RESUMEN
Reserpine (RES) is an irreversible inhibitor of VMAT2 used to study Parkinson's disease (PD) and screening for antiparkinsonian treatments in rodents. Recently, the repeated treatment with a low dose of reserpine was proposed as a model capable of emulating progressive neurochemical, motor and non-motor impairments in PD. Conversely, compared to Wistar rats, Spontaneously Hypertensive Rats (SHR) are resistant to motor changes induced by repeated treatment with a low dose of RES. However, such resistance has not yet been investigated for RES-induced non-motor impairments. We aimed to assess whether SHR would have differential susceptibility to the object recognition deficit induced by repeated low-dose reserpine treatment. We submitted male Wistar and SHR rats to repeated RES treatment (15 s.c. injections of 0.1 mg/kg, every other day) and assessed object memory acquisition and retrieval 48 h after the 6th RES injection (immediately before the appearance of motor impairments). Only RES Wistar rats displayed memory impairment after reserpine treatment. On the other hand, untreated SHR rats displayed object recognition memory deficit, but RES treatment restored such deficits. We also performed immunohistochemistry for tyrosine hydroxylase (TH) and α-synuclein (α-syn) 48 h after the last RES injection. In a different set of animals submitted to the same treatment, we quantified DA, 5-HT and products of lipid peroxidation in the prefrontal cortex (PFC) and hippocampus (HPC). SHR presented increased constitutive levels of DA in the PFC and reduced immunoreactivity to TH in the medial PFC and dorsal HPC. Corroborating the behavioral findings, RES treatment restored those constitutive alterations in SHR. These findings indicate that the neurochemical, molecular and genetic differences in the SHR strain are potentially relevant targets to the study of susceptibility to diseases related to dopaminergic alterations.
Asunto(s)
Trastornos del Conocimiento/inducido químicamente , Dopamina/metabolismo , Hipocampo , Enfermedad de Parkinson Secundaria/inducido químicamente , Corteza Prefrontal , Reconocimiento en Psicología/efectos de los fármacos , Reserpina/farmacología , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Endogámicas SHR/metabolismo , Ratas Wistar/metabolismo , Reserpina/administración & dosificación , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: Hypertension is a relevant sex and sex hormones-dependent risk factor where the cardiovascular and renal health of the population are concerned. Men experience greater losses of renal function (RF) than women, but the mechanisms remain somewhat unclear. Our goal was to evaluate the relationship between oxidative stress (OS), angiotensin-converting enzyme (ACE) and angiotensin-converting enzyme 2 (ACE2) activities and RF in male and female SHR. MAIN METHODS: Twelve-week-old spontaneously hypertensive rats (SHR) were submitted to either castration or SHAM surgery and divided into 4 groups, SHAM or Castrated (CAST) males or females. After 51 days we evaluated RF (inulin and sodium para-aminohippurate), ACE and ACE2 activities (fluorimetry), OS (flow cytometry), collagen deposition (picrosirius red) and protein expression (western blot). KEY FINDINGS: Males presented lower RF than females and castration impaired this parameter in both groups. Sexual dimorphism was not observed regarding OS and inflammation; however, castration increased this parameter more severely in males than in females. SHAM males exhibited higher collagen deposition than females, though castration increased it in both sexes, eliminating the difference. We found sexual dimorphism regarding renal ACE and ACE2 activities, which were lower in males than in females. Although castration did not alter ACE activity, it reduced ACE2 activity in females and increased it in males. SIGNIFICANCE: These results indicate that sex hormones affect RF in SHR. As alterations in the oxidative system were capable of promoting podocyte injury, inflammation, and collagen deposition, we put forward that these effects are differently modulated by ACE and ACE2.
Asunto(s)
Hormonas Esteroides Gonadales/metabolismo , Enfermedades Renales/etiología , Estrés Oxidativo , Peptidil-Dipeptidasa A/metabolismo , Ratas Endogámicas SHR/metabolismo , Enzima Convertidora de Angiotensina 2 , Animales , Western Blotting , Colágeno/metabolismo , Femenino , Riñón/enzimología , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Masculino , Orquiectomía , Ovariectomía , Estrés Oxidativo/fisiología , Ratas , Ratas Endogámicas SHR/fisiología , Especies Reactivas de Oxígeno/metabolismo , Factores SexualesRESUMEN
Accurate diagnosis and treatment of pain is dependent on knowledge of the variables that might alter this response. Some of these variables are the locality of the noxious stimulus, the sex of the individual, and the presence of chronic diseases. Among these chronic diseases, hypertension is considered a serious and silent disease that has been associated with hypoalgesia. The main goal of this study was to evaluate the potential nociceptive differences in spontaneously hypertensive rats (SHR) regarding the locality of the stimulus, i.e., the temporomandibular joint or paw, the sex, and the role of ovarian hormones in a model of mechanical nociception (Von Frey test) or formalin-induced inflammatory nociception. Our results indicate that SHR had lower orofacial mechanical nociception beyond the lower mechanical nociception in the paw compared with WKY rats. In a model of formalin-induced inflammatory nociception, SHR also had decreased nociception compared with normotensive rats. We also sought to evaluate the influence of sex and ovarian hormones on orofacial mechanical nociception in SHR. We observed that female SHR had higher mechanical nociception than male SHR only in the paw, but it had higher formalin-induced orofacial nociception than male SHR. Moreover, the absence of ovarian hormones caused an increase in mean arterial pressure and a decrease in paw nociception in female SHR.
Asunto(s)
Hormonas/farmacología , Hipertensión/fisiopatología , Nocicepción/fisiología , Caracteres Sexuales , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Femenino , Hormonas/metabolismo , Hipertensión/metabolismo , Masculino , Nocicepción/efectos de los fármacos , Ovario , Dolor/fisiopatología , Dimensión del Dolor , Ratas Endogámicas SHR/metabolismo , Ratas Endogámicas WKYRESUMEN
The SHR and SLA16 inbred strains present behavioral differences in anxiety/emotionality that could be under the influence of dopaminergic neurotransmission. In order to investigate the role of D2 receptors in modulating such differences, an agonist (quinpirole) and an antagonist (haloperidol) of this receptor were administered, either via systemic injection (IP), or microinjected into the ventral area of the hippocampus (vHIP). Quinpirole and haloperidol IP decreased locomotor activity, only in SLA16 rats in the open-field (OF), and in both strains in the elevated plus-maze (EPM). Quinpirole also increased the preference for the aversive areas of the EPM. Quinpirole vHIP decreased locomotor activity in both strains. Haloperidol vHIP did not elicit behavioural changes and no differences in the levels of D2 receptors and of dopamine transporter in the hippocampus were found. Results indicate that systemic activation/blocking of D2 receptors caused a strain-dependent hypolocomotion, whereas activation of D2 receptors in the vHIP, but not D2 receptor antagonism, regardless of dose, decreased general locomotor activity in the two strains. Therefore, we suggest that genomic differences in the chromosome 4 can influence the locomotor activity regulated by the D2 dopaminergic receptor, especially in the vHIP.
Asunto(s)
Conducta Animal/efectos de los fármacos , Locomoción/efectos de los fármacos , Ratas Mutantes/metabolismo , Animales , Ansiedad , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2/metabolismo , Vías de Administración de Medicamentos , Haloperidol/farmacología , Hipocampo/efectos de los fármacos , Masculino , Actividad Motora/fisiología , Quinpirol/metabolismo , Quinpirol/farmacología , Ratas , Ratas Endogámicas SHR/genética , Ratas Endogámicas SHR/metabolismo , Ratas Mutantes/genética , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismoRESUMEN
The mineralocorticoid receptor (MR) has been considered as both neuroprotective and damaging to the function of the central nervous system. MR may be also involved in central regulation of blood pressure. In the present study, we compared the expression of MR and the glucocorticoid receptor (GR) in the hippocampus and hypothalamus of 16-week-old spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats. In the hippocampus, MR expression was studied by in situ hybridization (ISH), quantitative polymerase chain reaction (PCR) and immunohistochemistry, whereas GR expression was analysed using the latter two procedures. Hypertensive animals showed an increased expression of MR mRNA in the whole hippocampus according to qPCR data and also in CA3 by ISH. Immunocytochemical staining for MR of the dorsal hippocampus, however, did not reveal differences between SHR and WKY rats. SHR showed elevated hypothalamic MR mRNA by qPCR, as well as an increased number of MR immunopositive cells in the magnocellular paraventricular region, compared to WKY rats. By contrast, expression levels of GR mRNA or protein in the hippocampus and hypothalamus of SHR were similar to those of WKY rats. Furthermore, we investigated the role of MR in the hypertensive rats by i.c.v. injection of the MR antagonist RU-2831. This compound produced a significant drop in blood pressure for SHR. In conclusion, MR expression is increased in the hippocampus and hypothalamus of SHR. We suggest that pathological MR overdrive may take responsibility for up-regulation of blood pressure and the encephalopathy of hypertension.
Asunto(s)
Hipocampo/metabolismo , Hipotálamo/metabolismo , Ratas Endogámicas SHR/metabolismo , Receptores de Mineralocorticoides/biosíntesis , Animales , Presión Sanguínea/efectos de los fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacología , Ratas , Ratas Endogámicas WKY , Receptores de Glucocorticoides/biosíntesis , Espironolactona/análogos & derivados , Espironolactona/farmacologíaRESUMEN
In this study, the effects of nicotine on global gene expression of cultured cells from the brainstem of spontaneously hypertensive rat (SHR) and normotensive Wistar Kyoto (WKY) rats were evaluated using whole-genome oligoarrays. We found that nicotine may act differentially on the gene expression profiles of SHR and WKY. The influence of strain was present in 321 genes that were differentially expressed in SHR as compared with WKY brainstem cells independently of the nicotine treatment. A total of 146 genes had their expression altered in both strains after nicotine exposure. Interaction between nicotine treatment and the strain was observed to affect the expression of 229 genes that participate in cellular pathways related to neurotransmitter secretion, intracellular trafficking and cell communication, and are possibly involved in the phenotypic differentiation between SHR and WKY rats, including hypertension. Further characterization of their function in hypertension development is warranted.
Asunto(s)
Tronco Encefálico/metabolismo , Perfilación de la Expresión Génica , Nicotina/farmacología , Ratas Endogámicas SHR/metabolismo , Ratas Endogámicas WKY/metabolismo , Animales , Animales Recién Nacidos , Tronco Encefálico/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Hipertensión/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , RatasRESUMEN
FUNDAMENTO: Embora dietas hiperlipídicas (DH) promovam distúrbios nutricionais e cardíacos, poucos estudos avaliaram sua influência em ratos normotensos Wistar-Kyoto (WKY) e espontaneamente hipertensos (SHR). OBJETIVO: Avaliar e comparar o perfil nutricional e cardiovascular de WKY e SHR tratados com DH. MÉTODOS: 20 WKY e 20 SHR foram distribuídos em quatro grupos: WKY-controle (WKY-C), WKY-DH, SHR-controle (SHR- C) e SHR-DH. Os grupos C e DH receberam, respectivamente, dieta normocalórica e DH durante 20 semanas. Foram avaliados: peso corporal (PC), adiposidade, glicemia, lípides séricos, com dosagens de colesterol total e triacilglicerol, insulina e leptina. O estudo cardiovascular contemplou a pressão arterial sistólica (PAS), avaliação cardiopulmonar anatômica, ecocardiograma e histologia cardíaca. RESULTADOS: Os SHRs apresentaram menor PC, adiposidade, glicose, colesterol, triacilglicerol, leptina e insulina, quando comparados aos WKYs. Nos SHR, a ingestão calórica aumentou com a DH. Já nos WKYs, a DH elevou a eficiência energética, a adiposidade e a leptina e reduziu a glicemia. Na avaliação cardiovascular, os SHR apresentaram maior PAS, umidade pulmonar, hipertrofia e fibrose intersticial miocárdica em relação aos WKYs (p<0,01); mas a função cardíaca foi similar entre as cepas. A DH reduziu o diâmetro sistólico ventricular nos WKY e acentuou a relação E/A mitral, as espessuras diastólicas do septo interventricular e da parede posterior bem como a fibrose intersticial do ventrículo esquerdo. CONCLUSÃO: Embora não tenha afetado significativamente o perfil nutricional dos SHRs, o tratamento acentuou a remodelação cardíaca e precipitou o aparecimento de disfunção diastólica ventricular. Nos WKY, a dieta aumentou a adiposidade e a leptinemia, e promoveu modificações cardiovasculares não significantes.
BACKGROUND: Although a high fat diet (HFD) promotes nutritional and heart disorders, few studies have assessed its influence in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). OBJECTIVE: To evaluate and compare the nutritional and cardiovascular profiles of WKY and SHR on a high fat diet. METHODS: 20 WKY and 20 SHR were divided into four groups: Control-WKY (C-WKY), HFD-WKY, Control-SHR (C-SHR) and HFD-SHR. The C and HFD groups received, respectively, a normocaloric diet and a HFD for 20 weeks. The following features were evaluated: body weight (BW), adiposity, blood glucose, serum lipids, with measurements of total cholesterol and triacylglycerol levels, insulin and leptin. The cardiovascular study included the systolic blood pressure (SBP), a cardiopulmonary anatomical evaluation, an echocardiography and heart histology. RESULTS: The SHR had BW, adiposity, glucose, cholesterol, triacylglycerol, leptin and insulin levels lower than the WKY. In SHR, the caloric intake increased with HFD. In WKY, the HFD increased energy efficiency, adiposity and blood leptin, and reduced glucose. In the cardiovascular assessment, the SHR had SBP, pulmonary moisture, myocardial hypertrophy and interstitial fibrosis higher than the WKY (p <0.01); the cardiac function was similar in both strains. The HFD reduced the ventricular systolic diameter in the WKY and increased the mitral E/A ratio, the diastolic thickness of the interventricular septum and the posterior wall, as well as the interstitial fibrosis of the left ventricle. (Arq Bras Cardiol 2009; 93(5) : 487-494) CONCLUSION: Although it had not significantly affected the nutritional profile of the SHR, the treatment increased cardiac remodeling and precipitated the emergence of ventricular diastolic dysfunction. In WKY, the diet increased adiposity and leptinemia, and promoted non-significant cardiovascular changes.
FUNDAMENTO: Embora dietas hiperlipídicas (DH) promovam distúrbios nutricionais e cardíacos, poucos estudos avaliaram sua influência em ratos normotensos Wistar-Kyoto (WKY) e espontaneamente hipertensos (SHR). OBJETIVO: Evaluar y comparar el perfil nutricional y cardiovascular de WKY y SHR tratadas con DH. MÉTODOS: Un total de 20 WKY y 20 SHR se distribuyó en cuatro grupos: WKY-control (WKY-C), WKY-DH, SHR-control (SHR-C) y SHR-DH. Los grupos C y DH recibieron, respectivamente, dieta normocalórica y DH durante 20 semanas. Se evaluaron: peso corporal (PC), adiposidad, glucemia, lípidos séricos, con dosificaciones de colesterol total y triacilglicerol, insulina y leptina. El estudio cardiovascular contempló la presión arterial sistólica (PAS), evaluación cardiopulmonar anatómica, ecocardiograma e histología cardiaca. RESULTADOS: Las SHRs presentaron menor PC, adiposidad, glucosa, colesterol, triacilglicerol, leptina e insulina, cuando comparadas a las WKYs. En las SHR, la ingestión calórica aumentó con la DH. Sin embargo en las WKYs, la DH elevó la eficiencia energética, la adiposidad y la leptina y reduzco la glucemia. En la evaluación cardiovascular, las SHR presentaron mayor PAS, humedad pulmonar, hipertrofia y fibrosis intersticial miocárdica en cuanto a las WKYs (p<0,01); sin embargo la función cardiaca se halló similar entre las cepas. La DH reduzco el diámetro sistólico ventricular en los WKY y acentuó la relación E/A mitral, los espesores diastólicos del septo interventricular y de la pared posterior así como la fibrosis intersticial del ventrículo izquierdo. CONCLUSIÓN: Aunque no afectó significativamente el perfil nutricional de las SHRs, el tratamiento acentuó la remodelación cardiaca y precipitó el aparecimiento de disfunción diastólica ventricular. En los WKY, la dieta aumentó la adiposidad y la leptinemia, y promovió modificaciones cardiovasculares no significantes.
Asunto(s)
Animales , Masculino , Ratas , Grasas de la Dieta/administración & dosificación , Corazón/fisiología , Estado Nutricional/fisiología , Ratas Endogámicas SHR/fisiología , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Modelos Animales de Enfermedad , Grasas de la Dieta/efectos adversos , Métodos Epidemiológicos , Corazón/fisiopatología , Metabolismo de los Lípidos/fisiología , Ratas Endogámicas WKY , Ratas Endogámicas SHR/metabolismoRESUMEN
BACKGROUND: Although a high fat diet (HFD) promotes nutritional and heart disorders, few studies have assessed its influence in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). OBJECTIVE: To evaluate and compare the nutritional and cardiovascular profiles of WKY and SHR on a high fat diet. METHODS: 20 WKY and 20 SHR were divided into four groups: Control-WKY (C-WKY), HFD-WKY, Control-SHR (C-SHR) and HFD-SHR. The C and HFD groups received, respectively, a normocaloric diet and a HFD for 20 weeks. The following features were evaluated: body weight (BW), adiposity, blood glucose, serum lipids, with measurements of total cholesterol and triacylglycerol levels, insulin and leptin. The cardiovascular study included the systolic blood pressure (SBP), a cardiopulmonary anatomical evaluation, an echocardiography and heart histology. RESULTS: The SHR had BW, adiposity, glucose, cholesterol, triacylglycerol, leptin and insulin levels lower than the WKY. In SHR, the caloric intake increased with HFD. In WKY, the HFD increased energy efficiency, adiposity and blood leptin, and reduced glucose. In the cardiovascular assessment, the SHR had SBP, pulmonary moisture, myocardial hypertrophy and interstitial fibrosis higher than the WKY (p <0.01); the cardiac function was similar in both strains. The HFD reduced the ventricular systolic diameter in the WKY and increased the mitral E/A ratio, the diastolic thickness of the interventricular septum and the posterior wall, as well as the interstitial fibrosis of the left ventricle. (Arq Bras Cardiol 2009; 93(5) : 487-494) CONCLUSION: Although it had not significantly affected the nutritional profile of the SHR, the treatment increased cardiac remodeling and precipitated the emergence of ventricular diastolic dysfunction. In WKY, the diet increased adiposity and leptinemia, and promoted non-significant cardiovascular changes.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Corazón/fisiología , Estado Nutricional/fisiología , Ratas Endogámicas SHR/fisiología , Animales , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Grasas de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Métodos Epidemiológicos , Corazón/fisiopatología , Metabolismo de los Lípidos/fisiología , Masculino , Ratas , Ratas Endogámicas SHR/metabolismo , Ratas Endogámicas WKYRESUMEN
The present study was undertaken to identify whether inflammation or oxidative stress is the primary abnormality in the kidney in spontaneously hypertensive rats (SHR). Renal inflammation and oxidative stress were evaluated in 2- and 3-week-old prehypertensive SHR and age-matched genetically normotensive control Wistar-Kyoto (WKY) rats. Blood pressure was similar in WKY and SHR rats at 2 and 3 weeks, of age. Renal inflammation (macrophage and nuclear factor-kappaB) was elevated in SHR at 3 weeks, but not at 2 weeks, of age compared with age-matched WKY rats. Renal oxidative stress (nitrotyrosine, 8-hydroxy-2'-deoxyguanosine and p47phox) was also clearly elevated in 3-week-old SHR compared with age-matched WKY rats. Additionally, NADPH oxidase subunit p47phox was found elevated in 2-week-old SHR compared to age-matched WKY rats. Moreover, antioxidant (N-acetyl-L-cysteine and Tempol) treatment reduced renal inflammation in prehypertensive SHR. We therefore conclude that the oxidative stress appears before inflammation as a primary abnormality in the kidney in prehypertensive SHR.
Asunto(s)
Nefritis/metabolismo , Estrés Oxidativo , Ratas Endogámicas SHR/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina , Acetilcisteína/uso terapéutico , Factores de Edad , Animales , Antioxidantes/uso terapéutico , Presión Sanguínea , Óxidos N-Cíclicos/uso terapéutico , Daño del ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/análisis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Glutatión/análisis , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Hipertensión/genética , Hipertensión/metabolismo , Corteza Renal/metabolismo , Masculino , NADPH Oxidasas/análisis , Nefritis/tratamiento farmacológico , Nefritis/genética , Nefritis/prevención & control , Ratas , Ratas Endogámicas WKY , Marcadores de Spin , Tirosina/análogos & derivados , Tirosina/análisisRESUMEN
The release of 45Ca induced by Ca2+ was studied in genetically hypertensive (SHR) and normotensive (WKY) rats using EGTA-skinned aortic strips. Strips preloaded with 45Ca (pCa 6.6) were desaturated at 5 mM of EGTA. A slow component of the washout in aorta from SHRs exhibited higher Ca content and a lower rate of Ca leak than that in aorta from WKY rats. This slow component was stimulated during washing with 0.03, 0.3, 1 or 10 microM free Ca2+. The release of 45Ca induced by Ca2+ proceeded at similar rates in preparations of the two strains. Compared to WKY aortic strips the stimulated efflux of 45Ca was greater in SHR aortic strips due to the higher Ca content. About half of the release of 45Ca induced by 1 microM free Ca2+ during the first 6 minutes of stimulation was blocked by 0.6 mM of ryanodine or 50 microM of ruthenium red, thus identifying the sarcoplasmic reticulum as a source of Ca release. The results suggest that this intracellular storage of Ca in aorta from genetically hypertensive rats is relevant for the generation of high levels of cytosolic Ca2+.
Asunto(s)
Calcio/metabolismo , Músculo Liso Vascular/metabolismo , Ratas Endogámicas SHR/metabolismo , Ratas Wistar/metabolismo , Animales , Aorta/metabolismo , Técnicas In Vitro , Masculino , RatasRESUMEN
OBJECTIVE: To examine the metabolism of kinins and angiotensin I in the pulmonary circulation of spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR). METHODS: Bradykinin inactivation was estimated in vivo by comparison of the hypotensive effect of intra-arterial and intravenous injections, and in the in situ perfused lung by analysing the breakdown products using high-performance liquid chromatography. RESULTS: In vivo pulmonary degradation of bradykinin, but not that of higher homologues of this peptide, was shown to be significantly greater in SHR. Angiotensin I converting activity was found to be increased in lungs of SHR. The recovery of bradykinin and homologues from perfused SHR lung was decreased relative to NWR. Des-(Phe-Arg) fragments of all kinin analogues were identified in the pulmonary perfusates. When bradykinin and des-Arg9-bradykinin were injected in the perfused lungs, the respective fragments 4-9 and 4-8 were also identified in the perfusates. When kininase II was inhibited with enalaprilat, the recovery of bradykinin increased from 10 to 43% in SHR and from 23 to 58% in NWR, whereas about 90% of the higher bradykinin homologues were recovered in both SHR and NWR. Aminopeptidase P and dipeptidylaminopeptidase IV, as measured by the recovery of fragment 4-9 under kininase II inhibition, accounted for about 40% of the total pulmonary kininase activity in the SHR lungs and 25% of that of the NWR lungs. CONCLUSIONS: The results show that SHR have increased kininase and angiotensin converting activity compared with NWR, and that kinins as well as angiotensin may contribute to the pathogenesis of hypertension. Aminopeptidase P and dipeptidylaminopeptidase IV may contribute to the increased in vivo degradation of bradykinin observed in the SHR.
Asunto(s)
Angiotensina I/metabolismo , Bradiquinina/metabolismo , Pulmón/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Circulación Pulmonar/fisiología , Ratas Endogámicas SHR/metabolismo , Ratas Wistar/metabolismo , Aminopeptidasas/metabolismo , Animales , Presión Sanguínea/fisiología , Bradiquinina/administración & dosificación , Bradiquinina/sangre , Dipeptidil Peptidasa 4 , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Pulmón/enzimología , Masculino , RatasRESUMEN
1. The angiotensin converting enzyme (ACE) activity of spontaneously hypertensive (SHR) and spontaneously hypertensive stroke-prone (SHRSP) rats was compared to the ACE activity of normotensive Wistar-Kyoto rats (WKY). 2. ACE activity was assessed indirectly in conscious unrestrained rats using the equipressor response end point to simultaneously calculate the extent of conversion of angiotensin I (AI) to angiotensin II (AII) and the pulmonary degradation of bradykinin (BK). 3. The pulmonary degradation of BK was significantly elevated (99.4%) in SHR rats whereas the elevation was not significant in SHRSP rats (99.2%) compared to WKY rats, even though the pulmonary inactivation of BK in WKY rats was higher (98.6%) than in normotensive Wistar rats (95.6% and 97.5%) previously studied. 4. Blood pressure responsiveness to intra-aortically injected BK (bolus injection and infusion) was markedly increased in SHR and SHRSP rats with no change in reactivity to sodium nitroprusside. 5. Conversion of AI to AII assessed by the equipressor doses of the hormones which produced a 20-mmHg rise in blood pressure was markedly elevated in SHR (86 +/- 4%) and SHRSP (80 +/- 7%) rats when compared to WKY rats (38 +/- 4%). 6. The marked increase in conversion of AI to AII in hypertensive animals, accompanied by an increased pulmonary degradation of BK in SHR rats, suggests that ACE activity is increased in conscious SHR and SHRSP rats and may participate in the genesis of hypertension in this model of genetic hypertension.
Asunto(s)
Peptidil-Dipeptidasa A/metabolismo , Ratas Endogámicas SHR/metabolismo , Angiotensina I/administración & dosificación , Angiotensina I/metabolismo , Angiotensina II/administración & dosificación , Angiotensina II/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Bradiquinina/administración & dosificación , Bradiquinina/metabolismo , Trastornos Cerebrovasculares/enzimología , Trastornos Cerebrovasculares/genética , Trastornos Cerebrovasculares/fisiopatología , Relación Dosis-Respuesta a Droga , Hipertensión/enzimología , Hipertensión/genética , Hipertensión/fisiopatología , Pulmón/enzimología , Masculino , Nitroprusiato/farmacología , Ratas , Ratas Endogámicas WKYRESUMEN
1. The angiotensin converting enzyme (ACE) activity of spontaneously hypertensive (SHR) and spontaneously hypertensive stroke-prone (SHRSP) rats was compared to the ACE activity of normotensive Wistar-Kyoto rats (WKY). 2. ACE activity was assessed indirectly in conscious unrestrained rats using the equipressor response end point to simultaneously calculate the extent of conversion of angiotensin I (AI) to angiotensin II (AII) and the pulmonary degradation of bradykinin (BK). 3. The pulmonary degradation of BK was significantly elevated (99.4%) in SHR rats whereas the elevation was not significant in SHRSP rats (99.2%) compared to WKY rats, even though the pulmonary inactivation of BK in WKY rats was higher (98.6%) than in normotensive Wistar rats (95.6% and 97.5%) previously studied. 4. Blood pressure responsiveness to intra-aortically injected BK (bolus injection and infusion) was markedly increased in SHR and SHRSP rats with no change in reactivity to sodium nitroprusside. 5. Conversion of AI to AII assessed by the equipressor doses of the hormones which produced a 20-mmHg rise in blood pressure was markedly elevated in SHR (86 +/- 4%) and SHRSP (80 +/- 7%) rats when compared to WKY rats (38 +/- 4%). 6. The marked increase in conversion of AI to AII in hypertensive animals, accompanied by an increased pulmonary degradation of BK in SHR rats, suggests that ACE activity is increased in conscious SHR and SHRSP rats and may participate in the genesis of hypertension in this model of genetic hypertension