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.

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.

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.

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.

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.

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.

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.

Cardiovascular and cerebrovascular outcomes in elderly hypertensive patients treated with either ARB or ACEI

Background Although angiotensin converting enzyme inhibitors （ACEI） and angiotensin receptor blockers （ARB） are equally important in the treatment of hypertension, there is less evidence whether they have equal cardiovascular and cerebrovascular protective effects, especially in elder hypertensive patients. This study aims to clarify this unresolved issue. Methods This cross-sectional study included clinical data on 933 aged male patients with hypertension who received either an ARB or ACEI for more than two months between January 2007 and May 2011. The primary outcome was the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The secondary endpoints were unstable angina, new atrial fibrillation, and transient ischemic attack. Results The median follow-up time was 24 months. Age, drug types, cerebral infarction history, renal dysfunction history were the independent predictors of the primary endpoint. The risk of an occurrence of a primary endpoint event was higher in the ARB group than the ACEI group [P = 0.037, hazard ratios （HR）： 2.124, 95% confidence interval （95% CI）： 1.048-4.306]. The Kaplan-Meier method also suggests that the rate of primary endpoint occurrence was higher in the ARB group than the ACEI group （P = 0.04）. In regard to the secondary endpoints, there were no significant differences between the two treatment arms （P = 0.137, HR： 1.454, 95% CI： 0.888-2.380）. Patient age and coronary heart disease history were independent predictors of the secondary endpoint. Conclusion ACEI were more effective than ARB in reducing cardiovascular and cerebrovascular morbidity and mortality in aged patients with hypertension.

Deciphering bioactive compounds of complex natural products by tandem mass spectral molecular networking combined with an aggregation-induced emission based probe

Natural products are great treasure troves for the discovery of bioactive components.Current bioassay guided fractionation for identification of bioactive components is time-and workload-consuming.In this study,we proposed a robust and convenient strategy for deciphering the bioactive profile of natural products by mass spectral molecular networking combined with rapid bioassay.As a proof-of-concept,the strategy was applied to identify angiotensin converting enzyme(ACE)inhibitors of Fangjihuangqi decoction(FJHQD),a traditional medicine clinically used for the treatment of heart failure.The chemical profile of FJHQD was comprehensively revealed with the assistance of tandem mass spectral molecular networking,and a total of 165 compounds were identified.With characterized constituents,potential clinical applications of FJHQD were predicted by Bioinformatics Analysis Tool for Molecular mech ANism of Traditional Chinese Medicine,and a range of cardiovascular related diseases were significantly enriched.ACE inhibitory activities of FJHQD and its constituents were then investigated with an aggregation-induced emission based fluorescent probe.FJHQD exhibited excellent ACE inhibitory effects,and a bioactive molecular network was established to elucidate the ACE inhibitory profile of constituents in FJHQD.This bioactive molecular network provided a panoramic view of FJHQD’s ACE inhibitory activities,which demonstrated that flavones from Astragali Radix and Glycyrrhizae Radix et Rhizoma,saponins from Astragali Radix,and sesquiterpenoids from Atractylodis Macrocephalae Rhizoma were principal components responsible for this effect of FJHQD.Among them,four novel ACE inhibitors were the first to be reported.Our study indicated that the proposed strategy offers a useful approach to uncover the bioactive profile of traditional medicines and provides a pragmatic workflow for exploring bioactive components.

Management of hypertension in COVID-19

The ACE2 receptor plays a central role in severe acute respiratory syndrome coronavirus 2 host cell entry and propagation.It has therefore been postulated that angiotensin converting enzyme inhibitors and angiotensin receptor blockers may upregulate ACE2 expression and thus increase susceptibility to infection.We suggest that alternative anti-hypertensive agents should be preferred among individuals who may be exposed to this increasingly common and potentially lethal virus.

Finally, Some Reason for Hope in Proteinuric Kidney Disease

Background: After years of predictable outcomes with limited tools to combat the ravages of proteinuric chronic kidney disease (CKD) associated with or without diabetes, exciting new options are available to slow the progression of CKD. Purpose: Focusing on sodium-glucose co-transporter 2 inhibitors (SGLT2), angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACE I), and new mineralocorticoid antagonists (MRA), this review examines how these agents compliment the standard of care in an attempt to educate and stimulate broader use of these agents. Methods: Using the search terms “mineralocorticoid antagonist, sodium glucose co-transporter 2 inhibitors, proteinuria, albuminuria, and diabetic kidney disease,” five randomized controlled clinical trials were identified and then analyzed in the context of the results found from the Irbesartan Diabetic Nephropathy Trial (IDNT). Two trials using SGLT2 and 2 using MRA were reviewed. Results: In the 2 SGLT2 trials renal outcomes were reduced by 30% - 39% among patients with estimated GFR ranging from roughly 25 - 90 mL/min. In the 2 MRA trials, renal outcomes fell by 13% - 18% among patients with estimated GFR ranging from 25 - 90 mL/min. In the IDNT, renal outcomes fell by 19%. Trial duration ranged from 28 - 41 months, and in all trials, the IDNT, Ace inhibitors (ACE I) and ARBs use was uniform. There is small overlap in the 5 trials in which both MRA and SGLT2 agents were used. Conclusions: Over a wide range of renal function, both MRA and SGLT2 inhibitors demonstrate outstanding efficacy in diabetic and non-diabetic (SGLT2) proteinuric kidney disease. Compared to the prior standard of care, these agents dramatically improve outcomes.

Effects of benazepril on renal function and kidney expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in diabetic rats

Background Excessive deposition of extraceUular matrix （ECM） in the kidney is the hallmark of diabetic nephropathy. Increased matrix synthesis has been well documented but the effects of diabetes on degradative pathways, particularly in the in vivo setting. The renal protective effect of these pathways on matrix accumulation has not been fully elucidated. The present study was understaken to investigate the activity of matrix metalloproteinase-2 （MMP-2）, the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 （TIMP-2） in kidney tissues of diabetic rats, and to explore the degradative pathway of type Ⅳ collagen （Ⅳ-C） and the renal protective effects of ACE inhibition- benazepril.

2019 novel-coronavirus: Cardiovascular insights about risk factors, myocardial injury, therapy and clinical implications

From December 31st,2019,a novel highly pathogenic coronavirus,severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide,reaching at present the dimension of a pandemic.In addition to damaging the lungs,SARS-CoV-2 may also damage the heart and this is corroborated by the evidence that cardiovascular comorbidities are associated with a higher mortality and poor clinical outcomes in patient infected by the virus.During the infection myocardial injury,myocarditis and arrhythmias have also been reported,but the pathophysiological mechanisms of these complications are yet to be understood.Great attention is also being posed on the potential beneficial/harmful role of angiotensin converting enzyme(ACE)inhibitors,as far as the virus binds to ACE2 to infect cells,but evidences lack.Furthermore,SARS-CoV-2 can also affect the aspect of acute coronary syndromes,not only because these two distinct pathological entities share pathogenic aspects(such as the systemic inflammatory state and cytokine release),but also and above all for the consequences that the need to contain the infection has on the management of cardiological urgencies.The aim of this review was therefore to summarize the relationship between the virus and the cardiovascular system.

Relationship between age and effect of early and long-term captopril treatment in patients with acute myocardial infarction

Abstract:Objective To analyse the relationship between age and treatment with captopril after acute myocardial infarction (AMI).Methods In a randomized trial, 822 patients with a first AMI received conventional medical treatment, including intravenous thrombolytic therapy and oral aspirin or metoprolol, and then were randomly allocated to captopril [dosage from the first 6.25?mg to 25?mg/t.i.d, 209 younger patients (≤64 years), 269 elderly patients (65-75 years)] or conventional treatment only (131 younger patients, 213 elderly). Survival in the four groups was calculated with the Kaplan-Meier method. Multivariate analysis was performed to understand the degree that multi-variables (including age) affect survival in patients taking captopril in the hospital or during long term follow-up.Results The survival of patients who took captopril correlated significantly with age (P<0.001). The survival of the elderly patients on captopril treatment did increase (P<0.0001), but not of the younger ones (P>0.05) during hospitalization. During follow-up, the survival of patients who took captopril correlated insignificantly with age (P>0.05), but both the elderly and the younger patients have good survival rates (all P<0.01) and lower cardiac events (all P<0.01) when they took captopril.Conclusions Captopril exerts a weak effect on the younger patients but a beneficial effect on the elderly patients during hospitalization after AMI. However, there is no difference between the younger and the elderly in the prognosis, both having good survival and lower cardiac events when they take captopril long term during follow-up.

Determination of lisinopril using anion exchange chromatography with integrated pulsed amperometric detection

A rapid and practical method for direct detection of lisinopril in anion exchange chromatography（AEC） has been developed with integrated pulsed amperometric detection（IPAD）.Dionex AS 18（250 mm×2 mm） and AG 18（50 mm×2 mm） columns and 40 mmol/L NaOH solution were used for separation.Multi-step potential waveform parameters were optimized to maximize the signal-to-noise ratio（S/N）.Utilizing the optimized waveform,the repeatability（intra-day） precision and intermediate（inter-day） precision were obtained with relative standard deviation（RSD） of 0.74,0.93,respectively.The limit of quantification（LOQ） and limit of detection（LOD） were found to be 0.37,0.12ng/mL,respectively,with the correlation coefficient of 0.9998 over concentration range 0.01-1μg/mL.The present method was successfully applied to the determination of lisinopril in human plasma.The recoveries of plasma sample spiked by 0.2μg/mL,0.8μg/mL lisinopril were 98.31-103.23%with RSD of 1.41%, 0.61%,respectively.

Gibbs Sampler approach for meta analysis of multiple clinical trials using generalized linear model with random effects

Objective To investigate the use of the Gibbs Sampler method in evaluating the relationship between clinic events and health risks in a meta analysis of multiple clinical trials Methods By using a generalized linear model with random effects, Gibbs Sampler technique was used in a meta analysis of multiple clinical trials of angiotensin converting enzyme (ACE) inhibitors in patients with myocardial infarction (MI) Results When heterogeneity across different trials can not be ignored, compared with the classic method, the odds ratio of relative reinfarction risk estimated by the Gibbs Sampler method would have less variation The gain in the reduction of variation in estimate of the overall odds ratio was 9 52% Conclusion Implementation of the Gibbs Sampler technique in meta analysis of multiple clinical trials has the potential of reducing the inaccuracy caused by heterogeneity across trials

A multi-center, double-blind, randomized, parallel group study to evaluate the effects of two different doses of losartan on morbidity and mortality in Chinese patients with symptomatic heart failure intolerant of angiotensin converting enzyme inhibitor treatment

Background There have been no mortality/morbidity endpoint studies with Iosartan in Chinese heart failure patients. The objective was to evaluate the effects of high-dose vs. low-dose Iosartan on clinical outcomes in Chinese subjects with heart failure.