Abstract
Long-term nitroglycerin (NTG) therapy causes tolerance to its effects attributing to increased oxidative stress and endothelial dysfunction. Shenmai injection (SMI), which is clinically used to treat cardiovascular diseases, consists of two herbal medicines, Ginseng Rubra and Ophiopogonjaponicas, and is reported to have antioxidant effects. The present study was designed to investigate the potential preventive effects of Shenmai injection on development of nitroglycerin-induced tolerance. The present study involves both in vivo and in vitro experiments to investigate nitroglycerin-induced tolerance. We examined the effect of Shenmai injection on the cardiovascular oxidative stress by measuring the serum levels of malondialdehyde (MDA) and superoxide dismutase (SOD). Endothelial dysfunction was determined by an endothelium-dependent vasorelaxation method in aortic rings and NOS activity. Inhibition of the cGMP/cGK-I signalling pathway was determined from released serum levels of cGMP and the protein expression levels of sGC, cGK-I, PDE1A and P-VASP by western blot. Here, we showed that SMI ameliorated the decrease in AV Peak Vel, the attenuation in the vasodilation response to nitroglycerin and endothelial dysfunction. SMI also reduced the cardiovascular oxidative stress by reducing the release of MDA and increasing the activity of SOD. Shenmai injection further ameliorated inhibition of the cGMP/cGK-I signalling pathway triggered by nitroglycerin-induced tolerance through up-regulating the protein expression of sGC, cGK-I, and P-VASP and down- regulating the proteins expression of PDE1A. In vitro studies showed that Shenmai injection could recover the attenuated vasodilation response to nitroglycerin following incubation (of aortic rings) with nitroglycerin via activating the enzymes of sGC and cGK-I. Therefore, we conclude that Shenmai injection could prevent NTG nitroglycerin-induced tolerance at least in part by decreasing the cardiovascular oxidative stress, meliorating the endothelial dysfunction and ameliorating the inhibition of the cGMP/cGK-I signalling pathway. These findings indicate the potential of Shenmai injection (SMI) as a promising medicine for preventing the development of nitroglycerin-induced tolerance.
Highlights
Nitroglycerin (NTG) has been used for the treatment of angina pectoris for more than 100 years [1]
At the end of the experiments, the serum was collected and centrifuged at 3000 rpm for 10 minutes storing at -80 ̊C.We investigated the activity of nitric oxide synthase (NOS), including total NOS, endothelial NOS neuronal NOS and inducible NOS by NOS typed assay kit, eNOS Elisa Assay Kit and nNOS Elisa Assay Kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China)
The rats were treated with NTG (25 mg/kg) or a co-treated with NTG and Shenmai injection (SMI) (0.4, 0.8, 1.6 mL/kg), and examined by M-mode and left ventricular outflow tract (LVOT) echocardiography (Fig 1A and 1B)
Summary
Nitroglycerin (NTG) has been used for the treatment of angina pectoris for more than 100 years [1]. A recent study showed that the level of P-VASP in vascular tissue from NTG-treated animals closely correlates with changes in endothelial function and vascular oxidative stress [11, 12]. More recent studies showed that oxidative stress, due to overproduction of reactive oxygen species (ROS), plays an essential role in the development of NTG tolerance [13]. Increased ROS may chemically interact with available NO, decreasing its vasodilation effect and interfering with NTG biotransformation, such as inhibiting the activity of mitochondrial aldehyde dehydrogenase (ALDH-2), sGC, and cGK-I [14,15,16,17]. No medicine is clinically available to inhibit the development of NTG-induced tolerance effectively. We proposed to use combined treatment of an antioxidant medicine and NTG to prevent NTGinduced tolerance
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