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PP.LB02.01: TETRAHYDROBIOPTERIN AND NEBIVOLOL IMPROVE SYNERGISTICALLY THE CARDIAC DIASTOLIC FUNCTION IN SPONTANEOUS HYPERTENSIVE RATS

Objective: we examined whether BH4 combination with Nebivolol recouples eNOS and reverses or prevents diastolic function dysfunction. BH4 And Nebivolol Improve Synergistically effect Figure. No caption available. Design and method: Nitric oxide (NO) is a crucial important regulatory factor to vasodilation. hypertension vascular system is in oxidative stress state that contribute to deplete cofactor named tetrahydrobiopterin (BH4) of endothelial nitric oxide synthase (eNOS) and cause eNOS uncoupling. It results in producing reactive oxygen species (ROS) rather than NO. Nebivolol as an antagonist for the beta1- adrenergic receptor (AR) promotes eNOS activity and NO bioavailability. We selected 12 weeks,60 spontaneous hypertensive rats (SHR) 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 echocardiography and invasive conductance catheter analysis. Myocardium BH4 levels, superoxide, RT-PCR, western-blot and immunohistochemistry were used to detect eNOS, protein kinase G(PKG), sarcoplasmic reticulum calcium ATPase expression of mRNA and their protein expression in myocardium. We also measured Brain Natriuretic Peptid (BNP) and nitrite (an NO storage molecule). Results: It showed that diastolic function control group worsen trend than baseline. After feeding high dose or low dose BH4 reversed the index of diastolic function, such as tau,min dp/dt, left ventricular end of diastolic pression (LVEDP), especially low dose BH4. High dose nebivolol didn’t reverse the LVEDP increase, even showed mildly increase versus control. However, low dose nebivolol reversed the increasing LVEDP. The mRNA of eNOS increase mildly after feeding only nebivolol or BH4,while cosupplementation BH4 and nebivolol mRNA of eNOS increased significantly .The protein of eNOS expression in myocardium suggested the same trend. This finding indicated that low dose BH4 combination low dose nebivolol were better than higher doses, especially to enhance aspect of disastolic function. Conclusions: Oral BH4 cosupplementation nebivolol for one week improve diastolic function by activation eNOS and augment NO production and bioactivityin SHR.