
	Control	AC	Control	AC	Treatment (2 mg/kg/day)
R-Carvediol	Control	AC	Control	AC	SR-Carvediol	S-Carvediol
IVSd (mm)	1.22±0.04	1.85±0.06^†	1.75±0.05	2.00±0.15^†	1.73±0.12^∗	.1.78±0.06^∗	1.70±0.09^∗
LVIDd (mm)	8.22±0.50	7.21±0.40^†	7.82±0.60	7.40±0.1^†0	7.40±0.20^∗	7.15±0.35	8.53±0.13^∗
PWTd (mm)	1.42±0.13	2.22±0.12^†	1.98±0.10	3.08±0.20^†	2.55±0.19^∗	.2.43±0.12^∗	2.22±0.10^∗
RWT(mm/mm)	0.34±0.01	0.62±0.05^†	0.51±0.01	0.84±0.09^†	0.68±0.06^∗	0.67±0.08	0.51±0.02^∗
FS (%)	30.6±2.11	39.72±3.850.	43.30±3.000	31.2±0.40^†	37.5±3.72^∗	33.8±5.28	34.4±1.69^∗

Data are means±SE; n≥6. AC, aortic constriction; IVSd, interventricular septum thickness in diastole; LVIDd, left ventricular internal dimension in diastole; PWTd, posterior wall thickness of the left ventricle in diastole, respectively; RWT, relative wall thickness; FS, fractional shortening.

^† P<0.05 compared with normal control group;

^∗ P<0.05 compared to the AC group.

Table 2.

The effect of carvedilol on the release of intracellular enzymes from hypertrophic heart

	AST (U/L)	ALT (U/L)	CK (U/L)	LDH (µmole/L)
Control	096.3±12.7	51.3±2.4	219.6±72.50	094.3±22.0
AC	134.0±28.0	60.0±5.0	.524.3±177.7^†	.132.7±22.6^†
Treatment (2 mg/kg/day)
R-Carvedilol	445.3±312.1	122.0±59.5	652.2±177.1	209.0±68.2
SR-Carvedilol	144.7±23.50	061.3±82.1	775.7±256.3	178.3±32.1
S-Carvedilol	^∗97.0±12.5^∗	^∗50.0±2.5^∗	^∗285.0±135.7^∗	0^∗83.3±21.1^∗

AST, aspartate transaminase; ALT, alanine transaminase; CK, creatine kinase; LDH, lactate dehydrogenase. Results are expressed as mean±SE. Control, treated with vehicle; AC, aortic constriction.

^† P<0.05 compared with normal control group;

^∗ P<0.05 compared to the AC group.

Table 3.

The effect of carvedilol on ECG parameters of hypertrophic heart

	RR interval (sec)	Heart rate (bpm)	PR interval (sec)	P duration (sec)	QTc (sec)	T amplitute (mV)
Control	0.19±0.01	319±16	0.045±0.001	0.015±0.002	0.150±0.023	.94.3±22.0
AC	0.26±0.02^†	236±18^†	0.047±0.003	.0.019±0.001^†	0.134±0.010	132.7±22.6^†
Treatment (2 mg/kg/day)
R-Carvedilol	0.20±0.01^∗	302±17^∗	0.047±0.004	0.018±0.002	0.177±0.006	209.0±68.2
SR-Carvedilol	0.21±0.035^∗	310±27^∗	0.040±0.003	^∗0.016±0.002^∗	0.147±0.003	178.3±32.1
S-Carvedilol	0.20±0.02^∗	318±24^∗	0.050±0.002	^∗0.017±0.001^∗	0.175±0.010	0.83.3±21.1^∗

AC, 18 weeks of aortic constriction; RR interval, interval from the onset of one QRS complex to the onset of the next QRS complex; PR interval, From the beginning of the P wave to the beginning of the QRS complex; QTc, QT interval corrected for rate; T wave, represents the repolarization of the ventricles.

^† P<0.05 compared with normal control group;

^∗ P<0.05 compared to the AC group.

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