-
Journal of Neuroinflammation Sep 2022Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an...
Evidence from experimental and clinical studies implicates immuno-inflammatory responses as playing an important role in epilepsy-induced brain injury. Captopril, an angiotensin-converting enzyme inhibitor (ACEi), has previously been shown to suppress immuno-inflammatory responses in a variety of neurological diseases. However, the therapeutic potential of captopril on epilepsy remains unclear. In the present study, Sprague Dawley (SD) rats were intraperitoneally subjected to kainic acid (KA) to establish a status epilepticus. Captopril (50 mg/kg, i.p.) was administered daily following the KA administration from day 3 to 49. We found that captopril efficiently suppressed the KA-induced epilepsy, as measured by electroencephalography. Moreover, captopril ameliorated the epilepsy-induced cognitive deficits, with improved performance in the Morris water maze, Y-maze and novel objective test. RNA sequencing (RNA-seq) analysis indicated that captopril reversed a wide range of epilepsy-related biological processes, particularly the glial activation, complement system-mediated phagocytosis and the production of inflammatory factors. Interestingly, captopril suppressed the epilepsy-induced activation and abnormal contact between astrocytes and microglia. Immunohistochemical experiments demonstrated that captopril attenuated microglia-dependent synaptic remodeling presumably through C3-C3ar-mediated phagocytosis in the hippocampus. Finally, the above effects of captopril were partially blocked by an intranasal application of recombinant C3a (1.3 μg/kg/day). Our findings demonstrated that captopril reduced the occurrence of epilepsy and cognitive impairment by attenuation of inflammation and C3-mediated synaptic phagocytosis. This approach can easily be adapted to long-term efficacy and safety in clinical practice.
Topics: Animals; Captopril; Cognitive Dysfunction; Epilepsy; Inflammation; Kainic Acid; Phagocytosis; Rats; Rats, Sprague-Dawley
PubMed: 36104755
DOI: 10.1186/s12974-022-02587-8 -
Archives of Pathology & Laboratory... Nov 2003Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been... (Comparative Study)
Comparative Study
CONTEXT
Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported.
OBJECTIVE
To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.
DESIGN
Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature.
RESULTS
The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously.
CONCLUSION
Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.
Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Chemical and Drug Induced Liver Injury, Chronic; Cholangiopancreatography, Endoscopic Retrograde; Cholestasis, Intrahepatic; Enalapril; Fosinopril; Humans; Jaundice; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Ramipril
PubMed: 14567716
DOI: 10.5858/2003-127-1493-RH -
British Heart Journal Aug 1985Plasma free captopril concentrations and haemodynamic response to captopril were studied in 20 patients with severe chronic heart failure. A 25 mg oral dose of captopril...
Plasma free captopril concentrations and haemodynamic response to captopril were studied in 20 patients with severe chronic heart failure. A 25 mg oral dose of captopril produced a 36% reduction in systemic vascular resistance, with individual responses varying from 13% to 64%. Mean systemic pressure fell by 20% and cardiac output rose 28%. The absorption of captopril was rapid. Peak plasma free captopril concentration occurred at 45 minutes after the dose and was followed by a smaller second peak. Peak plasma free captopril concentrations varied more than 20-fold but did not correlate with the maximal reduction in systemic vascular resistance. Elimination half life was seven hours. Fourteen patients were restudied after 1-2 months of captopril treatment and 12 showed symptomatic benefit. There was a sustained improvement in haemodynamic state and in non-invasive indices of myocardial function. During long term treatment the predose plasma free captopril concentration correlated well with dosage, but steady state captopril concentrations did not show a significant relation with haemodynamic response. On a dosage regimen of 25-50 mg three times daily the morning predose plasma free captopril concentration and plasma renin activity were relatively low and suggested that maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval.
Topics: Aged; Captopril; Heart Failure; Hemodynamics; Humans; Kinetics; Middle Aged; Proline; Renin; Time Factors; Vascular Resistance
PubMed: 3893490
DOI: 10.1136/hrt.54.2.160 -
Antiviral Research Jul 2023Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with...
Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.
Topics: Humans; Mice; Animals; SARS-CoV-2; COVID-19; Captopril; Myocytes, Cardiac; Angiotensin-Converting Enzyme Inhibitors; Inflammation; Apoptosis
PubMed: 37207821
DOI: 10.1016/j.antiviral.2023.105636 -
Langmuir : the ACS Journal of Surfaces... Aug 2021The peptide angiotensin-converting enzyme inhibitors captopril and lisinopril are unexpectedly shown to exhibit critical aggregation concentration (CAC) behavior through...
The peptide angiotensin-converting enzyme inhibitors captopril and lisinopril are unexpectedly shown to exhibit critical aggregation concentration (CAC) behavior through measurements of surface tension, electrical conductivity, and dye probe fluorescence. These three measurements provide similar values for the CAC, and there is also evidence from circular dichroism spectroscopy for a possible conformational change in the peptides at the same concentration. Cryogenic transmission electron microscopy indicates the formation of micelle-like aggregates above the CAC, which can thus be considered a critical micelle concentration, and the formation of aggregates with a hydrodynamic radius of ∼6-7 nm is also evidenced by dynamic light scattering. We also used synchrotron radiation X-ray diffraction to determine the single-crystal structure of captopril and lisinopril. Our results improve the accuracy of previous data reported in the literature, obtained using conventional X-ray sources. We also studied the structure of aqueous solutions containing captopril or lisinopril at high concentrations. The aggregation may be driven by intermolecular interactions between the proline moiety of captopril molecules or between the phenylalanine moiety of lisinopril molecules.
Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Lisinopril
PubMed: 34292730
DOI: 10.1021/acs.langmuir.1c01340 -
Nature Communications Sep 2023Endothelial dysfunction represents a major cardiovascular risk factor for hypertension. Sp1 and Sp3 belong to the specificity protein and Krüppel-like transcription...
Endothelial dysfunction represents a major cardiovascular risk factor for hypertension. Sp1 and Sp3 belong to the specificity protein and Krüppel-like transcription factor families. They are ubiquitously expressed and closely associated with cardiovascular development. We investigate the role of Sp1 and Sp3 in endothelial cells in vivo and evaluate whether captopril, an angiotensin-converting enzyme inhibitor (ACEI), targets Sp1/Sp3 to exert its effects. Inducible endothelial-specific Sp1/Sp3 knockout mice are generated to elucidate their role in endothelial cells. Tamoxifen-induced deletion of endothelial Sp1 and Sp3 in male mice decreases the serum nitrite/nitrate level, impairs endothelium-dependent vasodilation, and causes hypertension and cardiac remodeling. The beneficial actions of captopril are abolished by endothelial-specific deletion of Sp1/Sp3, indicating that they may be targets for ACEIs. Captopril increases Sp1/Sp3 protein levels by recruiting histone deacetylase 1, which elevates deacetylation and suppressed degradation of Sp1/Sp3. Sp1/Sp3 represents innovative therapeutic target for captopril to prevent cardiovascular diseases.
Topics: Male; Animals; Mice; Blood Pressure; Captopril; Endothelial Cells; Hypertension; Mice, Knockout; Endothelium
PubMed: 37735515
DOI: 10.1038/s41467-023-41567-1 -
Yakugaku Zasshi : Journal of the... Jan 2006Interactions between carnosine (beta-alanyl-L-histidine), being plentiful in skeletal muscles and neuronal tissues, and captopril, a widely used angiotensin-converting...
Interactions between carnosine (beta-alanyl-L-histidine), being plentiful in skeletal muscles and neuronal tissues, and captopril, a widely used angiotensin-converting enzyme (ACE) inhibitor, were examined concerning free radical scavenging activity and ACE activity in vitro. Not only captopril, but also carnosine, at concentrations less than those ordinarily found in muscles and neuronal tissues, significantly scavenged 2,2'-azinobis (3-ethylbenzothiazoline-6-sulphonate) (ABTS) radical cations, and inhibited ACE activity. Cupric ions reversed the ABTS scavenging activity of carnosine and captopril, whereas cupric ions strengthened the inhibitory action of carnosine on ACE activity. In contrast, cupric ions antagonized the inhibition of ACE activity induced by ethylenediaminetetraacetic acid, indicating that the inhibitory effect of carnosine on ACE activity is not related to the chelating action of carnosine. On the other hand, carnosine and captopril synergistically enhanced the free radical scavenging activity, but not the inhibitory effect on the ACE activity. These data suggest that carnosine in its concurrent use with captopril could act as a beneficial free radical scavenger, with less danger of overdose, in the inhibition of ACE activity.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Captopril; Carnosine; Cattle; Drug Synergism; Free Radical Scavengers; In Vitro Techniques
PubMed: 16394648
DOI: 10.1248/yakushi.126.37 -
Aging Cell Dec 2022Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the...
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
Topics: Mice; Male; Female; Animals; Acarbose; Sirolimus; Captopril; Longevity; Aging
PubMed: 36179270
DOI: 10.1111/acel.13724 -
Journal of Clinical Hypertension... Apr 2006Following a hypertension symposium in Rochester, NY, in October 2005, a roundtable was convened to discuss hypertensive emergencies. Dr. Marvin Moser, Clinical Professor...
Following a hypertension symposium in Rochester, NY, in October 2005, a roundtable was convened to discuss hypertensive emergencies. Dr. Marvin Moser, Clinical Professor of Medicine at the Yale University School of Medicine, New Haven, CT, moderated the session, which included Dr. Joseph L. Izzo, Jr., Professor of Medicine at the State University of New York at Buffalo, Buffalo, NY, and Dr. John Bisognano, Associate Professor of Medicine at the University of Rochester School of Medicine, Rochester, NY.
Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Clonidine; Diuretics; Emergencies; Emergency Medical Services; Humans; Hypertension; Labetalol
PubMed: 16596031
DOI: 10.1111/j.1524-6175.2006.05274.x -
British Medical Journal (Clinical... Oct 1983
Topics: Arthritis, Rheumatoid; Captopril; Humans; Proline
PubMed: 6416376
DOI: 10.1136/bmj.287.6401.1299