الملخص
Captopril can have nephrotoxic effects, which are largely attributed to accumulated renin and "escaped" angiotensin II (Ang II). Here we test whether angiotensin converting enzyme-1 (ACE1) inhibition damages kidneys via alteration of renal afferent arteriolar responses to Ang II and inflammatory signaling. C57Bl/6 mice were given vehicle or captopril (60 mg/kg per day) for four weeks. Hypertension was obtained by minipump supplying Ang II (400 ng/kg per min) during the second 2 weeks. We assessed kidney histology by periodic acid-Schiff (PAS) and Masson staining, glomerular filtration rate (GFR) by FITC-labeled inulin clearance, and responses to Ang II assessed in afferent arterioles in vitro. Moreover, arteriolar H2O2 and catalase, plasma renin were assayed by commercial kits, and mRNAs of renin receptor, transforming growth factor-β (TGF-β) and cyclooxygenase-2 (COX-2) in the renal cortex, mRNAs of angiotensin receptor-1 (AT1R) and AT2R in the preglomerular arterioles were detected by RT-qPCR. The results showed that, compared to vehicle, mice given captopril showed lowered blood pressure, reduced GFR, increased plasma renin, renal interstitial fibrosis and tubular epithelial vacuolar degeneration, increased expression of mRNAs of renal TGF-β and COX-2, decreased production of H2O2 and increased catalase activity in preglomerular arterioles and enhanced afferent arteriolar Ang II contractions. The latter were blunted by incubation with H2O2. The mRNAs of renal microvascular AT1R and AT2R remained unaffected by captopril. Ang II-infused mice showed increased blood pressure and reduced afferent arteriolar Ang II responses. Administration of captopril to the Ang II-infused mice normalized blood pressure, but not arteriolar Ang II responses. We conclude that inhibition of ACE1 enhances renal microvascular reactivity to Ang II and may enhance important inflammatory pathways.
الموضوعات
Animals , Mice , Angiotensin II/pharmacology , Arterioles/metabolism , Captopril/pharmacology , Hydrogen Peroxide/pharmacology , Kidneyالملخص
Abstract Ischemic heart disease is the leading cause of death in postmenopausal women. The activity of heart ACE increases whereas the activity of ACE-2 decreases after menopause. The present study was designed to investigate the role of ACE and ACE-2 in the abrogated cardioprotective effect of IPC in OVX rat heart. The heart was isolated from OVX rat and mounted on Langendorff's apparatus for giving intermittent cycles of IPC. The infarct size was estimated using TTC stain, and coronary effluent was analyzed for LDH, CK-MB, and nitrite release. IPC induced cardioprotection was significantly attenuated in the ovariectomized rat heart as compared to the normal rat heart. However, this attenuated cardioprotection was significantly restored by perfusion of DIZE, an ACE-2 activator, and captopril, an ACE inhibitor, alone or in combination noted in terms of decrease in myocardial infarct size, the release of LDH and CK-MB, and also increase in the release of NO as compared to untreated OVX rat heart. Thus, it is suggested that DIZE and captopril, alone or in combination restore the attenuated cardioprotective effect of IPC in OVX rat heart which is due to an increase in ACE-2 activity and decrease in ACE activity after treatment.
الموضوعات
Animals , Female , Rats , Ovariectomy/classification , Myocardial Ischemia , Heart/physiopathology , Infarction/pathology , Myocardial Infarction/pathology , Women , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Captopril/pharmacologyالملخص
This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs), AT1 receptor blockers (ARBs), voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs), on the effects of angiotensin-(1-7) [Ang-(1-7)] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB). To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7), AB male Wistar rats weighing 250–300 g were treated with vehicle or low doses (5 mg·kg-1·day-1, gavage) of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7) in thoracic aorta and coronary arteries, respectively. Ang-(1-7) induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7)-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7) in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7) in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7) and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases.
الموضوعات
Animals , Male , Angiotensin I/pharmacology , Antihypertensive Agents/pharmacology , Aorta, Abdominal/drug effects , Coronary Vessels/drug effects , Peptide Fragments/pharmacology , Amlodipine/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Blood Pressure/drug effects , Calcium Channel Blockers/pharmacology , Captopril/pharmacology , Losartan/pharmacology , Mineralocorticoid Receptor Antagonists/pharmacology , Models, Animal , Rats, Wistar , Reproducibility of Results , Spironolactone/pharmacology , Time Factors , Vasoconstriction/drug effects , Vasodilation/drug effectsالملخص
Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.
الموضوعات
Animals , Male , Renin-Angiotensin System/drug effects , Adipocytes/drug effects , Antihypertensive Agents/pharmacology , Captopril/pharmacology , Rats, Wistar , Adipocytes/metabolism , Losartan/pharmacology , Lipogenesis/drug effects , Fumarates/pharmacology , Amides/pharmacology , Glucose/metabolism , Glycerol/metabolism , Lipolysis/drug effectsالملخص
Central α2-adrenoceptors and the pontine lateral parabrachial nucleus (LPBN) are involved in the control of sodium and water intake. Bilateral injections of moxonidine (α2-adrenergic/imidazoline receptor agonist) or noradrenaline into the LPBN strongly increases 0.3 M NaCl intake induced by a combined treatment of furosemide plus captopril. Injection of moxonidine into the LPBN also increases hypertonic NaCl and water intake and reduces oxytocin secretion, urinary sodium, and water excreted by cell-dehydrated rats, causing a positive sodium and water balance, which suggests that moxonidine injected into the LPBN deactivates mechanisms that restrain body fluid volume expansion. Pretreatment with specific α2-adrenoceptor antagonists injected into the LPBN abolishes the behavioral and renal effects of moxonidine or noradrenaline injected into the same area, suggesting that these effects depend on activation of LPBN α2-adrenoceptors. In fluid-depleted rats, the palatability of sodium is reduced by ingestion of hypertonic NaCl, limiting intake. However, in rats treated with moxonidine injected into the LPBN, the NaCl palatability remains high, even after ingestion of significant amounts of 0.3 M NaCl. The changes in behavioral and renal responses produced by activation of α2-adrenoceptors in the LPBN are probably a consequence of reduction of oxytocin secretion and blockade of inhibitory signals that affect sodium palatability. In this review, a model is proposed to show how activation of α2-adrenoceptors in the LPBN may affect palatability and, consequently, ingestion of sodium as well as renal sodium excretion.
الموضوعات
Animals , Rats , /pharmacology , Body Fluids/drug effects , Homeostasis/drug effects , Parabrachial Nucleus/drug effects , /administration & dosage , Body Fluids/physiology , Captopril/administration & dosage , Captopril/pharmacology , Drinking/drug effects , Furosemide/administration & dosage , Furosemide/pharmacology , Homeostasis/physiology , Imidazoles/administration & dosage , Imidazoles/pharmacology , Parabrachial Nucleus/physiology , Sodium Chloride, Dietaryالملخص
PURPOSE: Limited studies have shown antifibrotic effects of pentoxifylline, captopril, simvastatin, and tamoxifen. No comparisons are available of the effects of these drugs on prevention of renal and bladder changes in partial urethral obstruction (PUO). MATERIALS AND METHODS: The rats were divided into six groups (n=7). The sham-operated rats (group I) only underwent laparotomy and did not receive any treatments. The PUO groups (group II-VI) received normal saline (PUO+NS), pentoxifylline (100 mg/kg/d; PUO+PEN), captopril (35 mg/kg/d; PUO+CAP), simvastatin (15 mg/kg/d; PUO+SIM), or tamoxifen (10 mg/kg/d; PUO+TAM) by gavage for 28 days. Then, the volume and/or length of the kidney components (tubules, vessels, and fibrous tissue) and the bladder components (epithelial and muscular layers, fibrous tissue, fibroblast and fibrocyte number) were quantitatively evaluated on the microscopic sections by use of stereological techniques. RESULTS: The volume of renal and bladder fibrosis was significantly ameliorated in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. Also, the volume and length of the renal tubules and vessels and bladder layers were more significantly protected in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. CONCLUSIONS: Treatment of PUO with PEN was more effective in the prevention of renal and bladder fibrosis and in the preservation of renal and bladder structures.
الموضوعات
Animals , Male , Rats , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Captopril/pharmacology , Disease Models, Animal , Estrogen Antagonists/pharmacology , Free Radical Scavengers/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Kidney/drug effects , Pentoxifylline/pharmacology , Simvastatin/pharmacology , Tamoxifen/pharmacology , Urethral Obstruction/drug therapy , Urinary Bladder Neck Obstruction/drug therapyالملخص
En enfermedades como la hipertensión arterial con frecuencia deben utilizarse tratamientos con dos o más medicamentos, por lo cual el uso incorrecto de ellos puede conllevar a interacciones de fármacos. En el contexto de la hipertensión arterial en América Latina, existen escasos estudios evaluando la magnitud de este problema. Se realizó el presente estudio, observacional, transversal, con un muestreó censal, con el fin de establecer la ocurrencia de potenciales interacciones de fármacos en pacientes con hipertensión arterial de hospitales de 11 municipios de Risaralda, Colombia, agosto 2009 a agosto 2010, usando un algoritmo diseñado para identificar posibles interacciones de fármacos. Se obtuvieron 65.535 registros de prescripción de antihipertensivos, de 3.813 pacientes hipertensos, 28,46% correspondieron con hidroclorotiazida y 2007% enalapril, entre otros. Del total de pacientes 17,60% (IC95% 16,34%-18,82%) presentaron interacciones potenciales de fármacos, siendo la mayor en el municipio Dosquebradas (21,09%; IC95% 18,79%-23,36%). La interacción más frecuente fue enalapril-hidroclorotiazida (45,58% de los pacientes) y la de mayor riesgo y frecuencia fue enalapril-espironolactona (2,41%). estos resultados, reflejan en parte, falta de cumplimiento de normas de tratamiento de la hipertensión arterial, asi como poca implementación de conductas de tratamiento basadas en evidencia, y también posiblemente dificultades en la formación universitaria, falta de programas de educación médica continuada, falta de interés y tiempo para acceder a los alertas y reportes de nuevas condicones de uso de los medicamentos y poca instrucción y enseñanza de la medicina basada en evidencias, aspectos sobre los cuales se debe intervenir integralmente con distintos enfoques
In diseases such as hypertension, commonly treatments with two or more drugs should be used, then their incorrect use can lead to drug interactions. In the context of the hypertension in Latin America, there are few studies assessing the magnitude of this problem. Current, observational, cross-sectional and census study was made in order to establish the potential ocurrence of drug interactions in patients with hypertension from hospitals of 11 municipalities of Risaralba, Colombia, august 2009 to august 2010, using an algorithm designed to identify possible drug interactions. A total of 5.535 antihypertensive prescription records from 3.813 hypertension patients, 28.46% corresponding to hydrochlorothiazide and 20.07% to enalapril, among others, were obtained. From the total of patients 17.60% (95% CI 16.34 %-18.32%) presented potential drug interactions, being highest at the municipality Dosquebradas (21.09%; 95% CI 18.79%-23.36%). Most frequent interaction was enalapril-hydrochlorothiazide (45.58% of patients) and that of higher risk and frequency was enalapril-spironolactone (2.41%). These results, reflected in part, the lack of adherence to hypertension treatment guidelines, as well few implementation of evidenced based treatment conducts, and possibly too defficulties in the university formation, lack of continue medical education programs. Lack of interest and time to access to the alerts and reports of new conditions of drugs use and few instructions and teaching of evidence based medicine, aspects that needs tobe integrally intervened with different approaches
الموضوعات
Female , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Hypertension/diagnosis , Hypertension/drug therapy , Hypertension/therapy , Hospitals/supply & distribution , Drug Prescriptions/standards , Arterial Pressure/physiology , Censuses , Captopril/pharmacology , Colombia/epidemiology , Enalapril/pharmacology , Hydrochlorothiazide/pharmacology , Public Healthالملخص
OBJECTIVE: The association between renal hypoxia and the development of renal injury is well established. However, no adequate method currently exists to non-invasively measure functional changes in renal oxygenation in normal and injured patients. METHOD: R2* quantification was performed using renal blood oxygen level-dependent properties. Five healthy normotensive women (50±5.3 years) underwent magnetic resonance imaging in a 1.5T Signa Excite HDx scanner (GE Healthcare, Waukesha, WI). A multiple fast gradient-echo sequence was used to acquire R2*/T2* images (sixteen echoes from 2.1 ms/slice to 49.6 ms/slice in a single breath hold per location). The images were post-processed to generate R2* maps for quantification. Data were recorded before and at 30 minutes after the oral administration of an angiotensin II-converting enzyme inhibitor (captopril, 25 mg). The results were compared using an ANOVA for repeated measurements (mean + standard deviation) followed by the Tukey test. ClinicalTrials.gov: NCT01545479. RESULTS: A significant difference (p<0.001) in renal oxygenation (R2*) was observed in the cortex and medulla before and after captopril administration: right kidney, cortex = 11.08 ± 0.56ms, medulla = 17.21 ± 1.47ms and cortex = 10.30 ± 0.44ms, medulla = 16.06 ± 1.74ms, respectively; and left kidney, cortex= 11.79 ± 1.85ms, medulla = 17.03 ± 0.88ms and cortex = 10.89 ± 0.91ms, medulla = 16.43 ± 1.49ms, respectively. CONCLUSIONS: This result suggests that the technique efficiently measured alterations in renal blood oxygenation after angiotensin II-converting enzyme inhibition and that it may provide a new strategy for identifying the early stages of renal disease and perhaps new therapeutic targets.
الموضوعات
Female , Humans , Middle Aged , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Captopril/pharmacology , Kidney/metabolism , Oxygen/metabolism , Kidney/blood supply , Magnetic Resonance Imaging , Oxygen/blood , Time Factorsالملخص
FUNDAMENTO: A ressuscitação de parada cardíaca pode apresentar disfunção miocárdica determinada pelo tempo da isquemia, e a inibição da enzima conversora de angiotensina (ECA) pode reduzir a disfunção cardíaca durante a reperfusão. OBJETIVO: Investigar os efeitos da angiotensina-I e diferentes períodos de isquemia na recuperação funcional em corações de ratos isolados. MÉTODOS: Os corações isolados de ratos Wistar (n = 45; 250-300 g) foram submetidos a diferentes períodos de isquemia global (20, 25 ou 30 min) e reperfundidos (30 min) com o tampão Krebs-Henseleit, ou com a adição de 400 nmol/L de angiotensina-I, ou com 400 nmol/L de angiotensina-I + 100 µmol/L de captopril durante o período de reperfusão. RESULTADOS: A derivada positiva máxima de pressão (+dP/dt max) e o produto frequência-pressão foram reduzidos nos corações expostos à isquemia de 25 min (~ 73 por cento) e à isquemia de 30 min (~ 80 por cento) vs. isquemia de 20 min. A pressão diastólica final do ventrículo esquerdo (PDFVE) e a pressão de perfusão (PP) foram aumentadas nos corações expostos à isquemia de 25 min (5,5 e 1,08 vezes, respectivamente) e à isquemia de 30 min (6 e 1,10 vezes, respectivamente) vs. isquemia de 20 min. A angiotensina-I ocasionou uma diminuição no +dP/dt max e no produto frequência-pressão (~ 85-94 por cento) em todos os períodos de isquemia e um aumento na PDFVE e na PP (6,9 e 1,25 vezes, respectivamente) apenas na isquemia de 20 min. O captopril foi capaz de reverter parcial ou completamente os efeitos da angiotensina-I na recuperação funcional nas isquemias de 20 e 25 min CONCLUSÃO: Os dados sugerem que a angiotensina-II participa direta ou indiretamente no dano pós-isquêmico e que a capacidade de um inibidor da ECA atenuar esse dano depende do tempo de isquemia.
BACKGROUND: Cardiac arrest resuscitation can present myocardial dysfunction determined by ischemic time, and inhibition of the angiotensin-converting enzyme (ACE) can reduce cardiac dysfunction during reperfusion. OBJECTIVE: To investigate the effects of angiotensin-I and different periods of ischemia on functional recovery in isolated rat hearts. METHODS: Isolated hearts from Wistar rats (n=45; 250-300 g) were submitted to different periods of global ischemia (20, 25 or 30 min) and reperfused (30 min) with Krebs-Henseleit buffer alone or with the addition of 400 nmol/L angiotensin-I, or 400 nmol/L angiotensin-I + 100 mmol/L captopril along the reperfusion period. RESULTS: The maximal positive derivative of pressure (+dP/dt max) and rate-pressure product were reduced in hearts exposed to 25 min ischemia (~73 percent) and 30 min ischemia (~80 percent) vs. 20 min ischemia. Left ventricular end-diastolic pressure (LVEDP) and perfusion pressure (PP) were increased in hearts exposed to 25 min ischemia (5.5 and 1.08 fold, respectively) and 30 min ischemia (6 and 1.10 fold, respectively) vs. 20 min ischemia. Angiotensin-I caused a decrease in +dP/dt max and rate-pressure product (~85-94 percent) in all ischemic periods and an increase in LVEDP and PP (6.9 and 1.25 fold, respectively) only at 20 min ischemia. Captopril was able to partially or completely reverse the effects of angiotensin-I on functional recovery in 20 min and 25 min ischemia. CONCLUSION: These data suggest that angiotensin-II directly or indirectly participates in the post-ischemic damage, and the ability of an ACE inhibitor to attenuate this damage depends on ischemic time.
الموضوعات
Animals , Male , Rats , Angiotensin I/pharmacology , Myocardial Ischemia/drug therapy , Myocardial Reperfusion/methods , Recovery of Function/drug effects , Analysis of Variance , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Captopril/pharmacology , Models, Animal , Myocardial Ischemia/physiopathology , Myocardial Reperfusion Injury/prevention & control , Random Allocation , Rats, Wistar , Time Factorsالملخص
This paper describes the studies performed with the candidate Certified Reference Material (CRM) of captopril, the first CRM of an active pharmaceutical ingredient (API) in Brazil, including determination of impurities (organic, inorganic and volatiles), homogeneity testing, short- and long-term stability studies, calculation of captopril content using the mass balance approach, and estimation of the associated measurement uncertainty.
Este artigo descreve os estudos realizados com o candidato a Material de Referência Certificado (MRC) de captopril, primeiro MRC de fármacos no Brasil, incluindo a determinação de impurezas (orgânicas, inorgânicas e voláteis), testes de homogeneidade, testes de estabilidade de curta e longa duração, cálculo do teor de captopril por balanço de massa e estimativa da incerteza de medição associada ao valor certificado.
الموضوعات
Captopril/analysis , Captopril/pharmacology , Captopril/chemistry , Pharmaceutical Preparations/standards , Chromatography, High Pressure Liquid , Drug Contamination/statistics & numerical data , Evaluation Studies as Topic , Quality Control , Reference Standardsالملخص
This paper describes the validation of a reversed-phase high performance liquid chromatography method (RP-HPLC) with diode array detection (DAD) for determination of related substances (impurities from organic synthesis and degradation products) of captopril according to the Brazilian Pharmacopeia IV. The aim of this study was to guarantee the method accuracy for quantification of related substances, an essential requisite to determine, using the mass balance approach, the captopril content in the first Brazilian certified reference material (CRM) of an active pharmaceutical ingredient (API), developed by Inmetro. The captopril instability in solution is discussed and the captopril content determined by mass balance is compared to the results from titration and differential scanning calorimetry (DSC).
Este artigo descreve a validação de método de cromatografia líquida de alta eficiência em fase reversa (CLAE-RP) com detector de fotodiodos (DAD) para determinação de substâncias relacionadas (impurezas orgânicas de síntese e produtos de degradação) de captopril segundo Farmacopéia Brasileira IV ed. Este estudo teve como objetivo garantir que o método é capaz de quantificar com exatidão o teor de substâncias relacionadas, um requisito essencial para que o teor de captopril seja determinado por balanço de massa no primeiro material de referência certificado (MRC) de fármacos brasileiro, o qual foi desenvolvido pelo Inmetro. A instabilidade do captopril em solução é discutida em detalhes e o teor de captopril determinado por balanço de massa é comparado com aqueles obtidos por titulação e por calorimetria exploratória diferencial (DSC).
الموضوعات
Captopril/analysis , Captopril/pharmacology , Captopril/isolation & purification , Chemical Compounds/methods , Chromatography, High Pressure Liquid/methods , Diagnosis/analysis , Drug Contamination , Quality Control , Chemistry, Pharmaceutical/methodsالملخص
The generation of bradykinin (BK; Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) in blood and kallidin (Lys-BK) in tissues by the action of the kallikrein-kinin system has received little attention in non-mammalian vertebrates. In mammals, kallidin can be generated by the coronary endothelium and myocytes in response to ischemia, mediating cardioprotective events. The plasma of birds lacks two key components of the kallikrein-kinin system: the low molecular weight kininogen and a prekallikrein activator analogous to mammalian factor XII, but treatment with bovine plasma kallikrein generates ornitho-kinin [Thr6,Leu8]-BK. The possible cardioprotective effect of ornitho-kinin infusion was investigated in an anesthetized, open-chest chicken model of acute coronary occlusion. A branch of the left main coronary artery was reversibly ligated to produce ischemia followed by reperfusion, after which the degree of myocardial necrosis (infarct size as a percent of area at risk) was assessed by tetrazolium staining. The iv injection of a low dose of ornitho-kinin (4 µg/kg) reduced mean arterial pressure from 88 ± 12 to 42 ± 7 mmHg and increased heart rate from 335 ± 38 to 402 ± 45 bpm (N = 5). The size of the infarct was reduced by pretreatment with ornitho-kinin (500 µg/kg infused over a period of 5 min) from 35 ± 3 to 10 ± 2 percent of the area at risk. These results suggest that the physiological role of the kallikrein-kinin system is preserved in this animal model in spite of the absence of two key components, i.e., low molecular weight kininogen and factor XII.
الموضوعات
Animals , Bradykinin/analogs & derivatives , Cardiotonic Agents/therapeutic use , Kinins/drug effects , Myocardial Infarction/prevention & control , Vasodilator Agents/therapeutic use , Acute Disease , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Blood Pressure/drug effects , Bradykinin/therapeutic use , Chickens , Captopril/pharmacology , Disease Models, Animal , Ischemic Preconditioning, Myocardial , Kinins/blood , Kinins/physiology , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Preoperative Care , Vascular Resistance/drug effectsالملخص
To study the effect of metronidazole, tinidazole, captopril and valsartan on the levels of zinc and magnesium in the serum of rabbits and humans and the histology of taste buds in rabbits. We conducted this study in the College of Medicine and Teaching Hospital, Basrah, Iraq from April 2005 to September 2006. It was in 2 parts: a clinical observational study of 54 patients treated with one of these drugs. The second part involved oral administration of metronidazole [45mg/kg], tinidazole [40mg/kg], captopril [3mg/kg] or valsartan [3mg/kg] or normal saline to 42 rabbits randomly. Serum zinc and magnesium were measured, and histological sections of tongues were examined for taste buds. In rabbits, oral metronidazole [13.6%] or tinidazole [7%] resulted in a significant reduction in serum zinc. Reductions in captopril [6.7%] and valsartan [4.2%] were smaller and insignificant. Body weight increased by 15.5gm [1391 +/- 225.3 gm to 1407 +/- 223.2 gm] in the control group, a lesser increase of approximately 8 gm, was found in the metronidazole group [1452 +/- 222.6 gm to 1460 +/- 221.9 gm]. Rabbit tongues showed moderate degeneration of taste buds caused by tinidazole, severe degeneration of captopril and minimal changes of valsartan. In humans, the drugs did not result in significant changes in serum zinc or magnesium. Approximately 73.3% of patients in the metronidazole group and 11.1% in the valsartan group had taste changes. It is concluded that metronidazole and tinidazole, but not captopril or valsartan resulted in a significant reduction of zinc level in rabbit, but not in human. Captopril and not valsartan caused severe degeneration in taste buds. Serum zinc level seems not to be related to taste buds changes
الموضوعات
Humans , Animals, Laboratory , Magnesium/blood , Metronidazole/pharmacology , Tinidazole/pharmacology , Captopril/pharmacology , Taste Buds/drug effects , Tetrazoles/pharmacology , Valine/analogs & derivatives , Taste/drug effects , Rabbitsالملخص
Hypertensive crisis is defined as a severe elevation in blood pressure [BP] without target organ injury. There are few data about the efficacy and safety of comparative oral antihypertensive drugs. To compare the efficacy and safety of oral captopril [25 mg] and nicardipine [20 mg] in hypertensive crisis. This prospective, randomized study included 50 patients attended at the emergency department with a hypertensive crisis [arterial blood pressure of at least 180/110 mmHg without target organ damage confirmed after 15 min of rest. Systolic [SBP] and diastolic blood pressure [DBP] and heart rate [HR] were assessed at several intervals during 4 h after the drug administration. Therapeutic success was defined by a SBP = 160 and DBP = 90 mmHg two hours after drug administration. The initial clinical characteristics as age, sex, initial systolic and diastolic BP and HR were no different in the two groups. BP levels started to significantly decrease within 15 minutes. At 2 hours, SBP and DBP dropped were similar in captopril group and nicardipine group, respectively to 162/94 vs 161/89 mmHg; p=ns. The therapeutic success at the second hour has been obtained in 68% of cases in the two groups. Age >70 years was a predictor's factor of therapeutic failure in the captopril group. Heart rate significantly dropped after 30 min in the captopril group [82.3 +/- 11.8 vs 77.6 +/- 12.7 c/min; p=0.037]. This effect was maintained over four hours. There were no side effects in this study. Oral captopril or nicardipine are efficacy and safe in the treatment of hypertensive crisis
الموضوعات
Humans , Male , Female , Captopril/pharmacology , Nicardipine/pharmacology , Administration, Oral , Prospective Studies , Randomized Controlled Trials as Topic , Blood Pressure , Systole , Diastole , Heart Rateالملخص
The purpose of this study was to explore the role of L-5-hydroxytryptophan (L-HTP) and its relationship with the renin-angiotensin system (RAS) on the drinking behavior in Japanese quails. Normally-hydrated quails that received injections of L-HTP (12.5; 25 and 50 mg.kg-1) by the intracoelomic route (ic) expressed an increase in water intake, which was inhibited by captopril, an angiotensin converting enzyme (ACE) inhibitor. In addition, captopril also induced such a response in birds under previous fluid deprivation. High doses of captopril (35-70 mg.kg-1, sc) in normally-hydrated quails decreased the spontaneous water intake while low doses of captopril (2-5 mg.kg-1, sc) did not prompt water intake after L-HTP administration. Losartan, an AT1 receptor antagonist in mammals, did not change the water intake levels in normally-hydrated or water-deprivated birds. Serotonin (5-HT) injections did not provoke its known dipsogenic response.
O objetivo deste estudo foi investigar a influência do L-5-hidroxitriptofano (L-HTP) e sua relação com o sistema renina-angiotensina (SRA) no comportamento dipsogênico de codornas. Codornas normohidratadas que receberam L-HTP em diferentes doses (12,5; 25 e 50 mg.kg-1) por via intracelomática (ic) expressaram um aumento na ingestão de água, o qual foi suprimido pela administração prévia de captopril (inibidor da ECA-enzima conversora de angiotensina). Esta ação inibitória do captopril, em menor intensidade, foi também evidenciada em aves previamente submetidas ao jejum hídrico. O tratamento isolado com captopril (35-70 mg.kg-1) reduziu consideravelmente a ingestão espontânea de água em codornas normohidratadas, enquanto baixas doses (2-5 mg.kg-1) não provocaram aumento na ingestão de água induzida pelo L-HTP. Losartan, um antagonista de receptores AT1 em mamíferos, não foi capaz de modificar os níveis de ingestão hídrica, tanto em aves normohidratadas quanto em aves privadas de água. Serotonina aplicada perifericamente não promoveu a conhecida resposta dipsogênica de mamíferos.
الموضوعات
Animals , Male , /pharmacology , Coturnix/physiology , Drinking Behavior/drug effects , Renin-Angiotensin System/drug effects , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Captopril/pharmacology , Drinking Behavior/physiology , Renin-Angiotensin System/physiology , Time Factorsالملخص
The effects of captopril and Ang II on morphine-induced conditioned place preference (CPP) and morphine self-administration in male Wistar rat were investigated. In CPP experiment, injection of captopril before test significantly decreased the difference of the time spent in compartment A between pre- and post-conditioning compared to morphine group. In self- administration experiment number of active lever pressing was significantly greater than passive in morphine group. In captopril group number of active lever pressing was significantly lower than morphine group however, there was not significant difference between active and passive lever pressed number. The results showed that captopril significantly decreased morphine-induced conditional place preference and morphine self-administration but the effect of Ang II was not significant. It can be concluded that RAS may have a role in rewarding properties of morphine.
الموضوعات
Angiotensin II/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Captopril/pharmacology , Conditioning, Psychological , Male , Morphine/administration & dosage , Rats , Rats, Wistar , Renin-Angiotensin System/drug effects , Reward , Self Administrationالملخص
Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers antagonists (ARAs) are widely used compounds in various cardiovascular disorders. ACEIs, but not ARAs, inhibit the enzyme dipeptidyl carboxypeptidase which is involved in the conversion of angiotensin I to II and degradation of kinins like bradykinin and substance P. Bradykinin and substance P are potent mediators of inflammation and pain. Hence the study was undertaken to evaluate the effects of captopril (an ACEI) and losartan (an ARA-AT1 receptor antagonist) on thermal and chemical induced nocioception by employing hot plate and acetic acid induced writhing tests respectively in mice. Inbred albino mice weighing between 25-30 g were used and they were divided into two sets, each set containing 7 groups. Control groups received normal saline and the remaining six groups received three doses (0.5, 1 and 2 mg/kg) of captopril and three doses (0.5, 1 and 2 mg/kg) of losartan. Drugs were administered intraperitoneally fifteen minutes before placing the animal over the hot plate or 30 minutes before injecting 0.6% acetic acid. Both drugs dose dependently reduced the reaction time in hot plate method. In chemical induced writhing test, both the drugs reduced the latency of onset of writhing and in captopril pretreated groups, acetic acid induced sustained abdominal contraction without any intermittent relaxation. However, in losartan pretreated animals acetic acid just increased the number of writhings without sustained abdominal contraction. Thus, our study suggests that both drugs have hyperalgesic effects.
الموضوعات
Angiotensin II/physiology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Captopril/pharmacology , Dose-Response Relationship, Drug , Female , Hyperalgesia/chemically induced , Losartan/pharmacology , Male , Mice , Reaction Time/drug effectsالملخص
The present study evaluated the acute effect of the intraperitoneal (ip) administration of a whey protein hydrolysate (WPH) on systolic arterial blood pressure (SBP) and renal sodium handling by conscious spontaneously hypertensive rats (SHR). The ip administration of WPH in a volume of 1 ml dose-dependently lowered the SBP in SHR 2 h after administration at doses of 0.5 g/kg (0.15 M NaCl: 188.5 ± 9.3 mmHg vs WPH: 176.6 ± 4.9 mmHg, N = 8, P = 0.001) and 1.0 g/kg (0.15 M NaCl: 188.5 ± 9.3 mmHg vs WPH: 163.8 ± 5.9 mmHg, N = 8, P = 0.0018). Creatinine clearance decreased significantly (P = 0.0084) in the WPH-treated group (326 ± 67 æL min-1 100 g body weight-1) compared to 0.15 M NaCl-treated (890 ± 26 æL min-1 100 g body weight-1) and captopril-treated (903 ± 72 æL min-1 100 g body weight-1) rats. The ip administration of 1.0 g WPH/kg also decreased fractional sodium excretion to 0.021 ± 0.019 percent compared to 0.126 ± 0.041 and 0.66 ± 0.015 percent in 0.15 M NaCl and captopril-treated rats, respectively (P = 0.033). Similarly, the fractional potassium excretion in WPH-treated rats (0.25 ± 0.05 percent) was significantly lower (P = 0.0063) than in control (0.91 ± 0.15 percent) and captopril-treated rats (1.24 ± 0.30 percent), respectively. The present study shows a decreased SBP in SHR after the administration of WPH associated with a rise in tubule sodium reabsorption despite an angiotensin I-converting enzyme (ACE)-inhibiting in vitro activity (IC50 = 0.68 mg/mL). The present findings suggest a pathway involving ACE inhibition but measurements of plasma ACE activity and angiotensin II levels are needed to support this suggestion.
الموضوعات
Animals , Male , Rats , Protein Hydrolysates/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Arterial Pressure/drug effects , Milk Proteins/pharmacology , Captopril/pharmacology , Electrophoresis, Capillary , Protein Hydrolysates/administration & dosage , Kidney Function Tests , Potassium/urine , Milk Proteins/administration & dosage , Rats, Inbred SHR , Sodium/urineالملخص
We determined if the dorsal raphe nucleus (DRN) exerts tonic control of basal and stimulated sodium and water intake. Male Wistar rats weighing 300-350 g were microinjected with phosphate buffer (PB-DRN, N = 11) or 1 æg/0.2 æl, in a single dose, ibotenic acid (IBO-DRN, N = 9 to 10) through a guide cannula into the DRN and were observed for 21 days in order to measure basal sodium appetite and water intake and in the following situations: furosemide-induced sodium depletion (20 mg/kg, sc, 24 h before the experiment) and a low dose of dietary captopril (1 mg/g chow). From the 6th day after ibotenic acid injection IBO-DRN rats showed an increase in sodium appetite (12.0 ± 2.3 to 22.3 ± 4.6 ml 0.3 M NaCl intake) whereas PB-DRN did not exceed 2 ml (P < 0.001). Water intake was comparable in both groups. In addition to a higher dipsogenic response, sodium-depleted IBO-DRN animals displayed an increase of 0.3 M NaCl intake compared to PB-DRN (37.4 ± 3.8 vs 21.6 ± 3.9 ml 300 min after fluid offer, P < 0.001). Captopril added to chow caused an increase of 0.3 M NaCl intake during the first 2 days (IBO-DRN, 33.8 ± 4.3 and 32.5 ± 3.4 ml on day 1 and day 2, respectively, vs 20.2 ± 2.8 ml on day 0, P < 0.001). These data support the view that DRN, probably via ascending serotonergic system, tonically modulates sodium appetite under basal and sodium depletion conditions and/or after an increase in peripheral or brain angiotensin II.
الموضوعات
Animals , Male , Rats , Ibotenic Acid/toxicity , Excitatory Amino Acid Agonists/toxicity , Appetite/drug effects , Drinking/drug effects , Raphe Nuclei/drug effects , Sodium, Dietary , Appetite/physiology , Buffers , Captopril/pharmacology , Furosemide/pharmacology , Drinking/physiology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Sodium Potassium Chloride Symporter Inhibitors/pharmacology , Phosphates , Rats, Wistar , Time Factorsالملخص
Contrast induced nephropathy is a potential cause of mortality and morbidity in patients undergoing angiography-angioplasty. Except for hydrating and probably low - isoosmolar contrast agents in high risk groups, other modalities have not provided benefit. We investigated preventive effects of captopril for contrast induced nephropathy during angiography-angioplasty. In a double blind placebo controlled clinical trial, 88 patients were randomized to two groups: 42 patients received captopril [12.5 mg] every 8 hours from 2 hours before the procedure until 48 hours thereafter, and 46 patients received placebo in the same manner. Serum creatinine was measured before and 48 hours after angioplasty. The data were analyzed by SPSS software, using unpaired student t-test for comparing mean creatinine rise in both groups and paired student t-test for the changes in serum creatinine in each group. The mean creatinine rise in captopril group [0.214 mg/dl] and placebo group [0.226 mg/dl] were not significantly different. The incidence of acute renal failure [creatinine rise more than 0.5 mg/dl] in the captopril [11.9%] and placebo group [10.8%] were not significantly different. Captopril does not effectively prevent contrast nephropathy, but it is not harmful for renal function and can be administered safely during angiography - angioplasty in patients with normal renal function. However, the effect of captopril in patients with high- risk characteristics remains to be clarified. Of note, we found a trend for less creatinine rise in diabetics who received captopril during the procedure in comparison to diabetics who received placebo