On angiotensin II receptor distribution after myocardial infarction in dogs / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the effects of valsartan on expression of angiotensin II receptors in different regions of heart after myocardial infarction (MI).</p><p><b>METHODS</b>Canines were divided into sham-operated control group (n=7), infarction group (n=7) and Valsartan group (10 mg x kg(-1) x day(-1) for 4 weeks after MI operation, n=7). Four weeks after operation, Doppler tissue imaging (DTI) was used to evaluate regional ventricular function in the noninfarcted myocardium (apical and basal near to the infarction region). The mRNA and protein expressions of angiotensin II type 1 receptor (AT1-R) and angiotensin II type 2 receptor (AT2-R) on the corresponding regions were detected by competitive reverse-transcriptase polymerase chain reaction technique and immunohistochemical technique respectively. Results The protein and mRNA expressions of AT1-R were significantly increased in both apical and basal regions near to the infarction in dogs with MI compared with those in control group (P < 0.05) which could be downregulated by valsartan (P < 0.05). AT2-R expressions were significantly upregulated in infarction group in both apical and basal regions compared with those in control group and valsartan further increased AT2-R expressions in both areas (P < 0.05). Myocardial peak systolic velocity (Sm), myocardial peak early diastolic velocity (Em) and myocardial peak late diastolic velocity (Am) at both apical and basal regions near to the infarction regions were significantly lower in MI group than those in the control group which could be significantly improved by valsartan.</p><p><b>CONCLUSION</b>Both mRNA and protein expressions of AT1-R and AT2-R are upregulated in noninfarcted regions near MI, valsartan improved myocardial function via inhibiting AT1-R upregulation and enhancing AT2-R upregulation.</p>

Effects of spironolactone on electrical and structural remodeling of atrium in congestive heart failure dogs / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Renin-angiotensin-aldosterone system has been demonstrated to be associated with both congestive heart failure (CHF) and atrial fibrillation (AF). This study investigated the effects of spironolactone, a kind of aldosterone antagonist, on atrial electrical remodeling and fibrosis in CHF dogs induced by chronic rapid ventricular pacing.</p><p><b>METHODS</b>Twenty one dogs were randomly divided into sham-operated group, control group, and spironolactone group. In control group and spironolactone group, dogs were ventricular paced at 220 beats per minute for 6 weeks. Additionally, spironolactone at 15 mg x kg(-1) x d(-1) was given to dogs 1 week before rapid ventricular pacing until pacing stopped. Transthoracic and transoesophageal echocardiographic examinations were performed to detect structural and functional changes of the atrium. Swan2 Ganz floating catheters were used to measure hemadynamics variances. Atrial effective refractory period (AERP), AERP dispersion (AERPd), intra- and inter-atrium conduction time (CT) and intra-atrium conduction velocity (CV) were determined. The inducibility and duration of AF were also measured in all groups. Finally, atrial fibrosis was quantified with Masson staining.</p><p><b>RESULTS</b>AERP did not change significantly after dogs were ventricular paced for 6 weeks. However, AERPd, intra- and inter-atrium CT increased significantly, and CV decreased apparently, which was negatively correlated to the atrial fibrosis (r = -0.74, P < 0.05). Simultaneously, left atriums were enlarged and cardiac hemadynamics worsened in pacing dogs. Although spironolactone could not affect cardiac hemadynamics effectively, it can obviously improve left atrial ejection fraction (P < 0.05). Spironolactone treatment did not alter AERP duration, but this medicine dramatically decreased AERPd (P < 0.05), shortened intra- and inter-atrium conduction time (P < 0.05), and increased atrium CV. Moreover, spironolactone decreased the inducibility and duration of AF (P < 0.05), as well as atrial fibrosis (P < 0.01) induced by chronic rapid ventricular pacing.</p><p><b>CONCLUSION</b>Spironolactone contributes to AF prevention in congestive heart failure dogs induced by chronic rapid ventricular pacing, which is related to atrial fibrosis reduction and independent of hemadynamics.</p>

Chronic blocking of beta 3-adrenoceptor ameliorates cardiac function in rat model of heart failure / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Stimulation of the heart beta 3-adrenoceptor (AR) may result in a negative inotropic effect. Being up-regulated, beta 3-AR plays a more important role in the regulation of cardiac function during heart failure. However, the effect of chronic blocking of beta 3-AR on heart failure has not been fully elucidated. In this study, we used a selective beta 3-AR antagonist SR59230A to treat a well defined heart failure rat model chronically, then evaluated its effect on cardiac function and investigated the mechanism.</p><p><b>METHODS</b>Male Wistar rats were chosen randomly as controls (n = 8). Isoproterenol induced heart failure rats were randomly divided into ISO group (n = 10) and SR group (n = 10). The ISO group received intraperitoneal injection of 1 ml saline twice a day; the SR group received intraperitoneal injection of SR59230A 85 nmol in 1 ml saline twice a day; and the control group received no treatment. The treatment was started 24 hours after the last isoproterenol injection and continued for 7 weeks. Then we measured the following indexes: the ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW), collagen volume fraction (CVF), left ventricular end diastolic dimension (LVEDd), left ventricular end systolic dimension (LVESd), ejection fraction (EF), fractional shortening (FS) and the ratio of E wave to A wave (E/A), the mRNA and protein expression of beta 3-AR and eNOS, and cGMP level in the heart.</p><p><b>RESULTS</b>The ratios HW/BW and LVW/BW were significantly increased in the ISO group compared with the control group (P < 0.01), but they were limited in the SR group (P < 0.05 compared with the ISO group). CVF increased in the ISO group and the SR group (P < 0.01), but it was significantly attenuated in the SR group (P < 0.01). LVEDd, LVESd and E/A ratio were significantly increased in the ISO group compared with the control group (P < 0.01), while EF and FS were significantly decreased (P < 0.01). Compared with the ISO group, the SR group showed that LVEDd, LVESd and E/A ratio were significantly decreased (P < 0.01), whereas EF and FS were significantly increased (P < 0.01). beta(3)-AR and eNOS mRNA and protein in the ISO group were significantly increased when compared with the control group (P < 0.01). These increases were all attenuated in the SR group compared with the ISO group (P < 0.01). The level of cGMP in myocardial tissue was significantly increased in the ISO group compared with the control group (P < 0.01), whereas SR59230A treatment normalized this increment (P < 0.01).</p><p><b>CONCLUSIONS</b>Chronic blocking of beta 3-AR could ameliorate cardiac function in heart failure rats and its mechanism involves inhibition of the negative inotropic effect and attenuation of cardiac remodeling.</p>

The effects of combined beta(1) adrenergic receptor antagonist and beta(2) adrenergic receptor agonist therapy on cardiac function and myocardial apoptosis in heart failure rats / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe the effects of combined beta(1) adrenergic receptor (AR) antagonist with beta(2)AR agonist therapy on cardiac function and cardiomyocyte apoptosis in heart failure rats.</p><p><b>METHODS</b>Heart failure was induced by isoproterenol and rats were randomly divided into metoprolol group (50 mg/kg twice daily/gavage, n = 11), combined treatment group (fenoterol 125 microg/kg and metoprolol 50 mg/kg twice daily/gavage, n = 11) and placebo group (saline, n = 10), another normal 9 male Wistar rats served as control group. After 8 weeks' treatment, cardiac function, apoptosis index (AI), Caspase-3 activity, expression levels of bcl-2 and bax protein, organ weight/body weight and collagen volume fraction (CVF) were evaluated.</p><p><b>RESULTS</b>(1) Left ventricular end diastolic dimension, left ventricular end systolic dimension and E/A ratio were significantly increased and fractional shortening, ejection fraction significantly reduced post isoproterenol (all P < 0.05 vs. control) and these changes were significantly attenuated by metoprolol alone (all P < 0.05 vs. placebo) and further attenuated by the metoprolol and fenoterol combination therapy (all P < 0.05 vs. placebo and metoprolol). (2) Left ventricular weight to body weight ratio, lung weight to body weight ratio and CVF were also significantly reduced in metoprolol and combined treatment group than those in placebo group (all P < 0.01). (3) Compared with placebo group, AI and Caspase-3 activity were significantly lower in metoprolol group (all P < 0.01 vs. placebo) and further reduced in combined treatment group (all P < 0.01 vs. metoprolol). (4) The expression level of bax protein was significantly lower in metoprolol group while bcl-2/bax significantly higher than those in placebo group. These changes were more significant in combined treatment group (all P < 0.01 vs. metoprolol).</p><p><b>CONCLUSIONS</b>beta(1)AR antagonist in combination with beta(2)AR agonist further improved the cardiac function and prevented cardiac remodeling compared with using beta(1)AR antagonist alone in heart failure rats. Downregulated bax and upregulated bcl-2/bax expressions might contribute to the observed beneficial therapy effects by reducing cardiomyocyte apoptosis in these animals.</p>