Experimental atherosclerosis: effects of oestrogen and atherosclerosis on thromboxane and prostacyclin formation

We evaluated the effect of oestrogen and experimental atherosclerosis on the in vivo formation of thromboxane and prostacyclin in rabbits. Twenty-four New Zealand White rabbits were divided into four groups. One group received control diet, one group received control diet and oestrogen, one group received control diet supplemented with 1% cholesterol and one group received cholesterol supplemented diet and oestrogen during 3 months. The in vivo formation of thromboxane and prostacyclin were measured as 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha in urine by gas chromatography/mass spectrometry. All rabbits on cholesterol diet became hypercholesterolaemic and developed atherosclerosis. As in previous experiments cholesterol and oestrogen-treated rabbits had only minor atherosclerosis compared to purely cholesterol-fed rabbits. The in vivo production of thromboxane in oestrogen-treated rabbits decreased from 1641 +/- 162 pg mg-1 creatinine pretreatment to 808 +/- 92 pg mg-1 creatine at 12 weeks (P = 0.0001). In contrast, the in vivo production of prostacyclin increased during oestrogen treatment (P = 0.0027). The in vivo production of prostacyclin decreased during pure cholesterol feeding without oestrogen 1384 +/- 219 pg mg-1 creatinine to 702 +/- 142 pg mg-1 creatinine (P = 0.0091). The ratio of in vivo prostacyclin to thromboxane formation increased 2-3-fold during oestrogen therapy (P = 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased thromboxane formation in patients with antiphospholipid syndrome

Thirty-one patients with IgG antibodies to cardiolipin (ACLA) were studied to determine their in vivo formation of the platelet aggregating and vasoconstricting substance thromboxane A2 (TxA2) and the platelet inhibiting and vasodilating substance prostacyclin (PGI2). This was done by measurements in urine of their enzymatically formed metabolites 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha, respectively, using gas chromatography-mass spectrometry. It is demonstrated that patients with IgG ACLA have a highly significant increase in the biosynthesis of TxA2 compared with age-matched healthy controls (807 +/- 163 [SEM] vs. 230 +/- 15 pg mg-1 creatinine, P = 0.0000005). A significant increment of the formation of PGI2 was also found (189 +/- 23 (SEM) vs. 125 +/- 11 pg mg-1 creatinine, P = 0.03), although this was much less pronounced than that for TxA2. We conclude that the highly increased formation of TxA2, reflecting platelet activation, in patients with IgG ACLA is of pathophysiologic relevance for their tendency to arterial and venous thrombosis and hence that they should be considered for prophylactic treatment with inhibitors of TxA2 formation, like aspirin.     

Excretion of thromboxane A2 and prostacyclin metabolites during treadmill exercise in patients with intermittent claudication

Platelet activation, with subsequent formation of thromboxane A₂ (TxA₂), is thought to play a role in the development of arterial occlusion. In patients with severe atherosclerosis of the lower limbs, characterized by leg ulcers and rest pain, the basal formation of TxA₂ and prostacyclin (PGI₂) is increased. Corresponding data in patients with more moderate atherosclerosis of the lower limbs have not been reported. Since the capacity to physical exercise is not blunted in such patients proper evaluation of their TxA₂-PGI₂ synthesis should comprise not only assessment of the basal formation, but also TxA₂/PGI₂ biosynthesis during conditions of elevated cardiovascular activity. To address this, we analysed these eicosanoids in patients with a history of intermittent claudication. Urinary dinormetabolites of TxB₂ and PGI₂ (Tx-M and PGI-M, respectively) were estimated by gas chromatography/negative ion-chemical ionization mass spectrometry in samples collected prior to, during and immediately after 20 min of severe treadmill exertion. The basal excretion of Tx-M was 105 ± 26 pg/mg creatinine. It was not changed during exercise, but increased to 176 ± 48 pg/mg creatinine (P<0·05) during the recovery. The basal excretion of PGI-M was 142 ± 25 pg/mg creatinine. The PGI-M response to exercise varied from no change at all to a 30-fold increase, without any obvious correlation to experienced leg pain, walking distance or other recorded variables. During the recovery period the outflow of PGI-M was significantly higher than at rest (482 ± 145 pg/mg creatinine; P<0·01). We conclude that in patients with intermittent claudication due to atherosclerosis (1) platelet activation does not occur during the course of the exercise, and (2) vascular prostacyclin formation can be dissociated from of TxA₂ synthesis. The observed increase in PGI-M in some of the patients is suggested to reflect tissue ischaemia induced by the lack of adequate hyperaemia during exercise.     

血浆血栓素A2和前列环素在不稳定型心绞痛发病中的意义

目的：探讨血管活性物质血栓素Ａ２（ＴＸＡ２）和前列环素（ＰＧＩ２）在不稳定型心绞痛发病中的作用。方法：测定５３例冠状动脉粥样硬化性心脏病（冠心病）患者血浆血栓素Ｂ２（ＴＸＢ２）和６酮前列腺素Ｆ１α（６ｋｅｔｏＰＧＦ１α）含量的变化。结果：不稳定型心绞痛３２例与稳定型心绞痛２１例比较，不稳定型心绞痛组血浆ＴＸＢ２的含量显著升高，为稳定型心绞痛组的３．９１倍（Ｐ＜０．００１）；ＴＸＢ２／６ｋｅｔｏＰＧＦ１α比值也明显高于稳定型心绞痛组（Ｐ＜０．００１）。结论：冠心病心绞痛发作时存在的血浆ＴＸＢ２含量异常增高，ＴＸＢ２与６ｋｅｔｏＰＧＦ１α平衡失调，导致冠状动脉舒缩障碍、痉挛等改变而致心绞痛发生。     

The potential role of thromboxane and prostacyclin in endotoxic and septic shock

The potential role of thromboxane (TxA2), a platelet aggregator and vasoconstrictor, and prostacyclin (PGI2) a platelet anti-aggregator and vasodilator, in endotoxic and septic shock was investigated. Early endotoxic shock in the rat is associated with marked elevations of plasma TxB2 (the stable metabolite of TxA2) and lesser increases in plasma 6-keto-PGF1 alpha (the stable metabolite of PGI2). Selective inhibition of TxA2 synthesis by several different chemical classes of Tx synthetase inhibitors was beneficial in endotoxic shock. In contrast, shock induced by acute intra-abdominal sepsis in the rat was characterized by high levels of plasma 6-keto-PGF1 alpha, which exceeded plasma TxA2 six- to eight fold at most time intervals studied. Tx synthetase inhibitors were not protective in this model of acute sepsis, but treatment with fatty acid cyclo-oxygenase inhibitors, an antibiotic (gentamicin), or reduction in arachidonic acid metabolism by essential fatty acid (EFA) deficiency significantly prolonged survival time. An important aspect of the latter study is that decreased arachidonic acid metabolism was an effective adjunct to antibiotic therapy. Conjoint administration of gentamicin in EFA-deficient rats or with indomethacin synergistically improved long-term survival, a result that was not evident with single treatment interventions. In addition to experimental studies, plasma TxB2 levels were measured during clinical sepsis. These studies demonstrated that plasma TxB2 levels were elevated tenfold in patients dying of septic shock compared with septic survivors or nonseptic controls. These composite experimental and clinical observations suggest that arachidonic acid metabolites play a role in the pathogenesis of endotoxic and septic shock.     

狼疮肾炎患者血中抗磷脂抗体与血栓素变化的观察

目的：观察血抗磷脂抗体（ａＰＬ）与前列环素（ＰＧＩ２）和血栓素Ａ２（ＴＸＡ２）在狼疮肾炎（ＬＮ）中的变化,并探讨其临床意义。方法：用酶联免疫吸附法（ＥＬＩＳＡ）和放射免疫法分别检测ＬＮ患者血ａＰＬ、６酮前列腺素Ｆ１α（６ｋｅｔｏＰＧＦ１α）和血栓素Ｂ２（ＴＸＢ２）水平。结果：５１例ＬＮ中３５例ａＰＬ阳性（６８．６％）,ａＰＬ与血栓形成、系统性红斑狼疮（ＳＬＥ）活性及皮肤血管炎显著相关。ａＰＬ阳性组ＴＸＢ２〔（２５６５．８７±５９３．４７）ｎｇ／Ｌ〕较ａＰＬ阴性组〔（７１８．７４±１３７．６３）ｎｇ／Ｌ〕和正常对照组〔（４２１．３７±１０８．５９）ｎｇ／Ｌ〕均显著升高（Ｐ均＜０．０１）;６ｋｅｔｏＰＧＦ１α和ＴＸＢ２比值均显著降低（ａＰＬ阳性组：０．５７０±０．０６９;ａＰＬ阴性组：１．０３０±０．０７７;对照组：１．９１０±０．１１７;Ｐ均＜０．０１）。结论：ａＰＬ与ＬＮ患者的血栓形成有明显关系,其原因可能与体内ＰＧＩ２ＴＸＡ２平衡破坏及ＴＸＡ２升高有关。     

Biosynthesis of prostacyclin and thromboxane A2 during chronic hypoxaemia in children with cyanotic congenital heart disease

The high risk of vaso-occlusive events in children younger than 4 years with cyanotic congenital heart disease and polycythaemia has been attributed to increased thromboxane (Tx) A₂ formation. In older children with cyanotic congenital heart disease, however, the risk of vaso-occlusive events is much lower. We therefore hypothesized that the formation of TxA₂ and prostacyclin is not disturbed in this age group. We measured urinary excretion of stable index metabolites of in vivo TxA₂ and prostacyclin formation by gas chromatography–mass spectrometry in nine children (age 5.9–14.4, median 8.7 years) with cyanotic congenital heart disease, and in nine healthy, age-matched control subjects. The patients excreted less 2,3-dinor-TxB₂ (systemic TxA₂ formation, P =0.03), 2,3-dinor-6-keto-PGF_1α (systemic prostacyclin formation, P =0.03) and TxB₂ (renal TxA₂ formation, P =0.01) than the control subjects. We conclude that in children older than 5 years with cyanotic congenital heart disease, endogenous synthesis of TxA₂ and prostacyclin is not stimulated. This result may explain the lower risk of vaso-occlusive events in this age group as compared with younger children. In addition, our results suggest that chronic hypoxaemia may affect the in vivo formation of TxA₂ and prostacyclin and the metabolic disposition of TxB₂.     

Maintained hyperexcretion of thromboxane A2 metabolite in healthy young cigarette smokers: results from a prospective study in randomly sampled males with stable smoking habits

Summary. Although several studies have identified cigarette smoking as a factor increasing platelet formation of thromboxane A₂ (TxA₂), no prospective data on this issue have been presented in a defined population with stable smoking habits. Therefore, we analysed the relation between smoking habits and urinary excretion of the 2, 3-dinor metabolites of thromboxane A₂ (Tx-M) and prostacyclin (PGI-M) in 87 males, randomly sampled from a population of 18–19-year-old men, at two different occasions separated by 31–49 months. The daily cigarette consumption among the smokers was unchanged between the study occasions (11 vs. 11 cigarettes day^-1), but 9 of 43 initial smokers had quit. None of the initial non-smokers had begun smoking. Tx-M was higher in the smokers than in the non-smokers and correlated with the daily cigarette consumption both at the initial (176 vs. 123 pg mg^-1 creatinine; P = 0.01) and the second (214 vs. 164 pg mg^-1; P = 0.002) study occasion. Those who had quit smoking since the initial study did not differ in Tx-M from the non-smokers at the second study occasion. Urinary PGI-M did not differ between cigarette smokers, non-smokers and quitters at either of the study occasions. We conclude that cigarette smoking elicits an increased formation of thromboxane A₂, indicating platelet activation, that is stable during an observation period of up to 4 years. The increased platelet activity is reversible upon quitting.     

缺氧时ET-1、NO、TXA_2、PGI_2的变化及对心肌血流量的调节作用

目的本文旨在探讨ET-1、NO、TXA2和PGI2在缺氧时对心肌血流量的调节作用。方法大鼠随机分为平原组和急性缺氧组,用99mTc标记蟾蜍红细胞测定心肌血流量,用Gess法测量NO-、用放免法分别测量ET-1、TXA2、PGI2的含量。结果急性缺氧导致左、右心室心肌血流量、心肌NO2-、ET-1、血浆TXB2含量、TXB2/6-keto-PGF1ɑ比值明显增高(P0.05),左、右心室心肌血管阻力、ET-1/NO2-比值明显下降(P0.05),血浆6-keto-PGF1ɑ无明显变化。结论急性缺氧时,左、右心室心肌血流量增加,ET-1/NO、TXA2/PGI2参与了急性缺氧时心肌血流量的调节,以NO的扩血管作用为主。     

Stimulation of peritoneal synthesis of vasoactive prostaglandins during peritonitis in patients on continuous ambulatory peritoneal dialysis

The peritoneal generation of arachidonic acid metabolites was studied in eight patients with end-stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD) during infection-free periods and during bacterial peritonitis. The prostacyclin metabolite 6-keto-PGF1 alpha was found to be the major prostanoid generated by human peritoneal mesothelium (1090 ng (6h)-1, SEM 86, n = 8) followed by lesser amounts of PGE2 (142 ng (6 h)-1, SEM 26, n = 8), PGF2 alpha (162 ng (6 h)-1, SEM 27, n = 8) and TXB2 (59 ng (6 h)-1, SEM 5, n = 8). During peritonitis a significant increase of all prostaglandins and TXB2 occurred (P less than 0.001). The ratio of the vasodilating prostaglandins and their metabolites (PGE2 and 6-keto-PGF1 alpha) to the vasoconstrictors and their metabolites (PGF2 alpha and TXB2) increased from 6.6 to 10.5 during peritoneal inflammation. Augmented peritoneal clearances of creatinin and urea and increased losses of proteins during peritonitis as well as the enhanced peritoneal generation of prostanoids were reduced to basal values by adequate antibiotic therapy. The present results suggest that the increased peritoneal blood flow during peritonitis, probably responsible for the observed changes of peritoneal transport properties, may be induced by a change in the ratio of vasoactive prostaglandins generated by peritoneal mesothelial cells.     

Increased platelet sensitivity and thromboxane B2 formation in type-II hyperlipoproteinaemic patients

Platelet aggregation induced by collagen, ADP and epinephrine, was monitored in 150 type-II patients (115 type IIA and 35 type IIB) and compared with a reference group of normolipidaemic controls; in addition, malondialydehyde formation and thromboxane B2 were examined in a subsample of the type-IIA patients. Threshold aggregatory concentrations were significantly lower in the whole group of type-II patients for all three aggregating agents; no difference in terms of aggregatory response was detected between platelets from type-IIA and -IIB patients. Only 56% of type-II patients, however, exceeded the 95th percentile of the threshold aggregatory concentrations in controls. The formation of malondialdehyde in platelet-rich plasma stimulated with thrombin and collagen, was significantly higher in platelets from type-IIA patients. The production of thromboxane B2 by platelets, from endogenous arachidonic acid in type-IIA patients, was significantly higher and exceeded the highest level found in controls.     

Effects of vitamin E therapy on ethanol-induced changes in platelet aggregation, thromboxane formation, factor VIII levels and serum lipids

A transient increase in platelet thromboxane formation has been observed in non-alcoholics during acute ethanol intoxication and in alcoholics shortly after ethanol withdrawal. Whether these effects are related to the generation of free radicals and lipid peroxidation was investigated by using vitamin E as a free radical scavenger and inhibitor of lipid peroxide formation. The results demonstrate that a high dose of vitamin E (1800 IU) taken daily by non-alcoholic men slightly (P less than 0.05) decreases aggregation-associated platelet thromboxane formation during ethanol oxidation. Likewise, vitamin E prevents the ethanol-induced increase (P less than 0.01) in factor VIII coagulant activity. These observations suggest that the enhancement of platelet thromboxane formation and factor VIII coagulant activity by acute ethanol ingestion may be related to stimulated lipid peroxidation. By contrast, similar effects of vitamin E were not found in alcoholics shortly after ethanol withdrawal suggesting other mechanisms for their platelet hyperreactivity.     

Thromboxane and prostacyclin biosynthesis in heart failure of ischemic origin: effects of disease severity and aspirin treatment

Summary. Background: Thromboembolism is a relatively common complication of chronic heart failure (HF) and the place of antiplatelet therapy is uncertain. Objectives: We characterized the rate of thromboxane and prostacyclin biosynthesis in chronic HF of ischemic origin, with the aim of separating the influence of HF on platelet activation from that of the underlying ischemic heart disease (IHD). Patients and Methods: We compared urinary 11‐dehydro‐thromboxane (TX)B₂, 2,3 dinor 6‐keto‐PGF_1α, 8‐iso‐prostaglandin (PG)F_2α, and plasma N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP), asymmetric dimethylarginine (ADMA), and soluble CD40 ligand (sCD40L), in 84 patients with HF secondary to IHD, 61 patients with IHD without HF and 42 healthy subjects. Results: HF patients not on aspirin had significantly higher urinary 11‐dehydro‐TXB₂ as compared with healthy subjects (P < 0.0001) and IHD patients not on aspirin (P = 0.028). They also showed significantly higher 8‐iso‐PGF_2α (P = 0.018), NT‐pro‐BNP (P = 0.021) and ADMA (P < 0.0001) than IHD patients not on aspirin. HF patients on low‐dose aspirin had significantly lower 11‐dehydro‐TXB₂ (P < 0.0001), sCD40L (P = 0.007) and 2,3‐dinor‐6‐keto‐PGF_1α (P = 0.005) than HF patients not treated with aspirin. HF patients in NYHA classes III and IV had significantly higher urinary 11‐dehydro‐TXB₂ than patients in classes I and II, independently of aspirin treatment (P < 0.05). On multiple linear regression analysis, higher NT‐pro‐BNP levels, lack of aspirin therapy and sCD40L, predicted 11‐dehydro‐TXB₂ excretion rate in HF patients (R² = 0.771). Conclusions: Persistent platelet activation characterizes HF patients. This phenomenon is related to disease severity and is largely suppressable by low‐dose aspirin. The homeostatic increase in prostacyclin biosynthesis is impaired, possibly contributing to enhanced thrombotic risk in this setting.     

Aspirin and the in vitro linear relationship between thromboxane A2‐mediated platelet aggregation and platelet production of thromboxane A2

Summary. Background: Currently, ‘aspirin resistance’, the anti‐platelet effects of non‐steroid anti‐inflammatory drugs (NSAIDs) and NSAID‐aspirin interactions are hot topics of debate. It is often held in this debate that the relationship between platelet activation and thromboxane (TX) A₂ formation is non‐linear and TXA₂ generation must be inhibited by at least 95% to inhibit TXA₂‐dependent aggregation. This relationship, however, has never been rigorously tested. Objectives: To characterize, in vitro and ex vivo, the concentration‐dependent relationships between TXA₂ generation and platelet activity. Method: Platelet aggregation, thrombi adhesion and TXA₂ production in response to arachidonic acid (0.03–1 mmol L^?1), collagen (0.1–30 μg mL^?1), epinephrine (0.001–100 μmol L^?1), ADP, TRAP‐6 amide and U46619 (all 0.1‐30 μmol L^?1), in the presence of aspirin or vehicle, were determined in 96‐well plates using blood taken from naïve individuals or those that had taken aspirin (75 mg, o.d.) for 7 days. Results: Platelet aggregation, adhesion and TXA₂ production induced by either arachidonic acid or collagen were inhibited in concentration‐dependent manners by aspirin, with logIC₅₀ values that did not differ. A linear relationship existed between aggregation and TXA₂ production for all combinations of arachidonic acid or collagen and aspirin (P < 0.01; R² 0.92; n = 224). The same relationships were seen in combinations of aspirin‐treated and naïve platelets, and in blood from individuals taking an anti‐thrombotic dose of aspirin. Conculsions: These studies demonstrate a linear relationship between inhibition of platelet TXA₂ generation and TXA₂‐mediated aggregation. This finding is important for our understanding of the anti‐platelet effects of aspirin and NSAIDs, NSAID–aspirin interactions and ‘aspirin resistance’.     

Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin

BACKGROUND: Patients treated with aspirin may have a reduced sensitivity to its antiplatelet effect. The mechanism accounting for such a reduced sensitivity might involve an impaired interaction of aspirin with cyclooxygenase-1 (COX)-1. OBJECTIVE: We sought to investigate whether platelets from patients under chronic treatment with aspirin still produce TxA2 and whether there is any relationship between the eventual persistent TxA2 formation and platelet aggregation. Finally, whether platelet-derived TxA2 can be inhibited by in vitro addition of aspirin. METHODS: Collagen-induced platelet aggregation and thromboxane-A2 (TxA2) were measured in 196 patients treated with aspirin (100-330 mg day(-1)) because of previous vascular events or presence of risk factors of atherosclerosis. RESULTS: Collagen-induced TxA2 production of the entire cohort was 128.7 +/- 21.6 pg 10(-8) cells, and was significantly correlated with platelet aggregation (Spearman's correlation coefficient = 0.44; P < 0.0001). Patients in the highest quartile of TxA2 showed higher platelet response to collagen (P < 0.0001) when compared with those in the lowest quartile. In a subgroup of 96 patients, platelets were treated in vitro with a TxA2 receptor antagonist (13-azaprostanoic acid) or aspirin before stimulation with collagen. 13-APA acid significantly inhibited platelet aggregation. Aspirin reduced (-72.9%) TxA2 production in patients with TxA2 values above the median but it was ineffective in those with TxA2 values below the median. CONCLUSION: In some patients chronically treated with aspirin platelet production of TxA2 may persist and account for enhanced platelet aggregation. Incomplete inhibition of COX-1 seems to be implicated in persistent TxA2 production.     

Release of sphingosine‐1‐phosphate from human platelets is dependent on thromboxane formation

Summary. Background: Platelets release the immune‐modulating lipid sphingosine‐1‐phosphate (S1P). However, the mechanisms of platelet S1P secretion are not fully understood. Objectives: The present study investigates the function of thromboxane (TX) for platelet S1P secretion during platelet activation and the consequences for monocyte chemotaxis. Methods: S1P was detected using thin‐layer chromatography in [³H]sphingosine‐labeled platelets and by mass spectrometry. Monocyte migration was measured in modified Boyden chamber chemotaxis assays. Results: Release of S1P from platelets was stimulated with protease‐activated receptor‐1‐activating peptide (PAR‐1‐AP, 100 μm ). Acetylsalicylic acid (ASA) and two structurally unrelated reversible cyclooxygenase inhibitors diclofenac and ibuprofen suppressed S1P release. Oral ASA (500‐mg single dose or 100 mg over 3 days) attenuated S1P release from platelets in healthy human volunteers ex vivo. This was paralleled by inhibition of TX formation. S1P release was increased by the TX receptor (TP) agonist U‐46619, and inhibited by the TP antagonist ramatroban and by inhibitors of ABC‐transport. Furthermore, thrombin‐induced release of S1P was attenuated in platelets from TP‐deficient mice. Supernatants from PAR‐1‐AP‐stimulated human platelets increased the chemotactic capacity of human peripheral monocytes in a S1P‐dependent manner via S1P receptors‐1 and ‐3. These effects were inhibited by ASA‐pretreatment of platelets. Conclusions: TX synthesis and TP activation mediate S1P release after thrombin receptor activation. Inhibition of this pathway may contribute to the anti‐inflammatory actions of ASA, for example by affecting activity of monocytes at sites of vascular injury.     

缺血心肌中环氧化酶-2的表达及其抑制剂的作用

目的：观察缺血心肌中环氧化酶－2（COX－2）的表达及其抑制剂对前列腺素族代谢产物的影响,以了解COX－2在缺血性心脏病中的作用。方法：新西兰兔21只,随机分为3组：正常对照组（A组,n=7),心肌缺血组（B组,n=7),心肌缺血加罗非昔布组（C组,n=7)。给药7日后,结扎冠状动脉左前降支制作心肌缺血模型。留取血液标本测定血栓素B2（TXB2）和6－酮－前列腺素F1α（6-keto-PGF1α);取缺血区和右心室非缺血区心肌组织测定TXB2和6－keto-PGF1α。对心肌组织行HE及COX－2单克隆抗体免疫组织化学染色进行病理观察。结果：缺血心肌中COX－2呈高度表达;心肌和血清内TXB2、6－keto-PGF1α水平均较对照组增高,而应用罗非昔布干预后,则可降低其升高水平。结论：缺血心肌细胞内COX－2被诱导表达,引起心肌组织中TXB2和6-keto-PGF1α浓度明显升高,COX－2抑制剂可抑制其升高程度。