Ramipril can alleviate the accumulation of renal mesangial matrix in rats with diabetic nephropathy by inhibiting insulin-like growth factor-1

Abstract Purpose: To investigate the impact of Ramipril (RAM) on the expressions of insulin-like growth factor-1 (IGF-1) and renal mesangial matrix (RMM) in rats with diabetic nephropathy (DN). Methods: The Sprague Dawley rats were divided into normal control (NC) group (n = 12), DN group (n = 11), and DN+RAM group (n = 12). The ratio of renal weight to body weight (RBT), fasting blood glucose (FBG), HbA1c, 24-h urine protein (TPU), blood urea nitrogen (BUN), creatinine (Cr), renal pathological changes, the levels of IGF-1, fibronectin (FN), type IV collagen (Col-IV), and matrix metalloproteinases (MMP)-2 were compared among the groups. Results: Compared with NC group, the RBT, FBG, HbA1c, TPU, BUN, Cr, and RMM in DN group were significantly increased (P < 0.05), the IGF-1, FN, and Col-IV were significantly upregulated (P < 0.05), while MMP was significantly downregulated (P < 0.05). Compared with DN group, the indexes except for the FBG and HbA1c in DN+RAM group were significantly improved (P < 0.05), among which IGF-1 exhibited significant positive correlation with TPU(r=0.937), FN(r=0.896) and Col-IV(r=0.871), while significant negative correlation with MMP-2 (r=-0.826) (P<0.05). Conclusion: RAM may protect the kidneys by suppressing IGF-1 and mitigating the accumulation of RMM.

Efeitos do ramipril sobre a doença periodontal induzida experimentalmente em ratos / Effect of ramipril on periodontal disease experimentally induced in rats

A doença periodontal (DP) corresponde a um grupo de doenças inflamatórias que acomete as estruturas periodontais de proteção e de suporte e pode levar à perda dentária. A etiologia está relacionada à placa dentobacteriana que leva à produção de grande quantidade de citocinas pró-inflamatórias importantes na destruição tecidual. A angiotensina (Ang) II também pode contribuir para a inflamação e destruição tecidual no periodonto agindo como mediador chave. A utilização de drogas que atuem na cascata do sistema renina-angiotensina (SRA) poderia interferir no estado de saúde ou inflamação do tecido mole, na perda óssea alveolar e na expressão gênica dos componentes do SRA e mediadores inflamatórios. Portanto, o objetivo do presente trabalho foi investigar se o ramipril, um inibidor da enzima conversora de angiotensina (ECA), altera a progressão da DP induzida experimentalmente em ratos. Foi utilizado o modelo de indução da DP por colocação de ligadura ao redor do primeiro molar inferior direito de ratos. Os grupos com 10 animais cada, foram divididos em tratados com ramipril (via gavagem 10mg/kg/dia) ou água (veículo) durante 14 e 21 dias e o grupo Sham submetido à indução fictícia da DP. Outros quatro grupos foram submetidos ao pré-tratamento com ramipril durante os períodos de 7 e 14 dias e após a indução da DP e tratados por 14 ou 21 dias. As metodologias de avaliação foram: extração de RNA total, transcrição reversa seguida de reação em cadeia da polimerase quantitativa (RTqPCR),análises histológica e da perda óssea alveolar. Os dados foram analisados por meio de gráficos e os resultados foram submetidos à análise unidirecional de variância (ANOVA) e representaram médias e respectivos desvios-padrão. Diferenças entre os grupos foram consideradas estatisticamente significativas quando p < 0,05. Com base nos resultados obtidos pode-se concluir que o ramipril foi capaz de reduzir a progressão da perda óssea no grupo tratado por 21 dias (DP-21d-Rami)...

Periodontitis (PD) consists of a group of inflammatory diseases that affect the protecting and supporting periodontal structures, and may lead to tooth loss. Theetiology is related to the dentobacterial plaque that produces a large amount of proinflammatory cytokines with an important action on tissue destruction. Angiotensin(Ang) II may also contribute to the inflammation and periodontal tissue destruction byacting as a key mediator. The use of drugs that affect the cascade of the reninangiotensin system (RAS) might interfere with the healthy or inflammatory status ofthe soft tissue, alveolar bone loss and gene expression of RAS components and inflammatory mediators. Therefore, the aim of this work was to evaluate whether ramipril, an angiotensin-converting enzyme (ACE) inhibitor, alters the progression of experimentally-induced PD in rats. The model of PD induction by placement of a silk ligature around the right lower first molar was used. Groups with 10 animals each were divided into ramipril-treated (10 mg/kg/day, via gavage), water (vehicle) and thesham surgery group (sham) for 7 or 14 days previously to PD induction and after this period the drug was administered for 14 and 21 days. The techniques employed were: total RNA extraction, reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) as well as histological and alveolar bone loss analyses. Data were analyzed by means of graphs and the results submitted to unidirectional analysis of variance (ANOVA) and represent the means with respective standard deviations. Differences between groups were considered statistically significant whenp < 0.05. Based on the results obtained in this work, it was concluded that ramipril was able to reduce the progression of alveolar bone loss in the group treated for 21...

Efeitos do ramipril sobre a doença periodontal induzida experimentalmente em ratos / Effect of ramipril on periodontal disease experimentally induced in rats

A doença periodontal (DP) corresponde a um grupo de doenças inflamatórias que acomete as estruturas periodontais de proteção e de suporte e pode levar à perda dentária. A etiologia está relacionada à placa dentobacteriana que leva à produção de grande quantidade de citocinas pró-inflamatórias importantes na destruição tecidual. A angiotensina (Ang) II também pode contribuir para a inflamação e destruição tecidual no periodonto agindo como mediador chave. A utilização de drogas que atuem na cascata do sistema renina-angiotensina (SRA) poderia interferir no estado de saúde ou inflamação do tecido mole, na perda óssea alveolar e na expressão gênica dos componentes do SRA e mediadores inflamatórios. Portanto, o objetivo do presente trabalho foi investigar se o ramipril, um inibidor da enzima conversora de angiotensina (ECA), altera a progressão da DP induzida experimentalmente em ratos. Foi utilizado o modelo de indução da DP por colocação de ligadura ao redor do primeiro molar inferior direito de ratos. Os grupos com 10 animais cada, foram divididos em tratados com ramipril (via gavagem 10mg/kg/dia) ou água (veículo) durante 14 e 21 dias e o grupo Sham submetido à indução fictícia da DP. Outros quatro grupos foram submetidos ao pré-tratamento com ramipril durante os períodos de 7 e 14 dias e após a indução da DP e tratados por 14 ou 21 dias. As metodologias de avaliação foram: extração de RNA total, transcrição reversa seguida de reação em cadeia da polimerase quantitativa (RTqPCR),análises histológica e da perda óssea alveolar. Os dados foram analisados por meio de gráficos e os resultados foram submetidos à análise unidirecional de variância (ANOVA) e representaram médias e respectivos desvios-padrão. Diferenças entre os grupos foram consideradas estatisticamente significativas quando p < 0,05. Com base nos resultados obtidos pode-se concluir que o ramipril foi capaz de reduzir a progressão da perda óssea no grupo tratado por 21 dias (DP-21d-Rami)...

Periodontitis (PD) consists of a group of inflammatory diseases that affect the protecting and supporting periodontal structures, and may lead to tooth loss. Theetiology is related to the dentobacterial plaque that produces a large amount of proinflammatory cytokines with an important action on tissue destruction. Angiotensin(Ang) II may also contribute to the inflammation and periodontal tissue destruction byacting as a key mediator. The use of drugs that affect the cascade of the reninangiotensin system (RAS) might interfere with the healthy or inflammatory status ofthe soft tissue, alveolar bone loss and gene expression of RAS components and inflammatory mediators. Therefore, the aim of this work was to evaluate whether ramipril, an angiotensin-converting enzyme (ACE) inhibitor, alters the progression of experimentally-induced PD in rats. The model of PD induction by placement of a silk ligature around the right lower first molar was used. Groups with 10 animals each were divided into ramipril-treated (10 mg/kg/day, via gavage), water (vehicle) and thesham surgery group (sham) for 7 or 14 days previously to PD induction and after this period the drug was administered for 14 and 21 days. The techniques employed were: total RNA extraction, reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) as well as histological and alveolar bone loss analyses. Data were analyzed by means of graphs and the results submitted to unidirectional analysis of variance (ANOVA) and represent the means with respective standard deviations. Differences between groups were considered statistically significant whenp < 0.05. Based on the results obtained in this work, it was concluded that ramipril was able to reduce the progression of alveolar bone loss in the group treated for 21...

Reduced cortical renal GLUT1 expression induced by angiotensin-converting enzyme inhibition in diabetic spontaneously hypertensive rats

Diabetes in spontaneously hypertensive rats is associated with cortical renal GLUT1 and GLUT2 overexpression. Our objective was to evaluate the effect of the angiotensin-converting enzyme blockade on cortical renal GLUT1 and GLUT2 expression, urinary albumin and urinary TGF-¦Â1. Streptozotocin, 50 mg/kg, or citrate buffer (N = 16) was administered as a single injection into the tail vein in adult spontaneously hypertensive rats (~260 g). Thirty days later, these diabetic spontaneously hypertensive rats received ramipril by gavage: 0.01 mg¡¤kg-1¡¤day-1 (D0.01, N = 14), 1 mg¡¤kg-1¡¤day-1 (D1, N = 9) or water (D, N = 11) for 15 days. Albumin and TGF-¦Â1 (24-h urine), direct arterial pressure, renal tissue angiotensin-converting enzyme activity (fluorometric assay), and GLUT1 and GLUT2 protein levels (Western blot, renal cortex) were determined. Glycemia and glycosuria were higher (P < 0.05) in the diabetic rats compared with controls, but similar between the diabetic groups. Diabetes in spontaneously hypertensive rats lowered renal tissue angiotensin-converting enzyme activity (40 percent), which was reduced further when higher ramipril doses were used. Diabetes associated with hypertension raised GLUT1 by 28 percent (P < 0.0001) and GLUT2 by 76 percent (P = 0.01), and both doses of ramipril equally reduced cortical GLUT1 (D vs D1 and vs D0.01, P ¡Ü 0.001). GLUT2 levels were reduced in D0.01 (P < 0.05 vs D). Diabetes increased urinary albumin and TGF-¦Â1 urinary excretion, but the 15-day ramipril treatment (with either dose) did not reduce them. In conclusion, ramipril is effective in lowering renal tissue angiotensin-converting enzyme activity, as well as blocking cortical GLUT1 overexpression, which may be beneficial in arresting the development of diabetic nephropathy.

Antidepressant activity of fosinopril, ramipril and losartan, but not of lisinopril in depressive paradigms of albino rats and mice.

Fosinopril, ramipril and losartan significantly decreased the duration (sec) of immobility in forced swim test and were comparable to amitriptyline. The duration of immobility were significantly decreased in fosinopril, ramipril and losartan in the tail suspension test and were comparable to amitriptyline. Only losartan significantly increased the rearing number of entries, time spent (sec) in open arm and in light area in comparison to control animals. Fosinopril and ramipril and not lisinopril showed significant antidepressant activity while losartan showed a significant antidepressant and anxiolytic activity. Present findings suggest that these drugs could be better antihypertensives in hypertensive patients with comorbidity like depression or anxiety.

Modulation of pain perception by ramipril and losartan in human volunteers.

The angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are a well known entity and have been used in therapeutics for various indications like hypertension, myocardial infarction and CHF. However, there is a renewed interest in these compounds in terms of their effects on pain perception in animals as well as in human beings. They have yielded contradictory results, showing hyperalgesia in some studies but analgesia in others. Hence this study was undertaken to evaluate the effect of Ramipril (an ACE-I) and Losartan (an ARB) on pain perception in human volunteers using cola caps and handcuff of sphygmomanometer. A total of 30 healthy, normotensive individuals with no previous history of intake of analgesics during or 4 weeks prior to the study were selected after an informed consent. The first group received a single dose of placebo, the second group received Ramipril (2.5 mg) & the third group received Losartan (50 mg). Pain perception threshold (the point at which an individual first experiences pain) and the maximum tolerated pain were assessed using the above method. The control group showed no significant changes in pain threshold, but the group receiving either Ramipril or Losartan showed a decline in threshold for maximum tolerated pain. Only Ramipril and not Losartan decreased the pain perception threshold. Our study revealed that single dose treatment of healthy volunteers with Ramipril and Losartan may cause algesia as early as after ingestion of the first dose and further studies are needed to study their long term effects on pain perception.

Effect of Ramipril, Valsartan, Candesartan and Lacidipine on inflammation and gastric ulcer in rats

The present study investigated and compared the effect of the angiotensin converting enzyme inhibitor ramipril and the angiotensin II receptor blockers valsartan and candesartan and the calcium channel blocker lacidipine on inflammation and gastric ulcer in rats. The acute inflammation was induced by intraplantar injection of carrageenan [1%] in the rat hind paw. Gastric ulcer was evoked by s.c. indomethacin [20 mg/kg]. When given s.c. 30 min prior to induction of inflammation, ramipril [0.23 and 0.45 mg/kg], valsartan [7.5 and 15 mg/kg], candesartan [0.72 and 1.44 gm/kg] failed to reduce paw oedema response. Meanwhile, lacidipine at the lower dose of 0.18 mg/kg displayed mild anti-inflammatory activity up to 1 hr, reducing paw odema by 26.7% for 1 hr post-carrageenan, while a higher dose of 0.36 mg/kg inhibited oedema formation by 33.5, 31, 23.6 and 22.3% at 1, 2, 3 and 4 hr post-carrageenan, respectively. The acute gastric mucosal lesions evoked by indomethacin in the rat were aggravated by co-administration of ramipril 0.23 and 0.45 mg/kg, valsartan 7.5 and 15 mg/kg, lacidipne 0.18 and 0.36 mg/kg and candesartan 0.72 mg/kg, but reduced by candesartan 1.44 mg/kg. Findings in the present study do not favor an anti-inflammatory activity for ramipril, valsartan and candesartan, but indicates an antioedema effect for lacidipine at the doses employed. These agents are likely to adversely affect gastric mucosal integrity and enhance the indomethacin-induced gastric injury

Effect of ACE inhibitors on creatinine clearance and albuminuria in diabetic nephropathy

30 diabetic female patients were studied for the effect of Ramipril on creatinine clearance and albuminuria, they all were type 2 diabetes mellitus and were on oral hypoglycemic drugs. They all had variable degrees of hypertenison. Ramipril was taken for 3 months in a variable doses between 5 and 10 mg/day. Creatinine clearance and albuminuria were determined before and after treatment. Patients were divided into 3 groups: Group 1: 10 patients with albuminuria and mild hypertension. Group 2: 10 patients with albuminuria and moderate hypertension. Group 3: 10 patients with macroalbuminuria and moderate to severe hypertension. In our study, Group 1 has made maximum benefit of Ramipril as regards highly significant decrease [P= .002] of creatinine clearance and of albuminuria which improved significantly [P=.001]. Group 2 had a lesser success with only decrease of albuminuria significantly [P=.005] but with insignificant decrease of level of creatinine clearance. Group 3 with macroalbuminuria did not benefit from Ramipril effect on albuminuria but there was a significant decrease in creatinine clearance below normal levels [P=.001]. Early and tight control of blood pressure by Ramipril is needed to achieve a success in treating diabetic nephropathy with microalbuminuria. In our study, patients with macroalbuminuria did not benefit from Ramipril treatment

Effects of chronic ramipril treatment in streptozotocin-induced diabetic rats.

The present investigation was undertaken to study the effects of chronic oral ramipril (1 mg/kg) treatment in streptozotocin (STZ) induced diabetic rats. Single tail vein injection of STZ (45 mg/kg, i.v.) produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinaemia and hyperglycaemia. The diabetic state was also found to be associated with bradycardia, hypothyroidism, cardiac depression and cardiomyopathy. Ramipril treatment prevented STZ-induced hypertension, bradycardia, hypothyroidism, hyperchosesterolaemia and partially the cardiomayopathy. Ramipril treatment could not, however prevent STZ-induced loss of body weight, polyuria, polydipsia, polyphagia, hyperglycaemia, hypoinsulinaemia, hypertriglyceridaemia and cardiac depression. Our data suggests that ramipril has a few beneficial effects in the STZ-treated diabetic rats.

Functional evidence that the central renin-angiotensin system plays a role in the pressor response induced by central injection of cabachol

We investigated the effects of losartan, an AT1-receptor blocker, and ramipril, a converting enzyme inhibitor, on the pressor response induced by angiotensin II (ANG II) and carbachol (a cholinergic receptor agonist). Male Holtzman rats (250-300 g) with a stainless steel cannula implanted into the lateral ventricle (LV) were used. The injection of losartan (50 nmol/l mul) into the LV blocked the pressor response induced by ANG II (12 ng/1 mul) and carbachol (2 nmol/ 1 mul). After injection of ANG II and carbachol into the LV, mean arterial pressure (MAP) increased to 31 + 1 and 28 + 2 mmHg, respectively. Previous injection of losartan abolished the increase in MAP induced by ANG II and carbachol into the LV (2 + 1 and 5 + 2 mmHg, respectively). The injection of ramipril (12 ng/ 1 mul) prior to carbachol blocked the pressor effect of carbachol to 7 + 3 mmHg. These results suggests an interaction between central cholinergic pathways and the angiotensinergic system in the regulation of arterial blood pressure.

Estudio multicéntrico colaborativo abierto de ramipril en hipertensión arterial leve y moderada

Objetivo: Estudiar la efectividad y seguridad del tratamiento de la hipertensión arterial (HTA) leve y moderada (Estadios I, II y III) con un inhibidor de enzima convertidora, ramipril administrado en dosis de 2.5 mg día o ramipril 5 mg día, como medicamento único o con la adición de hidroclorotiazida. Diseño: Experimento abierto no controlado, multicéntrico, en tres países (Colombia, Ecuador y Venezuela). La duración total fue de 10 semanas: Dos semanas de lavado y períodos de seguimiento de dos semanas cada uno, con cambios en el esquema terapéuticos, si era necesario, en las semanas seis y ocho; evaluación final en la semana diez. Pacientes: 216 sujetos de ambos sexos con HTA leve o moderada en los tres países participantes (rango de edad 25-79). Hubo 200 pacientes disponibles para el análisis final de efectividad, 200 pacientes para el análisis de seguridad hecho por el investigador y 189 pacientes para el análisis hecho por el paciente. Intervenciones: 1)ramipril 2.5 mg una vezal día; 2)En quienes no se controlaba la presión arterial 5 mg una vez al día; 3)En aquellos aun no controlados se adicionaba hidroclorotiazida 25 mg una vez al día. Mediciones: Determinación de la presión arterial cada dos minutos por tres veces en posición supina y lo mismo con el sujeto sentado y registro estandarizado de efectos adversos. En cada visita además peso, frecuencia cardíaca y fundoscopia; radiografía del tórax en la semana cero y electrocardiograma en las semanas dos y diez. Pruebas de laboratorio en las semanas dos, seis y diez. Resultados: La efectividad, medida en términos de disminución de la presión arterial un mínimo de 10 mmHg o hasta normalización (valor igual o menor de 90 mmHg) fue alcanzada en 152 sujetos...

Effect of intracerebroventricular injection of ramipril on the drinking response caused by injection of noradrenaline into the third ventricle

We studied the effect of ramipril injected into the third ventricle (3rdV) on the control of water intake induced by injection of noradrenaline into the 3rdV of adult male Holtzman rats (250-300 g) implanted with a chronic stainless steel cannula into the 3rdV. The injection volume was always 1mul and was injected over a period of 30-60 sec. Control animals were injected with 0.15 M NaCl. After the injection of isotonic saline (control, O.15 M NaCl) into the 3rdV, water ingestion was 0.3 ñ 0.1 ml/h. Ramipril(l mug/mul)injected into the 3rdV prior to isotonic saline produced no changes in water ingestion (0.4 ñ 0.2 ml/h). The injection of noradrenaline (40 nmol/mul) after isotonic saline induced an increase in water intake (3.0 ñ 1.1 ml/h). The prior injection of ramipril decreased this ingestion to 1.8 + 0.3 ml/ h. These data show that the inhibition of converting enzyme in the brain reduces the water intake induced by catecholaminergic stimulation. We conclude that the brain is able to transform the prodrug ramipril into the active drug ramiprilat.

Injection of ramipril into the lateral ventricle interferes with the drinking response induced by pharmacological and natural thirst stimuli

We investigated the effects of ramipril, an angiotensin I-converting enzyme (ACE) inhibitor, on water intake by male Holtzman rats (250-300 g) with cannulae implanted into the lateral ventricle. Intracerebroventricular (icv) injection of ramipril (1 µg/µl) significantly reduced drinking in response to subcutaneous (sc) injection of isoprenaline (100 µg/kg) from 8.49 + or - 0.69 to 2.96 + or - 0.36 ml/2 h, polyenthyleneglycol (PEG) (30 percent w/v, 10 ml/kg) from 9.51 + or - 2.20 to 1.6 + - 0.34 ml/2 h or water deprivation for 24 h from 12.61 + or - 0.83 to 5.10 + or - 1.37 ml/2 h. Ramipril had no effect on water intake induced by cellular dehydration produced by sc injection of hypertonic saline (2 M NaCl). These results are consistent with the hypothesis that ramipril acts as an ACE-blocking agent in the brain. The possibility that ramipril is transformed to ramiprilat, the active drug, by the brain is suggested