Effects of tetrahydrobiopterin combined with nebivolol on cardiac diastolic function in SHRs

抄録

This study aimed to evaluate the effects of combined use of BH4 and nebivolol on cardiac diastolic dysfunction in spontaneously hypertensive rats (SHRs). Twelve-week-old male SHRs were treated with tetrahydrobiopterin (BH4), nebivolol, or a combination of both. Left ventricle function was evaluated, and reactive oxygen species (ROS) production [including dihydroethidium (DHE) and 3-nitrotyrosine (3-NT)], NO synthase (NOS) activity and the level of nitric oxide (NO) in myocardial tissue were determined. The expression levels of endothelial NOS (eNOS), phospholamban (PLN), sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a), β₃-adrenoceptor, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) were assayed. Treatment with BH4, nebivolol, or both reversed the noninvasive indexes of diastolic function, including E/E′ and E′/A′, and the invasive indexes, including tau, -dP/dtmin, -dP/dtmin/LVSP, and LVEDP in SHRs. mRNA and protein expression levels of eNOS dimer, phosphorylated PLN, SERCA2a, cGMP, and PKG in the myocardium of treated SHRs were significantly up-regulated compared with those in control rats (P<0.05 or P<0.01). The expression levels of 3-NT and DHE were reduced in all treated groups (P<0.05 or P<0.01). Notably, combined use of BH4 and nebivolol had better cardioprotective effects than monotherapies. BH4 or nebivolol has a protective effect on diastolic dysfunction in SHRs, and BH4 combined with nebivolol may exert a synergistically cardioprotective effect through activation of β₃-adrenoceptor and the NO/cGMP/PKG signaling pathway.