Angiotensin converting enzymes inhibitors or angiotensin receptor blockers should be continued in COVID-19 patients with hypertension

BACKGROUND Recent studies have revealed that sustained ingestion of angiotensin converting enzymes inhibitors or angiotensin receptor blockers(ACEIs/ARBs)had no harmful effects on coronavirus disease 2019(COVID-19)patients complicated with hypertension.AIM To investigate the impact on COVID-19 patients complicated with hypertension who discontinued using ACEIs/ARBs.METHODS All COVID-19 patients complicated with hypertension admitted to our isolated unit were consecutively recruited in this study.Some patients switched from ACEIs/ARBs to calcium channel blocker(CCBs)after admission,while others continued using non-ACEIs/ARBs.We compared characteristics and clinical outcomes between these two groups of patients.RESULTS A total of 53 patients were enrolled,27 patients switched from ACEIs/ARBs to CCBs while 26 patients continued with non-ACEIs/ARBs.After controlling potential confounding factors using the Cox proportional hazards model,hospital stay was longer in patients who discontinued ACEIs/ARBs,with a hazard ratio of 0.424(95%confidence interval:0.187-0.962;P=0.040),upon discharge than patients using other anti-hypertensive drugs.A sub-group analysis showed that the effect of discontinuing use of ACEIs/ARBs was stronger in moderate cases[hazard ratio=0.224(95%confidence interval:0.005-0.998;P=0.0497)].CONCLUSION Patients in the discontinued ACEIs/ARBs group had longer hospital stays.Our findings suggest that COVID-19 patients complicated with hypertension should continue to use ACEIs/ARBs.

Hyperkalemia of Angiotensin-converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Hemodialysis: A Meta-analysis

The safety of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) used in hemodialysis (HD) patients was evaluated.Medline,Embase,the Cochrane Library,some databases of clinical trial registries,grey literatures,other reference lists of eligible articles and review articles for the randomized clinical trials (RCTs) on comparison of ACEIs/ARBs or placebo in HD patients were retrieved.RCTs reporting the risk of hyperkalemia by using ACEIs/ARBs in HD patients were selected.Eight articles met the eligibility criteria and were subjected to meta-analysis by using the Cochrane Collaboration’s RevMan 4.2 software package.The results showed that there was no significant difference in hyperkalemia in HD patients between ACEIs or ARBs group and control group (ACEIs vs.control:RD=0.03,95% CI=-0.13?0.18,Z=0.34,P=0.73;ARBs vs.control:RD=-0.02,95% CI=-0.07?0.03,Z=0.75,P=0.45).However,there was no significant difference in the serum potassium between ACEIs or ARBs group and control group in HD patients (ACEIs vs.control:WMD=0.10,95% CI=0.06?0.15,Z=4.64,P<0.00001;ARBs vs.control:WMD=-0.24,95% CI=-0.37--0.11,Z=3.58,P=0.0003).The use of ACEIs or ARBs could not cause an increased risk of hyperkalemia in HD patients,however the serum potassium could be increased with use of ACEIs in HD patients.Therefore the serum potassium concentration should still be closely monitored when ACEIs are taken during the maintenance HD.

Microwave-assisted Solid-phase Synthesis, Biological Evaluation and Molecular Docking of Angiotensin I-converting Enzyme Inhibitors

Short peptides based on the tripeptides, Leu-Arg-Pro and Leu-Lys-Pro, were synthesized by microwave assisted solid-phase synthesis method, in order to make a search for potential inhibitors for angiotensin I-converting enzyme（ACE） with minimum side effects in the treatment of hypertension. One peptide with the sequence Leu-Arg-Pro-Phe-Phe shows the strongest inhibition towards ACE with an IC50 value of 0.26 μmol/L in vitro. The study of structure-activity relationship shows that the introduction of a bulky group into the N-terminal of this series of inhibitors may enlarge steric hindrance, resulting in the poor inhibitory activity towards ACE. The inhibitory activity decreased in turn when L-Pro, D-Pro or Ac6c was at the C-terminal respectively. The binding interaction between each of these inhibitors and testicular ACE（tACE） was performed by molecular docking. The results suggest that Leu-Arg-Pro-Phe-Phe mainly occupied the S1 subsite of tACE, and made contact with tACE via seven H-bonds. It appeared that the site on the peptide that bound with tACE was influenced by the configuration of the amino acid, L or D-form, at the C-terminal of the peptide.

Effects of angiotensin converting enzyme inhibitors on cognitive function, apoptosis and oxidative stress in brain tissue of rats with cerebral infarction

Objective:To study the effects of angiotensin converting enzyme inhibitor(ACEI)on cognitive function,apoptosis and oxidative stress in brain tissue of rats with cerebral infarction.Methods:Adult male SD rats were randomly divided into control group,cerebral infarction group and ACEI group.The latter two groups were used to establish cerebral infarction model by thread embolism.The ACEI group was given oral administration of fosinopril 10mg/kg,and the other two groups were given oral administration of saline.The differences of Morris water maze cognitive function,apoptotic genes and oxidative stress indexes were compared among the three groups.Results:The escape latency of rats in cerebral infarction group was significantly longer than that in control group,the number of times of platform crossing was significantly less than that in control group,the duration of platform stay was significantly shorter than that in control group,the mRNA expression levels of Bcl-2 associated X protein(Bax),factor associated suicide(Fas),Fas ligand(FasL)and Caspase-3,the protein expression levels of phosphorylated Janus kinase(p-JAK2)and phosphorylated signal transducer and activator of transcription(p-STAT3)as well as the contents of reactive oxygen species(ROS)and malonaldehyde(MDA)in brain tissue were significantly higher than those in control group,and the mRNA expression level of B-cell lymphoma-2(Bcl-2)as well as the contents of catalase(CAT)and superoxide dismutase(SOD)in brain tissue was significantly lower than those in control group.The escape latency of rats in ACEI group was significantly shorter than that in cerebral infarction group,the number of times of platform crossing was significantly more than that in cerebral infarction group,the duration of platform stay was significantly longer than that in cerebral infarction group,the mRNA expression levels of Bax,Fas,FasL and Caspase-3,the protein expression levels of p-JAK2 and p-STAT3 as well as the contents of ROS and MDA in brain tissue were significantly lower than those in cerebral infarction group,and the mRNA expression level of Bcl-2 as well as the contents of CAT and SOD in brain tissue was significantly higher than those in cerebral infarction group.Conclusions:ACEI can improve the cognitive function of rats with cerebral infarction and inhibit the apoptosis and oxidative stress in ischemic brain tissue.

Effect of angiotensin Ⅱ type 1 receptor blocker and angiotensin converting enzyme inhibitor on the intraocular growth factors and their receptors in streptozotocin-induced diabetic rats

AIM： To investigate the effect of angiotensin II type 1 receptor blocker （ARB） and angiotensin converting enzyme inhibitor （ACEI） on intraocular growth factors and their receptors in streptozotocin-induced diabetic rats. METHODS： Forty Sprague-Dawley rats were divided into 4 groups： control, diabetes mellitus （DM）, candesartan- treated DM, and enalapril-treated DM （each group, n---10）. After the induction of DM by streptozotocin, candesartan [ARB, 5 mg/（kg · d）] and enalapril [ACEI, 10 mg/（kg · d）] were administered to rats orally for 4Wko Vascular endothelial growth factor （VEGF） and angiotensin II （Ang II） concentrations in the vitreous were measured using enzyme-linked immunosorbent assays, and VEGF receptor 2 and angiotensin II type 1 receptor （ATIR） levels were assessed at week 4 by Western blotting. RESULTS： Vitreous Ang II levels were significantly higher in the DM group and candesartan-treated DM group than in the control （P=0.04 and 0.005, respectively）. Vitreous ATIR increased significantly in DM compared to the other three groups （P〈0.007）. Candesartan-treated DM rats showed higher vitreal ATIR concentration than the enalapril-treated DM group and control （P〈0.001 and P=0.005, respectively）. No difference in vitreous Ang II and ATIR concentration was found between the enalapril- treated DM group and control. VEGF and its receptor were below the minimum detection limit in all 4 groups. CONCLUSION： Increased Ang II and ATIR in the hyperglycemic state indicate activated the intraocular renin-angiotensin system, which is inhibited more effectively by systemic ACEI than systemic ARB.

Angiotensin-converting enzyme and bradykinin gene polymorphisms and cough:A meta-analysis

AIM:To evaluate the association between genetic polymorphisms and angiotensin converting enzyme in-hibitor (ACEI)-related cough,and the race-or ethnicity-related difference in the prevalence of cough attributed to ACEI therapy.METHODS:We conducted a search in PubMed,EM-BASE,Cinahl,and the Cochrane Database without language limitation.A database of 11 studies on ACEI-related cough,with detailed information regarding ACE I/D or bradykinin B 2 receptor polymorphisms,was created.Eligible studies were synthesized using meta-analysis methods,including cumulative meta-analysis.A subgroup analysis was also performed using ethnicity.RESULTS:Six studies were included on ACE I/D poly-morphism (398 Caucasians,723 East Asians),and three studies were included on bradykinin B 2 receptor poly-morphism (300 East Asians).The distribution of ACE genotypes showed significant differences in the entire population (P=0.004) and in East Asians (P=0.005)but not in Caucasians (P=0.23).Allelic frequencies of ACE showed significant differences in East Asians [odds ratio (OR)=1.49 (1.11-2.02)].The meta-analysis with a random effects model showed a significant associa-tion between ACE allele I/D and ACEI-related cough [random effects (RE) OR=1.49 (1.11-2.02),P=0.009] in East Asians,but not in Caucasians [RE OR=0.90 (0.60-1.35)].The allelic frequencies of the bradykinin B 2 receptor gene were significantly different [OR=2.25 (1.42-3.57)].The distributions of the T/C genotypes of the bradykinin B 2 receptor gene were significantly dif-ferent (χ 2=8.366,P=0.015).The meta-analyses re-vealed that there was a significant association between the bradykinin B 2 receptor allele and ACEI-related cough in East Asians [RE OR=2.29 (1.42-3.69),P=0.001].CONCLUSION:ACE I/D and Bradykinin B 2 receptor polymorphisms contributed to the risk of ACEI-related cough in East Asians,but a negative association be-tween ACE I/D polymorphism and ACEI-related cough was observed in Caucasians.

Role of angiotensin converting enzyme and angiotensinogen gene polymorphisms in angiotensin converting enzyme inhibitor-mediated antiproteinuric action in type 2 diabetic nephropathy patients

AIM To investigate the role of genetic variants of angiotensin converting enzyme(ACE) and angiotensinogen(AGT) genes in the antiproteinuric efficacy of ACE inhibitor therapy in diabetic nephropathy(DN) patients.METHODS In the present study, 270 type 2 diabetes mellitus patients with nephropathy were enrolled and treated with ACE inhibitor(ramipril) and followed at 6 mo for renal function and albumin excretion by estimating serum creatinine, end stage renal disease, and albumin/creatinine ratio(ACR) in urine. Genotyping of ACE I/D and AGT M235 T polymorphisms were performed by using primer specific polymerase chain reaction(PCR) and PCR-RFLP techniques, respectively. RESULTS Forty-eight percent of DN patients(responders) benefited with respect to proteinuria from ACE inhibitor therapy at 6 mo follow-up. A significant reduction in ACR was observed after 6 mo treatment with ACE inhibitor irrespective of whether DN patients were micro-albuminuric(≥ 30 and < 300 mg/g creatinine) or macro-albuminuric(≥ 300 mg/g creatinine) at the time of enrollment. However, macro-albuminuric patients(55%) showed better response to therapy. A reduction in urinary ACR was found independent of genotypes of ACE I/D and AGT M235 T polymorphisms although macro-albuminuric patients having TT genotype showed statistically insignificant increased response(72%). CONCLUSION ACE inhibitor therapy reduced urinary ACR by ≥ 30% in 50% of DN patients and the response is independent of ACE I/D and AGT M235 T polymorphisms.

A new angiotensin-converting enzyme inhibitor from Peperomia pellucida(L.) Kunth

Objective:To isolate,identify,and evaluate a new angiotensin-converting enzyme inhibitor from Peperomia pellucida(L.)Kunth herbs.Methods:A dried sample of Peperomia pellucida herb was successively macerated with n-hexane and ethyl acetate.The ethyl acetate extract solution was evaporated to obtain the crude extract.Vacuum liquid column chromatography and thin layer chromatography were performed to obtain two pure compounds.Then,both compounds were elucidated and identified using the spectroscopic method.Angiotensin-converting enzyme inhibitory activity studies of both compounds were determined using angiotensin-converting enzyme kit WST-1 with spectrophotometer microplate reader 96-well at 450 nm wavelength.Results:Two bioactive compounds were successfully isolated from Peperomia pellucida herb,including a new compound of 2,3,5-trimethoxy-9-(12,14,15-trimethoxybenzyl)-1 H-indene and pellucidin A.Both compounds demonstrated angiotensin-converting enzyme inhibitory activity,with IC50 values of 72 μM(27.95 μg/mL)and 1 1μM(4.4 μg/mL),respectively.Conclusions:In the present study,two active angiotensin-converting enzyme inhibitors were successfully isolated and purified from Peperomia pellucida which is used as an antihypertensive in traditional medicine,and support its use as an angiotensin-converting enzyme-inhibiting drug.

The Significance of Angiotensin Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Use in Sudden Cardiac Death

Objectives: To investigate the relationship between the use of angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) and hyperkalemia in patients diagnosed with sudden cardiac death. Methods: We examined oral ACE inhibitor or ARB use among cardiopulmonary arrest patients brought by ambulance to our emergency room during a 5-year period from January 2012 to December 2016. The cause of death was determined to be sudden cardiac death, despite temporary return of spontaneous circulation after starting cardiopulmonary resuscitation. Subjects were dichotomized into 2 groups, those taking and those not taking an ACE inhibitor or ARB. Variables determined retrospectively included serum potassium, estimated glomerular filtration rate as an index of kidney function and time from cardiopulmonary arrest to return of spontaneous circulation. The Mann-Whitney U-test was used to compare continuous data, and the chi-square test to compare categorical data between groups. The results are expressed as the median plus range. Statistical significance was assumed at p Results: Thirty-five patients met the inclusion criteria. The mean age was 77.1 years (range, 35 - 93 years), and there were 26 males and 9 females. Eleven subjects were ACE inhibitor or ARB users, and 24 were non-users. The serum potassium level was significantly higher in users than non-users (median, 6.2 mEq/L (range, 4.5 - 10.0) vs. 5.2 mEq/L (range, 3.6 - 8.3);p = 0.001). The estimated glomerular filtration rate was significantly lower in users than non-users (median, 25.1 mL/min/1.73 m2 (range, 4.6 - 60.3) vs. 46.9 mL/min/1.73 m2 (range, 19.8 - 97.1);p = 0.009). There was no significant difference in time from cardiopulmonary arrest to return of spontaneous circulation between the 2 groups (median, 24 minutes (range, 3 - 111) vs. 29 minutes (range, 10 - 54);p = 0.355). Conclusion: It is possible that hyperkalemia induced by ACE inhibitor or ARB use is a cause of sudden cardiac death, especially in patients with chronic kidney disease.

Angiotensin-Converting Enzyme Inhibitor Induced Angioedema Occurring after 8 Years of Taking Lisinopril: A Case Report

Angiotensin-converting enzyme inhibitor induced angioedema (AIIA) can vary from mild to life-threatening. A vast majority of cases of AIIA occur within a month of starting an angiotensin-converting enzyme-inhibitor (ACE-I). We present a 48-year-old male who presented with respiratory failure secondary to AIIA, after being on lisinopril for over 8 years. He had no previous complications secondary to lisinopril and aside from smoking, carried no risk factors for AIIA. Despite conventional treatment for angioedema, he had a prolonged stay in the Medical Intensive Care Unit (MICU). Following discharge, there hasn’t been a recurrence of AIIA since the discontinuation of lisinopril. The case is intended to caution that AIIA remains possible even late into a chronic regimen of ACE-I. This is a risk that shouldn’t be neglected, even with sparse risk factors or longer duration of ACE-I use. Conventional treatment is not currently in line with proposed etiologies of AIIA. We advocate for more clinical trials involving pharmaceutical agents targeting bradykinin accumulation.

Prevention of atrial fibrillation with renin-angiotensin system inhibitors on essential hypertensive patients:a meta-analysis of randomized controlled trials

We aimed to investigate the effectiveness and safety of angiotensin-converting enzyme inhibitors （ACEIs） or angiotensin Ⅱ receptor blockers （ARBs） on preventing atrial fibrillation in essential hypertensive patients. Systematic literature retrieval was carried out to obtain randomized controlled trials on the effects of ACEI/ ARBs on essential hypertensive patients before December, 2013. Data extraction and quality evaluation were performed. Meta-analysis was performed by Review Manager 5.2.3. Ten high quality studies （11 articles） with a total of 42,892 patients （20,491 patients in the ACEI/ARBs group and 22,401 patients in the β-blocker or the calcium antagonist group） met the inclusion criteria and were included in the meta-analysis. The results showed that ACEI/ARBs reduced the incidence of atrial fibrillation （AF） recurrence compared to calcium antagonists （RR=0.48; 95%CI, 0.40-0.58; P〈0.00001） or β-blockers （RR=0.39; 95%CI, 0.20-0.74; P=0.005） in long-term follow-up, respectively. Furthermore, ACEI/ARBs reduced the incidence of conges- tive heart failure （RR=0.86; 95%CI, 0.77-0.96; P=0.007）. However, no significant effects were observed on the incidence of new AF, cardiac death, myocardial infarction, and stroke. Our results suggest that ACEI/ ARBs may reduce the incidence of AF recurrence and congestive heart failure, with fewer serious adverse effects.

Time to re-evaluate effects of renin-angiotensin system inhibitors on renal and cardiovascular outcomes in diabetic nephropathy

The use of renin-angiotensin system(RAS) inhibitors, such angiotensin converting enzyme inhibitors/angiotensin-Ⅱreceptor blockers, to slow progression of chronic kidney disease(CKD) in a large group dominated by elderly people in the real world is not supported by available evidence. Large-scale clinical trials had many faults,among them a lack of focus on the elderly. However,it would be difficult to conduct clinical trials of a similar scale in elderly CKD patients. Besides, progression ofkidney disease is often slow in elderly persons, and the vast majority of older adults with CKD will die before reaching end stage renal disease. Moreover, since it is not clear that progression of kidney disease, and even of proteinuric diabetic nephropathy, is not inhibited through the use of RAS inhibitors, the most patientcentric goal of therapy for many elderly individuals should be individualized.

Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on lymphangiogenesis of gastric cancer in a nude mouse model

Background Angiotensin-converting enzyme inhibitors （ACEI） and angiotensin II type 1 receptor blockers （ARB） can inhibit tumor growth by inhibition of angiogenesis. This study was designed to study the anticancer effects of ACEI and ARB on tumor growth and lymphangiogenesis in an implanted gastric cancer mouse model. Methods A model of gastric cancer was established by subcutaneously inoculating human gastric cancer cell line SGC-7901 into 60 nude mice. One week later, all mice were randomly divided into 5 groups. A control group received physiologic saline once daily for 21 days. Mice in the 4 treatment groups received one of the following agents by gavage once daily for 21 days： perindopril, 2 mg/kg; captopril, 5 mg/kg; Iosartan, 50 mg/kg; or valsartan, 40 mg/kg. Twenty-one days after treatment, all the mice were sacrificed and the tumors were removed. Tumor sections were processed, and immunohistochemical methods were used to observe the expressions of vascular endothelial growth factor C （VEGF-C）, matrix metalloproteinase 7 （MMP-7）, and lymphatic microvessel density （LMVD）. Results Tumor volume was significantly inhibited in all ACEI and ARB groups, compared with the control group （all P 〈0,01）. LMVD in the ACEI and ARB groups was also significantly lower than that of the control group （all P 〈0.01）. In the ACEI groups, the expressions of VEGF-C and MMP-7 were both significantly decreased, compared with the control group （all P 〈0.05）. In the ARB groups, expression of VEGF-C was significantly decreased compared with the control group （all P 〈0.05）. However, no significant difference was found in the expression of MMP-7 between ARB groups and the control group. Conclusion In a mouse model, ACEI and ARB might inhibit gastric cancer tumor growth by suppressing lymphangiogenesis.

Effects of angiotensin converting enzyme inhibitor,angio-tensin II type I receptor blocker and their combination on postinfarcted ventricular remodeling in rats

Background Transforming growth factor （TGF） β1-Smads signal plays an important role in cardiac remodeling following myocardial infarction （MI）. In addition, both angiotensin converting enzyme inhibitor （ACEI） and angiotensin Ⅱ type Ⅰ receptor blocker （ARB） can effectively prevent left ventricular remodeling. The current study focused on whether the combination of ACEI and ARB is more beneficial for preventing ventricular remodeling and whether Smad proteins mediate this beneficial effect. Methods MI was induced by ligating the left anterior descending coronary artery in rats. Twenty-four hours after ligation, the survived rats were randomly divided into five groups and treated for 8 weeks： placebo group, ACEI group （benazepril 10 mg · kg^-1· d^-1）, ARB group （irbesartan 50mg · kg^-1· d^-1）, ACEI＋ARB group （benazepril 10 mg · kg^-1· d^-1＋irbesartan 50 mg · kg^-1· d^-1） and control group （sham-operated rats）. After 8 weeks, we examined the following indexes： the ratio of ventricular weight to body weight （VW/BW）, left ventricular end diastolic dimension （LVDd）, ejection fraction （EF）, fractional shortening （FS）, ratio of E-wave to A-wave velocity, collagen of noninfarcted zone, the mRNA expression of TGFβ1, Smad 2, and Smad 3 by RT-PCR in noninfarcted zone, the protein expression of Smad 2 and Smad 3 in noninfarcted zone by Western blot. Results VW/BW significantly increased in the placebo groups compared with that in the control group （P〈0.01）. This increase was limited in ACEI, ARB, and combined groups （P〈0.01 compared with placebo group）. There was no significant difference among the three actively treated groups. Collagen was increased in placebo group （5.68±0.5）% compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment attenuated this increase of collagen [（4.3 ± 0.5）%, （3.5 ± 0.5）%, （3.2± 0.4）%] in comparison with that in placebo group （P〈0.01 respectively）. Combined treatment showed more significant effect on collagen deposition. EF and FS significantly decreased, LVDd and E/A significantly increased in placebo group compared with that in control group （P〈0.01 respectively）. ACEI, ARB and combined treatment ameliorated these indexes （P〈0.01 compared with placebo group）. The mRNA expression of TGFβ1, Smad 2, and Smad 3 （0.700±0.045, 0.959±0.037 and 0.850±0.051） increased in placebo group compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment normalized the increase （P〈0.01）. Furthermore, ARB and combined treatment proved to be more effective in decreasing TGF β1 and Smad mRNA expression than ACEI treatment （P〈0.01）. The expression of Smad 2 and Smad 3 protein increased in placebo group compared with that in control group （P〈0.01）. ACEI, ARB and combined treatment normalized the increase （P〈0.01）. Furthermore, ARB and combined treatment proved to be more effective than ACEI alone （P〈0.01）.Conclusions TGFβ1-Smads signal activation is correlated With ventricular remodeling following MI. ACEI and ARB treatment prevents ventricular remodeling by inhibiting expression of Smad 2 and Smad 3. ARB and combined treatment are more effective than ACEI alone.

Traditional Chinese Medicine Based on Zheng Differentiation versus Angiotensin Receptor Blocker/Angiotensin?converting Enzyme Antagonist in Efficacy of Treating Diabetic Kidney Disease: A Meta?analysis of Randomized Clinical Trials

Objective: To compare the efficacy of traditional Chinese medicine(TCM) based on Zheng differentiation with angiotensin receptor blocker/angiotensin-converting enzyme inhibitor(ARB/ACEI) in treating diabetic kidney disease(DKD) from the aspects of decreasing urinary microalbumin, declining 24-h urinary protein, reducing endpoint events, and renal function protection. Methods: The Chinese Biomedical Literature Database(CBM), the Chinese Academy of Sciences database(CNKI), the VIP Chinese journal database, Wanfang DATA, Medline database, Cochrane library, excerpt medical database(Embase), and Web of science were used for literature searching. The reviewer manager5.3 software was utilized to analyze the data. Results: Twenty-four studies including 1956 participants were involved in this review. Results showed that TCM had a better effect(mean difference [MD],-23.20, 95% confidence interval [CI],-30.60 to-15.79, P < 0.00001) than ARB/ACEI on lowering urinary albumin excretion rate(UAER) and urine albumin-to-creatinine ratio(MD-4.56 mg/mmol, 95% CI,-5.76 to-3.36, P < 0.00001). Moreover, the advantage of decreasing UAER was greater as the follow-up period become longer(P = 0.04). TCM also had a better effect in 24-h urinal protein, decreasing 0.36 g/24 h(95% CI,-0.45 to-0.27, P < 0.00001) more than the control in shorter follow-up period(ranged from 12 to 24 weeks) subgroup but only 0.08 g/24 h(95% CI,-0.13 to-0.03, P = 0.0006) in the longer follow-up period(>24 weeks) subgroup. TCM worked as well as ACEI/ARB in reducing endpoint events(relative risk, 0.67, 95% CI, 0.20–2.224, P = 0.51)and decreasing urinary albumin concentration(UAC)(MD,-16.50, 95% CI,-46.28–13.28, P = 0.28). As for protecting renal function, TCM had an equal effect to AECI/ARB in improving creatinine clearance ratio(MD,-3.30, 95% CI,-6.66–0.03, P = 0.05) or estimated glomerular filtration rate(MD, 1.00, 95% CI,-0.59–2.58, P = 0.22). However, TCM had a better effect in releasing the glomerular hyperfiltration state(MD,-9.64, 95% CI,-14.45 to-4.84, P < 0.0001). Conclusions: TCM based on Zheng differentiation can work as well as ACEI/ARB in treating DKD and even better in decreasing urinary microalbumin and releasing glomerular hyperfiltration. It is a good alternative treatment of DKD.

Effect of angiotensin converting enzyme inhibitor on the calcium transients and calcium handling proteins in ventricular myocytes from rats with heart failure

Background Chronic heart failure (CHF) is associated with calcium transients and calcium handling proteins. Angiotensin converting enzyme (ACE) inhibitor has been demonstrated to have beneficial effect on CHF. Yet studies addressed to the relationship between ACE inhibitor and calcium transients in CHF are rare. The aim of this study was to investigate the influence of ACE inhibitor (perindopril) on the contractility and calcium transients and calcium handling proteins in ventricular myocytes from rats with experimental heart failure.Methods Male Wistar rats were randomized to heart failure group treated with perindopril (CHF-T, 3 mg·kg -1 ·d -1 ), heart failure group without treatment (CHF-C) and sham-operated group (PS). Heart failure was induced by abdominal aortic constriction. All groups were further followed up for 12 weeks. Left ventricular myocytes were then isolated. Single cell shortening fraction and [Ca 2+ ]_i were simultaneously measured by laser scanning confocal microscope under the field stimulation (1.0 Hz). Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot were performed to evaluate the changes of mRNA and protein of Na +-Ca 2+ exchanger (NCX_1), sarcoplasmic reticulum Ca 2+ -ATPase (SERCA_2) and phospholamban (PLB).Results The fraction of cell shortening (FS%) and [Ca 2+ ]_ imax (nmol/L) were significantly reduced in group CHF-C compared with group PS (FS%: 7.51±1.15 vs 13.21±1.49;[Ca 2+ ]_ imax :330.85±50.05 vs 498.16±14.07; both P <0.01), and restored at least partially in CHF-T group. In CHF-C group, the left ventricular mRNA of NCX_1 and PLB were significantly upregulated in comparing with PS group (R_ NCX1/β-Actin : 0.51±0.12 vs 0.19±0.06, P <0.01; R_ PLB/β-Actin : 0.26±0.12 vs 0.20±0.08, P <0.05), while SERCA_2 mRNA was downregulated (0.48±0.10 vs 0.80±0.11, P <0.01). The mRNA levels of NCX_1 and SERCA_2 in CHF-T group were between the CHF-C and PS group, and the differences of the latter two groups were significant (all P <0.05). In CHF-C and CHF-T groups, the protein expression of NCX_1 were 1.141±0.047 and 1.074±0.081 times of that in PS group respectively (both P <0.05), and SERCA_2 protein levels were 0.803±0.100 and 0.893±0.084 times of that in PS group respectively (both P <0.05). The protein expression of NCX_1 and SERCA_2 in the CHF-C and CHF-T groups is significantly different (both P <0.05).ConclusionACE inhibitor could improve cardiac function of failing heart through directly enhancing the contractility of single cardiomyocyte, and these effects are probably mediated by its roles in preventing the deleterious changes of calcium transients and calcium handling proteins in CHF.

Effect of preoperative renin-angiotensin system blockade on vasoplegia after cardiac surgery:A systematic review with metaanalysis

BACKGROUND Vasoplegia is a common complication of cardiac surgery but its causal relationship with preoperative use of renin angiotensin system(RAS)blockers[angiotensin converting enzyme inhibitors(ACEIs)and angiotensin receptor blockers(ARB)]is still debated.AIM To update and summarize data on the effect of preoperative use of RAS blockers on incident vasoplegia.METHODS All published studies from MEDLINE,EMBASE,and Web of Science providing relevant data through January 13,2021 were identified.A random-effects metaanalysis method was used to pool estimates,and post-cardiac surgery shock was differentiated from vasoplegia.RESULTS Ten studies reporting on a pooled population of 15672 patients(none looking at ARBs exclusively)were included in the meta-analysis.All were case-control studies.Use of ACEIs was associated with an increased risk of vasoplegia[pooled adjusted odds ratio(Aor)of 2.06,95%CI:1.45-2.93]and increased inotropic/vasopressor support requirement(pooled aOR 1.19,95%CI:1.10-1.29).Post-cardiac surgery shock was increased in the presence of left ventricular dysfunction(pooled aOR 2.32,95%CI:1.60-3.36;I249%)but not increased by the use of beta blockers(pooled aOR 0.78,95%CI:0.36-1.69;I277%).Two randomized control trials(RCTs),not eligible for the meta-analysis,did not show an association between continuation of RAS blockers and vasoplegia.CONCLUSION Preoperative continuation of ACEIs is associated with an increased need for inotropic support postoperatively and with an increased risk of vasoplegia in observational studies but not in RCTs.The absence of a consensus definition of vasoplegia should lead to the use of perioperative cardiovascular monitoring when designing RCTs to better understand this discrepancy.

What is the optimal initiation timing of angiotensin converting enzyme inhibitor treatment for maximum benefits in acute myocardial infarction patients？

Randomized clinical trials led to the clinical recommendation that angiotensin-converting enzyme inhibitors （ACEI） should be used as standard therapy in most patients experiencing an acute myocardial infarction （AMI）. However, the optimal initiation timing of treatment, as well as the exact mechanisms, have not been completely resolved, especially with the development of reperfusion strategy after AMI. Earlier initiation of ACEI might be associated with more prompt recovery of left ventricular ejection fraction due to more rapid attenuation of negative remodeling.

利用受体配体亲和技术筛选黄芩中血管紧张素转换酶2和二肽基肽酶4抑制剂

目的筛选中药黄芩中血管紧张素转换酶2(ACE2)和二肽基肽酶4(DPP-4)抑制剂。方法以ACE2和DPP-4作为靶蛋白,利用受体配体亲和超滤和液质联用技术,对黄芩中与ACE2和DPP-4亲和的化合物进行筛选和分析,以筛选具有同时抑制ACE2和DPP-4的化合物。结果从黄芩中筛选出了5,7,2′,6′-4羟基黄酮、5,7,2′,5′-4羟基-8,6′-二甲氧基黄酮、白杨素-7-O-葡萄糖醛酸苷、黄芩素-6-O-葡萄糖醛酸苷、千层纸素A-7-O-葡萄糖醛酸苷、汉黄芩苷、白杨素、千层纸素A,可以同时亲和抑制ACE2和DPP-4,具有潜在的抗新型冠状病毒的作用。结论从黄芩中筛选出与新型冠状病毒肺炎有关的靶蛋白抑制剂,具备潜在开发价值。

血管紧张素转化酶抑制剂或血管紧张素Ⅱ受体阻滞剂联合糖皮质激素治疗IgA肾病疗效观察

目的探讨血管紧张素转化酶抑制剂(ACEI)或血管紧张素Ⅱ受体阻滞剂(ARB)联合糖皮质激素治疗IgA肾病患者的临床疗效。方法选择2019年10月至2022年10月安阳地区医院收治的125例IgA肾病患者为研究对象。将患者随机分为对照组(n=62)和观察组(n=63),对照组患者给予ACEI或ARB类药物治疗,观察组患者在对照组的基础上加用丙酸氟替卡松吸入气雾剂治疗,2组患者均连续治疗3个月。比较2组患者治疗后的效果。分别于治疗前后检测2组患者24 h尿蛋白定量、肾功能指标血肌酐(Scr)、肾小球滤过率(GFR)和血常规指标白细胞计数(WBC)、血红蛋白(HGB)水平、血小板计数(PLT)。记录2组患者治疗期间不良反应发生情况。结果对照组和观察组患者治疗总有效率分别为54.84%(34/62)、84.13%(53/63),观察组患者治疗总有效率显著高于对照组(χ^(2)=12.669,P<0.05)。治疗前2组患者24 h尿蛋白定量、Scr、GFR比较差异无统计学意义(P>0.05)。对照组患者治疗前后24 h尿蛋白定量比较差异无统计学意义(P>0.05),观察组患者治疗后24 h尿蛋白定量显著低于治疗前(P<0.05);2组患者治疗后Scr显著低于治疗前,GFR显著高于治疗前(P<0.05)。治疗后,观察组患者24 h尿蛋白定量显著低于对照组(P<0.05);2组患者Scr、GFR比较差异无统计学意义(P>0.05)。2组患者治疗前后WBC、HGB、PLT水平比较差异均无统计学意义(P>0.05)。2组患者治疗过程中均未出现糖耐量异常、类固醇性糖尿病、血压升高等不良反应。结论丙酸氟替卡松吸入气雾剂联合ACEI或ARB类药物治疗IgA肾病患者,可降低24 h尿蛋白定量,有助于肾功能的改善,疗效显著,且不会对患者造成血液系统损伤,安全性较高。