Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction

Abstract

The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty-nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES-induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non-infarct zone (NIZ) were determined by real-time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down-regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up-regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES-induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression.

Fig 1

Echocardiography results and images of three groups. M-mode images were taken from the level of the LV outflow tract and the mitral valve was studied during the activity of ventricular wall, especial anterior wall. (A–C) The changes of LVDd, LVDs and LVEF 3 days after operation and after 8 weeks. The LV wall motion in Sham group (D) was better than the other groups. The condition of MI + Val group (F) was improved better compared with the MI group (E). LVDd: LV dimension end diastole; LVDs: LV dimension end systole; LVEF: LV ejection fraction; *P < 0.01 versus Sham group; ^†P < 0.01 versus MI group; ^#P < 0.05 versus 3 days after operation.

Fig 2

Results displayed the incidence of inducible VT or VF, and QTc in ECG parameters among three groups. (A) Incidence of VT and VF induced by PES. The incidence of ventricle arrhythmias was significantly increased in MI group (*P < 0.05 versus Sham group); and declined in MI + Val group (^†P < 0.05 versus MI group). (B) Mean QTc in ECG before PES was significantly longer in MI group (*P < 0.05 versus Sham group); and shorter in MI + Val group (^†P < 0.05 versus MI group). (C) VT induced by PES. Sham group (n = 20), MI group (n = 20) and MI + Val group (n = 19).

Fig 3

Effects of valsartan on expressions of AT1R and Cx43. The mRNA levels of (A) AT1R and (B) Cx43 were evaluated by the real-time PCR (n = 6). The protein levels of (C) AT1R and (D) Cx43 were analysed by Western blot (n = 7). Proteins loading of each sample in different groups were normalized by Tublin, the house keeping gene. BZ: border zone; NIZ: non-infarct zone. *P < 0.05 versus Sham group; ^#P < 0.05 versus NIZ; ^†P < 0.05 versus MI group.

Fig 4

Effect of valsartan on the collagen staining in the LV border zone section after MI. (A) Collagen staining of myocardial tissues with Masson’s trichrome (stained in blue) in rat hearts 8 weeks after MI. (B) Quantitative data evaluated the levels of collagen deposition in both BZ and NIZ sections (n = 7 in MI group, n = 6 in MI + Val group. *P < 0.05 versus MI group).

Fig 5

Heart infarct sizes in rats of MI and MI + Val groups were detected after 8 weeks by (A) Mallory’s trichrome staining, and quantified by (B) Qwin Plus3.0 (Leica, Germany). MI group (n = 7) and MI + Val group (n = 6).