RESUMEN
1. Angiotensin-converting enzyme (ACE) inhibitor treatment leads to beneficial effects on kidney function. The aim of the present study was to determine whether ACE inhibition at high or low doses affects glomerular capillary surface area and length, glomerular number or total renal filtration surface area in rats with established hypertension and, if so, to determine whether these effects are mediated through bradykinin potentiation. 2. Spontaneously hypertensive rats (SHR) were treated with the ACE inhibitor perindopril at either 3 or 0.1 mg/kg per day (high and low doses, respectively) from 16 to 24 weeks of age. Some rats were concomitantly treated with the bradykinin B2 receptor antagonist S16118 (10 nmol/kg per day). Blood pressure was measured twice weekly during the treatment period. At 24 weeks of age, rats were perfusion fixed at 140 mmHg, the kidneys removed, embedded in resin and examined stereologically to estimate glomerular number and volume, length and surface area of glomerular capillaries and total renal filtration surface area. 3. High- and low-perindopril treatment significantly reduced systolic blood pressure compared with control SHR. However, the rats treated with low-dose perindopril were still considered hypertensive. Neither low-dose nor high-dose perindopril treatment had any observable effect on glomerular number (23 876 +/- 1201 vs 26 240 +/- 1465 glomeruli/kidney, respectively) or volume (2.25 +/- 0.21 and 1.96 +/- 0.06 x 10-3 mm3, respectively) compared with controls (glomerular number 25866 +/- 1210 glomeruli/kidney; glomerular volume 2.24 +/- 0.21 x 10-3 mm3). As a result, there was no significant difference in total renal filtration surface area between any of the experimental groups (8161.6 +/- 550.9, 8699.7 +/- 427.6, 9081.9 +/- 453.6, 8830.2 +/- 521.2 and 8559.4 +/- 341.4 mm2 for SHR, SHR low-dose perindopril, SHR low-dose perindopril + B2 antagonist, SHR high-dose perindopril and SHR high-dose perindopril + B2 antagonist, respectively). Coadministration of the bradykinin antagonist had no observable effect on any of the parameters studied. 4. In conclusion, because neither high-dose nor low-dose perindopril had any effect on total renal filtration surface area, the observed beneficial effects of ACE inhibition on kidney function are not the result of enhancement in glomerular capillary surface area.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Presión Sanguínea/efectos de los fármacos , Bradiquinina/análogos & derivados , Riñón/efectos de los fármacos , Riñón/fisiopatología , Perindopril/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Animales , Peso Corporal/efectos de los fármacos , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Relación Dosis-Respuesta a Droga , Tasa de Filtración Glomerular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Glomérulos Renales/efectos de los fármacos , Tamaño de los Órganos , Perindopril/administración & dosificación , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitor treatment leads to protective effects on the cellular structure of the glomerulus and the kidney. The aim of this study was to determine whether ACE inhibition increases renal filtration surface area in the spontaneously hypertensive rat (SHR). METHODS: SHR were treated with the ACE inhibitor perindopril at a high dose (3 mg/kg/day) or a low dose (0.1 mg/kg/day) during the period of hypertension development, from 7 to 14 weeks of age. Some animals were treated concomitantly with the bradykinin B2 receptor antagonist, S16118. Tail-cuff systolic blood pressure and body weights were measured twice weekly. At termination of treatment, glomerular number and volume, length, and surface area of glomerular capillaries and renal filtration surface area were estimated using unbiased stereological techniques. RESULTS: There were significant dose-related reductions in blood pressure with high- and low-dose perindopril treatment. Neither low- nor high-dose perindopril treatment had any effect on glomerular number or size or glomerular capillary length and surface area. Hence, there was no significant difference in total renal filtration surface area between any of the experimental groups (8721 +/- 610 mm2 in untreated SHR and 7879 +/- 338 mm2 and 8767 +/- 437 mm2 in the low and high dose perindopril-treated groups, respectively). Coadministration of the bradykinin antagonist did not affect any of the glomerular parameters. CONCLUSIONS: ACE inhibition during the period of hypertension development does not lead to an enhanced glomerular capillary growth or increases in total renal filtration surface area in this model.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Hipertensión/tratamiento farmacológico , Riñón/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Filtración , Hipertensión/metabolismo , Riñón/metabolismo , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Sístole/efectos de los fármacosRESUMEN
Type 2 bradykinin (B2)-receptor antagonists have been used to define the role of endogenous kinin peptides. However, interpretation of the effects of B2-receptor antagonists has been limited by lack of information concerning the effects of these antagonists on endogenous kinin and angiotensin peptide levels. If kinin levels were subject to short-loop-feedback regulation mediated through B2 receptors, then a reactive increase in kinin levels might blunt the effects of B2-receptor antagonism and stimulate type 1 bradykinin receptors. Moreover, kinins have been implicated in the control of renin secretion. We investigated whether endogenous kinin levels are subject to short-loop-feedback regulation mediated by the B2 receptor and whether endogenous kinins acting through the B2 receptor influence plasma renin levels and circulating and tissue angiotensin peptide levels. The B2-receptor antagonist icatibant (1 mg/kg) was administered to rats by intraperitoneal injection, and circulating and tissue levels of angiotensin and kinin peptides were measured after 4 hours. Icatibant produced 75% occupancy of B2 receptors in the inner stripe of the renal medulla. Icatibant did not influence plasma levels of renin, angiotensinogen, angiotensin-converting enzyme, neutral endopeptidase, or circulating or tissue levels of angiotensin and bradykinin peptides. This study demonstrated that kinin levels are not subject to short-loop-feedback regulation mediated through B2 receptors and that endogenous kinin levels acting through the B2 receptor do not modulate the renin-angiotensin system.
Asunto(s)
Angiotensina II/análisis , Antagonistas de los Receptores de Bradiquinina , Cininas/fisiología , Receptores de Bradiquinina/fisiología , Angiotensina II/sangre , Angiotensinógeno/sangre , Animales , Aorta/química , Autorradiografía , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Interpretación Estadística de Datos , Retroalimentación , Fluorometría , Técnicas In Vitro , Riñón/química , Cininas/análisis , Cininas/sangre , Pulmón/química , Masculino , Miocardio/química , Neprilisina/sangre , Peptidil-Dipeptidasa A/sangre , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Renina/sangre , Factores de TiempoRESUMEN
Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK-(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.
Asunto(s)
Angiotensina II/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bradiquinina/metabolismo , Cardiomegalia/patología , Infarto del Miocardio/patología , Neprilisina/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Animales , Peso Corporal/efectos de los fármacos , Cardiomegalia/complicaciones , GMP Cíclico/orina , Sinergismo Farmacológico , Indoles/farmacología , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Peptidil-Dipeptidasa A/sangre , Perindopril , Potasio/orina , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Renina/sangre , Sodio/orina , Tiorfan/análogos & derivados , Tiorfan/farmacologíaRESUMEN
The combination of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these peptides. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, 100 mg/kg per day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly gavage for 7 days. Ecadotril produced diuresis, natriuresis, increased urine cyclic guanosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril reduced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation of these effects of separate NEP and ACE inhibition. In addition, perindopril potentiated the ecadotril-mediated diuresis, natriuresis and decrease in urine BK-(1-7)/BK-(1-9) ratio, which is an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II levels in plasma and lung. These data indicate that summation of the effects of separate NEP and ACE inhibition provides the basis for the therapeutic efficacy of their combination. Whereas potentiation by perindopril of the diuretic and natriuretic effects of ecadotril may contribute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibition.
Asunto(s)
Angiotensina II/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bradiquinina/metabolismo , Neprilisina/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Angiotensina II/sangre , Angiotensinógeno/sangre , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Bradiquinina/sangre , Bradiquinina/orina , GMP Cíclico/orina , Diuresis , Electrólitos/orina , Corazón/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Peptidil-Dipeptidasa A/sangre , Ratas , Ratas Sprague-Dawley , Renina/sangreRESUMEN
Dual inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin-converting enzyme (ACE) offers the potential for improved therapy of hypertension and cardiac failure. S 21402-1 [(2S)-2-[(2S,3R)-2-thiomethyl-3-phenylbutanamido] propionic acid] is a sulfhydryl-containing potent inhibitor of both NEP (Ki = 1.7 nM) and ACE (Ki = 4.5 nM). S 21402-1 and the sulfhydryl-containing ACE inhibitor captopril were administered to rats by intraperitoneal injection (0, 0.3, 3, 30, 300 mg/kg). Urine was collected for 4 h; then plasma and kidneys were collected. The difference in NEP and ACE inhibition by S 21402-1 in vivo was greater than 1000-fold. All doses of S 21402-1 inhibited NEP, as indicated by plasma NEP activity, radioinhibitor binding to kidney sections, urinary sodium excretion and bradykinin-(1-7)/bradykinin-(1-9) ratio. However, only 300 mg/kg S 21402-1 inhibited ACE, as indicated by plasma angiotensin II/angiotensin I ratio, renin and angiotensinogen levels. Although S 21402-1 (30 and 300 mg/kg) inhibited renal NEP, as indicated by the bradykinin-(1-7)/bradykinin-(1-9) ratio in kidney, S 21402-1 had no effect on renal ACE, as indicated by the angiotensin II/angiotensin I ratio in kidney. Moreover, captopril was greater than 10-fold more potent than S 21402-1 as an ACE inhibitor in vivo. In separate experiments, the pressor response of anesthetized rats to angiotensin I showed more rapid decay in ACE inhibition by S 21402-1 than by captopril. These studies indicated that in vivo modification of S 21402-1 caused a much greater decrease in potency of ACE inhibition than NEP inhibition. Consequently, effective ACE inhibition by S 21402-1 required doses much higher than those required for NEP inhibition.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Neprilisina/antagonistas & inhibidores , Propionatos/farmacología , Compuestos de Sulfhidrilo/farmacología , Angiotensina II/sangre , Animales , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , GMP Cíclico/orina , Relación Dosis-Respuesta a Droga , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Renina/sangreRESUMEN
A retrospective analysis was conducted to determine the effects of metformin on glycosylated hemoglobin (HbA1c), body weight, and adverse events in an African-American population. Thirty-six patients who were receiving combination therapy with metformin and either a sulfonylurea or insulin were identified from a hospital pharmacy database. Nineteen patients met the criteria for efficacy analysis. The combination of metformin with either a sulfonylurea or insulin resulted in a decrease of the average HbA1c from a baseline of 10.07% to 7.92% (delta = 2.15%). The effect of combination therapy on weight was variable; however, twice as many patients lost weight compared with those who gained weight. Metformin appeared to be well-tolerated, with gastrointestinal symptoms being the most commonly reported adverse events.
Asunto(s)
Población Negra , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/efectos de los fármacos , Hipoglucemiantes/administración & dosificación , Metformina/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/etnología , Quimioterapia Combinada , Femenino , Glipizida/administración & dosificación , Gliburida/administración & dosificación , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/efectos adversos , Insulina/administración & dosificación , Insulina Isófana/administración & dosificación , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosAsunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/economía , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/economía , Antihipertensivos/uso terapéutico , Benzazepinas/economía , Benzazepinas/uso terapéutico , Revisión de la Utilización de Medicamentos/economía , Enalapril/economía , Enalapril/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/economía , Presión Sanguínea/efectos de los fármacos , Costos de los Medicamentos , Formularios de Hospitales como Asunto , Georgia , Humanos , Hipertensión/fisiopatología , Estudios RetrospectivosRESUMEN
The action of the marine furanoditerpenes, spongiatriol (SP) and episopongiatriol (ESP), were compared in two sublines of human melanoma cells (MM96E and MM96L) derived from the same metastatic lesion. MM96E had higher tyrosinase activity and lower expression of alkaline phosphatase but was otherwise indistinguishable from MM96L. SP and ESP treatment of both cell lines for 72 h at cytostatic doses inhibited B8G3 expression and tyrosinase activity but had little effect on the expression of tyrosinase antigen. MM96L cells were affected more than MM96E. SP and ESP induced apoptosis in both cell lines, ESP causing dendritic morphology in a proportion of MM96L cells. SP induced a marked G2/M arrest in MM96E cells. SP and ESP together define subtle qualitative and quantitative differences in human melanoma phenoypes, possibly based on expression of a repertoire of neurotransmitter receptors.