PP.14.17

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Objective: To investigate whether tetrahydrobiopterin (BH4) combination with Nebivolol recouple eNOS and reverse or prevent cardiac hypertrophy, fibrosis, and diastolic dysfunction in spontaneous hypertensive rats (SHR). Design and method: 12 weeks, 60 SHR were purchased from Vital River Laboratories in Beijing and were randomized to10 groups (n = 6 for each). All SHR were acclimatized to a new situation for a week and receive low-dose (87.5 mg/kg.d) or high-dose(175 mg/kg.d) BH4, or combination with low dose nebivolo (5 mg/kg.d) and high dose(10 mg/kg.d) and placebo for one week. Cardiac function was measured by arious conventional and tissue Doppler echocardiographic index transthoracic check and invasive conductance catheter analysis before and after treatment. RT-PCR, western-blot and immunohistochemistry were used to detect the levels of myocardium BH4, superoxide, eNOS, phospholamban (PLB), protein kinase G(PKG), sarcoplasmic reticulumCa2+ATPase(SERCA 2a)expression of mRNA and their protein expression in myocardium. We also measured Brain Natriuretic Peptid (BNP) and nitrite (an NO storage molecule). α Results: The results showed that cardiac diastolic function of SHR in vehicle(VEH) group trend worsen than that of baseline. After feeding high dose or low dose BH4 the index of diastolic function,such as tau,min dp/dt,left ventricular end of diastolic pressure(LVEDP) reversed especially low dose BH4,but P = NS. High dose nebivolol didn’t reverse the LVEDP increase, even showed mildly improvement compared with VEH. However, low dose nebivolol reversed the increasing LVEDP (12.318 ± 3.177 vs 18.1295 ± 2.0673,P = 0.029). The mRNA level of eNOS increase mildly after separately feeding nebivolol or BH4,while cosupplementation BH4 and nebivolol the mRNA of eNOS increased significantly. The protein expression of eNOS in myocardium suggested the same trend. This finding indicated that low dose BH4 (17.5 mg/d) combination low dose nebivolol (1.25 mg/d) were better than higher doses of them for expression of mRNA and protein in eNOS, especially in the enhance aspect of diastolic function. ± ± Conclusions: Oral BH4 cosupplementation nebivolol for one week improves the cardiac diastolic function in SHR by activation eNOS, augment NO production and its bioactivity. They act synergistically to improve the diastolic function after combination them with low doses.

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