Preventive effect of tetramethylpyrazine on nitroglycerin-tolerance in rats by improving oxidative stress and ribosome homeostasis.

Nitroglycerin (NTG) is recommended as the first-line drug in angina pectoris though its prolonged use impacts nitroglycerin tolerance. In this study, we investigated the preventive effect of Tetramethylpyrazine (TMP), a famous Chinese medicine used for cardiovascular diseases, on NTG-induced tolerance and further explained the underlying mechanism of its action. The results revealed that pretreatment of TMP improved NTG-induced tolerance in vitro thoracic aorta rings and in rats. Proteomic analysis showed oxidative stress and ribosome proteins dyshomeostasis in NTG-tolerance vessels. TMP attenuated the oxidative stress by enhancing the protein expression of ALDH2, Nrf2 and HO-1. In addition, TMP recovered the down-regulated expression of RpL10a induced by nitroglycerin. Therefore, TMP could prevent nitroglycerin tolerance in rats, which may be mediated by up-regulation of ALDH2 and Nrf2/HO-1 signaling pathway and involved in the restoration of ribosome homeostasis. These findings indicate the potential of TMP as a promising medicine for preventing the development of nitroglycerin-induced tolerance.

Nitric Oxide Is the Cause of Nitroglycerin Tolerance: Providing an Old Dog New Tricks for Acute Heart Failure.

Our paper highlights the past 50 years of research focusing solely on tolerance involving nitroglycerin (glyceryl trinitrate, GTN). It also identifies and discusses inconsistencies in previous mechanistic explanations that have failed to provide a way to administer GTN continuously, free of limitations from tolerance and without the requirement of a nitrate-free interval. We illustrate, for the first time in 135 years, a mechanism whereby nitric oxide, the mediator of vasodilation by GTN, may also be the cause of tolerance. Based on targeting superoxide from mitochondrial complex I, uncoupled by glutathione depletion in response to nitric oxide from GTN, a novel unit dose GTN formulation in glutathione for use as a continuous i.v. infusion has been proposed. We hypothesize that this will reduce or eliminate tolerance seen currently with i.v. GTN. Finally, to evaluate the new formulation we suggest future studies of this new formulation for the treatment of acute decompensated heart failure.

Decreased PKG transcription mediated by PI3K/Akt/FoxO1 pathway is involved in the development of nitroglycerin tolerance.

Phosphoinositide 3-kinase (PI3K)/Akt plays a pivotal role in the vascular response. The present study is to determine whether PI3K/Akt pathway in vascular smooth muscle cells is involved in nitroglycerin (NTG) tolerance and the underlying mechanism. Nitrate tolerance of porcine coronary arteries in vitro was induced by incubation of NTG (10-5 M) for 24 h. Nitrate tolerance in vivo was obtained by subcutaneous injection of mice with NTG (20 mg kg-1, tid, 3 days) and the aortas were used. Protein levels of total and phosphorylated Akt, forkhead box protein O1 (FoxO1), and cGMP-dependent protein kinase (PKG) were determined by western blot analysis. Isometric vessel tension was recorded by organ chamber technique. PKG mRNA was determined by real-time PCR. The cellular translocation of FoxO1 was observed by immunofluorescence. Reactive oxygen species (ROS) level was measured by DHE staining. The vascular relaxation to NTG was significantly inhibited in in vivo and in vitro NTG tolerant arteries. Meanwhile, the protein level of phosphorylated Akt at Ser473 was increased in the tolerant arteries. The attenuated relaxation and the augmented Akt-p were ameliorated by LY294002, a specific inhibitor of PI3K. The protein and mRNA expression of PKG were significantly down-regulated in NTG tolerant arteries, which were reversed by LY294002. The level of phosphorylated FoxO1 at Ser256 and its translocation from the nucleus to the cytosol were both increased in NTG tolerance and were also inhibited by LY294002. ROS production was significantly increased in NTG tolerant arteries, which was not be affected by LY294002 but inhibited by N-acetyl-L-cysteine. In conclusion, the present study suggests that PI3K/Akt in vascular smooth muscle is involved in the development of NTG tolerance via inhibiting PKG transcription and the effect is mediated by FoxO1.

Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats.

Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100mg/kg/d for 3.5days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5mg/kg/d) or BAY 41-8543 (1 and 5mg/kg/d) for 6days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial dysfunction and nitrate tolerance, corrected the decrease in aortic nitric oxide levels, improved the cGMP dependent activation of protein kinase I in aortic tissue and reduced vascular, cardiac and whole blood oxidative stress (fluorescence and chemiluminescence assays; 3-nitrotyrosine staining). In contrast to BAY 41-8543, the vasodilator potency of BAY 60-2770 was not impaired in isolated aortic ring segments from nitrate tolerant rats. sGC activator therapy improves partially the adverse effects of nitroglycerin therapy whereas sGC stimulation has only minor beneficial effects pointing to a nitroglycerin-dependent sGC oxidation/inactivation mechanism contributing to nitrate tolerance.

Progress of mitochondrial aldehyde dehydrogenase in cardioprotection / 中国药理学通报

Mitochondrial aldehyde dehydrogenase(ALDH2),one of the isoforms of aldehyde dehydrogenase,has multiple enzymatic functions including the activity of dehydrogenase and esterase.The metabolisms of ethanol,amino acids,biogenic amine,vitamin or steroid in the body produce various substances of aldehyde.With the help of co-factor NAD(P)+,ALDH2 can convert aldehydes into corresponding carboxylic acid,which plays a key role in reducing toxic effects of aldehydes on the body.It does not need co-factor when ALDH2 works as esterase.It can convert carboxylic ester or other acids into corresponding carboxylic acids or alcohols.Recently,it has been shown that the decrease of ALDH2 activity exacerbates multiple factors(such as ethanol,ischemia)-induced myocardial injury and accelerates the development of nitroglycerin tolerance.Therefore,the development of specific agonists of ALDH2 may provide a novel approach to the therapy and prevention of heart diseases.

Clinical observation of 5-mono nitre isosorbide combined with ginkgo leaf in treating angina pectoris / 中成药

Objective: To observe clinical therapeutic effective of 5 mono nitre isosorbide combined with ginkgo leaf in the treatment of angina pectoris. Methods:100 cases of angina pectoris were randomly divided into control group (5 mono nitre isosorbide) and treated group (5 mononitre isosorbide combined with ginkgo leaf). The therapeutic course lasted four monthes. Results: Nitroglycerin consumption in treated group was lower significantly than that in control group. The effective rate was 94.8% in the treated group and 84.2% in the control group after four monthes ( P