| Background:Chronic heart failure (CHF)is the end stage of various cardiovascular disease, and is the main cause of fatality for patients with cardiovascular disease. There are many kinds of compensatory mechanisms participate in the emergence and development of heart failure. In these mechanisms, the activation of sympathetic nervous system(SNS) plays an important role in the process of heart failure.At present, beta adrenergic receptor blocker has been used as the basic medicine for the treatment of CHF.βARs belong to the large superfamily of G-protein coupled receptors (GPCRs),and could be divided intoβ1AR,β2AR,β3AR,β4AR.β3AR was found as a receptor in cardiovascular system and has a close relationship with CHF. Differ fromβ1AR,β2AR,β3AR has a distinct function and intracellular signal transduction pathway. It can be found that selectiveβ3 agonist leading a dosage dependent negative contraction in the prostrated heart tissue or cells , induced a increase of heart destroy and the rate of death, accelerated cardiomyocyte apoptosis. At present, there are little research on the electrophysiological effect ofβ3AR,and arguments are never stopped. Therefore, our research is to build the heart failure rat models and mainly to explore the expression ofβ3AR in the prostrated ventricle as well as the effect ofβ3AR activation on L-type calcium channel current.Objective:1. Build the chronic heart failure rat models and explore influence of BRL-37344 (a selectiveβ3 AR agonist) on the expression ofβ3AR mRNA in heart failure rat ventricle.2. Explore effect of beta3 AR activation of ICa-L in heart failure rat models an in beta3 regulation-up heart failure rat models.Methods:1.36 rats were randomly divided into three groups: the sham-operated group (Sham group,n=10),and the model set group (MS group, n=26).Rat model was established by aortic constriction. After 3 months, 12 rats in MS group were selected into heart failure control group (HF group) four months later, the others were selected into BRL group. In the coming 4 weeks, the rats in BRL group received BRL37344 (0.4nmol/Kg·min) via tail vein injection in10 minutes twice a week. The rats in Sham group and HF group received same amount of saline via tail vein injection2. The following index can be monitored in all the groups:2.1 Haemodynamic indexes: heart rate (HR),left ventricular end systolic pressure (LVESP),left ventricular end diastolic pressure (LVEDP),the maximal rate of rise and fall of left ventricular pressure (±dp/dt) .2.2 The index of left ventricular mass (LVMI).2.3 The expression ofβ3AR mRNA mRNA in left ventricles.2.4 Isolated single left ventricular myocytes. The concentration dependent effects of BRL-37344 on the ICa-L of left ventricular myocardium were studied with the whole cell patch clamp technique.Results:(1) Compared HF group with Sham group, LVEDP were significantly increased (P<0.01),LVESP and the absolute values of the±dp/dt were significantly decreased (P<0.01).Compared BRL group with HF group, LVEDP were significantly increased (P<0.01),LVESP and the absolute values of±dp/dt were significantly decreased (P<0.01).Compared MS group with Sham group, LVMI was significantly increased, the LVMI in BRL group was significantly increased.(2) The expressions ofβ3AR mRNA are higher in MS group than Sham group (P<0.01). The expressions ofβ3AR mRNA are higher in BRL group than HF group (P<0.01).(3) Compared to Sham group, The ICa-L of MS group are lower (P<0.01). Compared BRL group with HF group, the ICa-L BRL group are higher (P<0.05).The single cell of different groups were treated with different dose BRL37344, it can be seen that ICa-L was increased, and the raise of different groups were different: the raise of BRL are the biggest.(4) The single cell of different groups were treated with L-748,337 (a selectiveβ3- AR inhibitor),when it is stable, treated with BRL-37344 again. The L-type calcium current stay the same.Conclusion:(1)When treated withβ3AR agonist BRL37344, left ventricular function in chronic heart failure rats became worse with expressions ofβ3AR mRNA regulated up much more.(2)There is remarkable change of L-type calcium current in model set rats ,BRL37344 can significant increased L-type calcium current. The result suggest that the influence of beta 3 receptor activation on Ca2+ influx is required. |
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