Abstract
BackgroundHypertension is the the primary cause of diastolic heart failure. Oxidative stress plays an important role in cardiac diastolic dysfunction caused by hypertension. The occurrence of oxidative stress is related to the level of nitric oxide (NO) in the body. Tetrahydrobiopterin (BH4) is an essential cofactor for NO synthesis. Nebivolol can reduce myocardial oxidative stress and increase NO activity. Therefore, we investigated the effects of monotherapy or combination therapy of different doses of BH4 and nebivolol on cardiac diastolic function in spontaneously hypertensive rats, and preliminarily expounded the related mechanisms.MethodsLeft ventricular function was evaluated by non-invasive echocardiographic assessment and invasive right carotid artery catheterization methods. ELISA was used to measure myocardial 3-nitrotyrosine content, NO production, and cyclic guanosine monophosphate (cGMP) concentration in the myocardium; quantitative real-time PCR (qRT-PCR) was used to determine endothelial nitric oxide synthase (eNOS), phospholamban and sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) mRNA expression levels; Western blot was used to detect the protein expression levels of eNOS and eNOS dimers in myocardial tissue, and immunohistochemical detection of cGMP expression in the myocardium was performed.ResultsStudies have shown that compared with those in the control group, NO generation and the expression level of myocardial eNOS mRNA, eNOS expression of dimers, phospholamban, SERCA2a and cGMP increased significantly after the combined intervention of BH4 and nebivolol, while the expression of 3-nitrotyrosine was significantly decreased.ConclusionsThe combined treatment group had a synergistic effect on reducing myocardial oxidative stress, increasing eNOS content, and increasing NO production, and had a more obvious protective effect on diastolic dysfunction through the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway.
Highlights
Hypertension is the the primary cause of diastolic heart failure
The purpose of this study was to investigate the effects of nebivolol and BH4 on myocardial oxidative stress and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway signalling molecule expression levels, thereby confirming whether it has a protective effect in diastolic dysfunction in spontaneously hypertensive rats (SHRs), determining whether it has a synergistic effect, and preliminarily clarifying its related mechanism
The following changes in SHRs diastolic function after BH4 combined with nebivolol were observed: compared with those in the placebo group, both non-invasive blood pressure and heart rate were significantly decreased in the combined treatment group (P < 0.05 or P < 0.01, Table 3)
Summary
Oxidative stress plays an important role in cardiac diastolic dysfunction caused by hypertension. Hypertension is the most common chronic noncommunicable disease and the most important risk factor for cardiovascular disease. It is known as the silent killer [1]. Diastolic dysfunction is an evolving clinical syndrome, and the contradiction between the increasing incidence and lack of effective clinical diagnosis and treatment options needs to be resolved urgently [3]. It is very urgent for medical researchers to conduct in-depth research on the prevention and treatment of diastolic dysfunction caused by hypertension. It is important to improve the prognosis or prevent further deterioration of these patient groups
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