硝酸酯类药物耐药问题（Resistance problems of nitrates）

硝酸酯类药物耐药问题（Resistance problems of nitrates） 硝酸酯类药物耐药问题(Resistance problems of nitrates) Resistance problems of nitrates Update: 06-09 Abstract: continuous or frequent application of nitrates when administered rapidly due to drug resistance, the resistance of a variety of factors, mainly related to the neuroendocrine system and adjust the intracellular metabolism of nitroglycerin in two aspects. This article reviews the possible mechanisms and preventive aspects of these drugs in recent years. Organic nitrate is used earlier and more widely in the field of cardiovascular medicine, while the treatment of acute angina effectively, but the continuous application of 24-72h or frequent dosing is prone to drug resistance, clinical performance on anti myocardial ischemia effect and hemodynamic effects of rapidly reduced or completely disappeared [1]. Over the past 20 years, angina, acute myocardial infarction (AMI), congestive heart failure (CHF) and hypertension (EHD) application of nitrates gradually increased, nitroglycerin (TNG) and isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) continuous application (intravenous infusion, oral or transdermal patch) have occurred in reports of resistance [2], which limits the clinical application of drugs, the drug resistance mechanism of attention. The mechanism of nitrate resistance is complex, and there are many controversies about it. [3]. Recently, the fourteenth session of the North American nitrates conference held a special discussion. In this paper, the possible mechanisms and preventive measures of nitrate resistance were reviewed. Clinical effects and mechanisms of nitrates The basic pharmacological action of [2 and 4] organic nitrates is to relax the smooth muscle of the esophagus, blood vessel and uterus, and mainly relax the vascular smooth muscle in clinic. Nitrates are a class of drugs that enter vascular smooth muscle cells (VSMCs) and undergo a series of nitro metabolic processes at the serosal site or in the extracellular pathway, eventually converting to nitric oxide (NO). At present, the multistep enzymatic reaction to biotransformation of NO catalyzed by nitrate esters is not clear. The possible steps for the formation of NO are [5]: first, the nitric acid molecule enters the smooth muscle membrane and combines with the thiol (-SH) in the sarcolemma to form S-nitrosothiols, and then form NO. NO is a potent vasodilator substance, and muscle membrane soluble guanylate cyclase (sGC) combined with the heme active site on the formation of Fe2+ complex, which activates sGC, catalytic three guanosine monophosphate (GTP) formation of cyclic guanosine monophosphate (cGMP) to cGMP cells increased, which accelerated the release of Ca2+ from the cells, inhibit Ca2+ influx, accelerate the uptake of sarcoplasmic reticulum of Ca2+ cells, resulting in the cytoplasm of VSMCs Ca2+ reduced vascular smooth muscle relaxation. What mechanisms does cGMP rely on to reduce cytosolic Ca2+ concentration, which may involve alterations in sarcoplasmic reticulum Ca2+ pump -ATP enzyme activity?. Recently, the Cohen research group suggested that NO's vasodilator action does not depend on cGMP, but directly activates the calcium dependent potassium channel (KCa2+) of the VSMCs. The experimental research of Bany confirmed in complete coronary artery endothelial cells, vascular relaxation effect of TNG was obviously affected by Iberiotoxine (a KCa2+ inhibitor) inhibited the coronary artery endothelial has no inhibitory effect, It was further demonstrated that TNG mainly activates the endothelium by KCa2+ induced smooth muscle relaxation. There are a few studies indicate the vasodilator effect of TNG is through the promotion of prostacyclin (prostacyclin, PGI2) synthesis regulation because of cyclooxygenase (cyclooxygenase) inhibitor pretreatment decreased vasodilator effect of TNG. The normal vascular endothelial cell growth factor NO (EDRF/NO, or endogenous pathway) and nitrate ester NO source (nitrate/NO, i.e. exogenous) produced by NO, although can activate cGMP and dilation of blood vessels, but the relationship between the two little. The former is through the NO synthase catalytic L- arginine into cystine formed, reduce release in coronary heart disease, with only a local effect, influence on circulation is short, without proof of resistance; latter is formed by multi step enzyme catalytic nitro, in coronary heart disease activity increased with systemic effect of cyclic long-term effect on hemodynamics, prone to drug resistance [6]. Vasodilator (venous, arterial, and collateral vessels) effects of [2, 7], and in general therapeutic doses, nitrate dilated veins predominate. Dilatation of the venous system, decrease of cardiac output, and reduction of cardiac preload. The dilated arteries are dose-dependent and cause rapid arterial dilatation, decreased blood pressure and reduced afterload after heavy or rapid intravenous infusion. A decrease in arterial pressure can cause tachycardia. Early that nitrate dilatation of the coronary artery is the main mechanism of angina relief, in recent years that the nitrate prevention and reversal of myocardial ischemia due to peripheral vasodilatation and reduced cardiac work, followed by increased coronary blood flow. Nitrate mainly expansion of coronary circulation large artery vascular delivery (large arterial conductance vessels) and collateral vessel stenosis, expanding coronary artery segments, promote collateral circulation, make the subendocardial / epicardial blood flow ratio normalization, thereby improving myocardial ischemia. Because nitrates have the beneficial effects of reducing cardiac preload, decreasing myocardial oxygen consumption and increasing myocardial blood supply, CHF can improve or reverse the left ventricular remodeling induced by myocardial infarction or [8, 9]. Antiplatelet activity, [2-7], 1967, Hampton first reported that TNG inhibits platelet aggregation in vitro, and subsequent studies have continued to deepen. Loscalze and Amarante[1] platelet rich blood incubation with TNG or incubation with TNG two were added ADP, the average concentration of TNG inhibits ADP mediated platelet aggregation is needed, the results of the two specimens of inhibition of average concentration of platelet aggregation were 40 mol/L and 360 mool/L, showed that TNG can inhibit platelet aggregation. Other investigators used TNG to reduce platelet aggregation to ADP by 7.7 + 0.8 to 5.3 + 0.8 ohms (P < 0.05); the aggregation rate of thrombin decreased from 15.6 + 1.2 to 12 + 1.2 ohms (P < 0.05). At high strain rate (hign shear rate) under the condition of the thrombus from 2.8 + 0.7 to 1 + 0.3 M2 reduced (P < 0.05); at low shear rate under the condition of thrombus from 2.5 + 0.5 to 1 + 0.3 M2 reduced (P < 0.05), show that TNG can inhibit platelet aggregation and thrombus formation, is conducive to the treatment of coronary heart disease. Lam also demonstrated that TNG can reduce the intravascular adhesion of platelets to mechanical injuries. The mechanism of NO platelet aggregation and anti thrombosis is similar to that of vasodilation. SGC, which mainly activates platelets, catalyzes the increase of cGMP and changes the fibrinogen binding with platelet surface. Mechanism of nitrate resistance Sulfhydryl depletion theory, [2, 10], needlmen, et al. Suggest that the mechanism of nitrate resistance is related to the depletion of thiol in the vascular intima. That needs to be transformed to NO in thiol metabolism in TNG biological process, in the continuous application of TNG thiol vascular tissue gradually consumed, resulting in mass transfer to NO NO disorder, nitrate/NO generation gradually reduced, or even zero. This theory has been supported by a number of experiments in vitro and accepted by the majority of scholars as a classic theory". In recent years, several studies in vivo have raised doubts about the reliability of the findings. The levels of cysteine and glutathione in the aorta, vena cava and glutathione in the TNG resistant rats were not significantly different from those in the non drug resistant group, such as Boesgaard. Laursen electron spin (cryogenic electron resonance spectroscopy) spectroscope NO in direct detection of rat aorta and vena cava and heart and lung tissues, NO and the amount of TNG/NO is not less than the resistance. Grutter has observed no increase in the cGMP content of the cells after supplementation with cysteine. Munzel and other experiments using methionine (converted to cysteine in cells) that do not reverse TNG resistance also fail to confirm prior speculation. These data suggest that nitrate resistance in vivo is neither thiol depletion nor nitrate metabolism, and NO reduction in biotransformation. It may be that the biological activity of NO decreases, or target enzyme sGC changes and cGMP degradation increases, [2, 4]. Although it is controversial whether sulfhydryl is involved in nitrate resistance, its use in the prevention or reversal of drug resistance remains to be noted. A few animal and clinical studies show that N- (N-acetylcys-teine) and TNC combined with NAC can improve or even reverse drug resistance, and can also partly prevent drug resistance. But Boesgaard and others believe that NAC non thiol donors have the role of angiotensin-converting enzyme inhibitor (ACEI) in vivo and may act as an antioxidant to protect nitrate/NO function.