RESUMO
OBJECTIVE: To assess the effect on the cardiovascular system, of enalapril (E) or losartan (L) given since weaning during 6 or 18 months to normal rats. METHODS: Animals were divided in three groups: control (C), E-treated and L-treated; treated rats received 10 mg/ kg per day of drug. Systolic blood pressure (SBP), body weight, water and food intake (WI, FI), cardiac, left ventricular and aortic weight as well as the length of the tail were recorded. NADPH-diaphorase activity was determined as a marker of nitric oxide synthase (NOS) activity in aorta, arterioles of small intestine, heart and kidney of normal rats. NOS activity was measured as optical density (OD) in the stained tissue. Nitrate + nitrite urinary excretion was measured in 24 h urine. Only significant differences (P < 0.05) are reported. RESULTS: SBP, absolute cardiac, left ventricular and aortic weight increased with age. Both treatments delayed these increments. At 6 and 18 months, NOS activity was higher in aortic endothelium (Em) of L- and E-treated animals. Losartan treatment during 6 months also increased NOS activity in aortic smooth muscle (SM). Aortic Em NOS activity fell in the 18 months-treated and untreated animals. E increased NOS activity in the SM of intestinal arterioles at 6 months but reduced it at 18 months. CONCLUSIONS: The fact that both E and L delayed cardiac hypertrophy/hyperplasia and aortic growth and raised aortic endothelium NOS activity indicates a protective effect on cardiovascular damage due to aging, exerted through inhibition of angiotensin II.
Assuntos
Envelhecimento/metabolismo , Angiotensina II/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Enalapril/farmacologia , Óxido Nítrico Sintase/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/enzimologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Losartan/farmacologia , Masculino , NADPH Desidrogenase/metabolismo , Nitratos/urina , Nitritos/urina , Ratos , Ratos Wistar , Valores de Referência , Fatores de TempoRESUMO
Previous studies have demonstrated in normal rats that chronic treatment, from weaning to 30 days, with either enalapril or losartan, induced significant changes in cardiovascular structure and function. The present study was performed to assess the effect of either enalapril or losartan on the structure and function of the heart and arteries given to normal rats from weaning until 6 months of age. Animals (n = 48) were divided into three groups: control, enalapril treated, and losartan treated; treated rats received 10 mg/kg/day of drug. Blood pressure, body weight, and water intake were recorded for that time period. DNA, cGMP, collagen, degree of fibrosis, and nitric oxide synthase-NADPH-diaphorase-dependent activity in the heart and arteries were determined. Only significant differences (P < .05) are reported. Blood pressure increased only in control rats (13 +/- 1 mm Hg), enalapril treatment enhanced water intake and reduced the rate of body growth (control, 672.9 +/- 15.4 g; losartan, 692.4 +/- 21.8 g; enalapril, 541.8 +/- 13.8 g). In the heart, DNA (control, 120 +/- 5; losartan, 99 +/- 4; enalapril, 93 +/- 6 microg/100 mg), collagen (control, 2.5 +/- 0.2; enalapril, 1.85 +/- 0.08 microg/100 mg), and fibrosis (control, 3.5 +/- 0.4%; losartan, 2.2 +/- 0.3%; enalapril, 2.1 +/- 0.4%) were reduced by treatment. In the aorta, cGMP (control, 0.15 +/- 0.01; losartan, 0.24 +/- 0.02 pmol/mg), and NADPH-diaphorase (control, 0.114 +/- 0.003; losartan, 0.148 +/- 0.006; enalapril, 0.169 +/- 0.003 as optical density) were enhanced. The enzyme was also higher in the aortic endothelium of treated animals (control, 0.193 +/- 0.010; losartan, 0.228 +/- 0.009; enalapril, 0.278 +/- 0.005). The lower rate of body weight increase, the enhanced water intake, and the reduced cardiac and left ventricular weight attributable to enalapril treatment do not seem to be related to inhibition of the renin-angiotensin system. On the other hand, renin-angiotensin system inhibition induces a protective effect on the heart and aorta through structural and functional changes. Most of this action seems to be exerted through angiotensin II type 1 receptors.
Assuntos
Angiotensina II/antagonistas & inibidores , Sistema Cardiovascular/efeitos dos fármacos , Enalapril/farmacologia , Losartan/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Colágeno/antagonistas & inibidores , GMP Cíclico/metabolismo , DNA/antagonistas & inibidores , Ingestão de Líquidos/efeitos dos fármacos , Fibrose , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , NADPH Desidrogenase/metabolismo , Ratos , Ratos Wistar , Valores de Referência , Sístole , Fatores de TempoRESUMO
This study examined the effect on mean blood pressure of a new orally active nonpeptide angiotensin II (Ang II) receptor antagonist, EXP 3174, in doses that completely block exogenous Ang II action. Anesthetized and conscious two-kidney, two clip chronic renovascular hypertensive rats and sham-operated animals were used. In anesthetized hypertensive rats, intracerebroventricular administration of the inhibitor had no effect on blood pressure, whereas blood pressure was normalized by intravenous injection of the antagonist (163 +/- 12 to 110 +/- 9 mm Hg, P < .05). In sham anesthetized rats, intravenous injection of EXP 3174 also lowered blood pressure (112 +/- 6 to 96 +/- 6mm Hg, P < .05). In conscious rats, intravenous EXP 3174 induced a fall in pressure that was larger in hypertensive (156 +/- 9 to 132 +/- 5 mm Hg, P < .05) than in sham (104 +/- 3 to 94 +/- 4 mm Hg, P < .05) rats. Plasma renin activity was very high in anesthetized animals (hypertensive versus sham, 87.8 +/- 8.3 versus 95.7 +/- 10.2 ng Ang I/mL per hour); differences were not significant either between anesthetized hypertensive and sham or in conscious animals (hypertensive versus sham, 9.42 +/- 1.58 versus 6.74 +/- 2.32 ng Ang I/mL per hour). Angiotensinogen concentration was higher in cerebrospinal fluid in anesthetized hypertensive rats (36.4 +/- 3.0 versus 26.0 +/- 2.4 ng Ang I/mL, P < .05) and in the artery wall of hypertensive conscious rats (103.1 +/- 10.3 versus 75.2 +/- 7.8 ng Ang I/g, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão Renal/sangue , Hipertensão Renal/fisiopatologia , Imidazóis/farmacologia , Renina/sangue , Tetrazóis/farmacologia , Angiotensinogênio/líquido cefalorraquidiano , Angiotensinogênio/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Artérias/metabolismo , Imidazóis/administração & dosagem , Injeções Intravenosas , Injeções Intraventriculares , Losartan , Masculino , Ratos , Ratos Wistar , Tetrazóis/administração & dosagemRESUMO
The norepinephrine (NE) content, the uptake of [3H]NE, the turnover time, the turnover and the synthesis rate of the neurotransmitter in the heart and blood vessels were studied in the chronic phase of two kidney and one kidney Goldblatt renovascular hypertension, in the rat. Intact and sham operated animals were used as controls. Fifty percent of the rats subjected to renal clipping developed hypertension. This fact allowed us to compare changes in clip operated hypertensive and normotensive animals. The weight of the hearts and blood vessels was significantly increased in clip operated rats. Changes were greater in hypertensive animals. NE concentration and total content in the heart and in the artery wall were significantly decreased in the clipped rats. [3H]NE uptake was significantly diminished in the heart of experimental animals; in the artery wall, uptake was much lower than in the heart but no differences were observed between clip operated and sham animals. The turnover of NE was not different among control and clip operated rats either in the heart or in the blood vessels. Synthesis rate was lower in hypertensive animals than in their respective controls, explaining the lower concentration of the amine in cardiovascular tissues. The present data do not suggest that an increased turnover of NE in the cardiovascular sympathetic nerve endings is involved in the maintenance of high blood pressure in both types of Goldblatt renovascular hypertension.
Assuntos
Vasos Sanguíneos/metabolismo , Hipertensão Renovascular/metabolismo , Miocárdio/metabolismo , Norepinefrina/metabolismo , Animais , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Coração/anatomia & histologia , Masculino , Tamanho do Órgão , Ratos , Ratos Wistar , TrítioAssuntos
Hipertensão/complicações , Complicações Cardiovasculares na Gravidez/fisiopatologia , Sódio na Dieta/administração & dosagem , Animais , Aorta/metabolismo , Pressão Sanguínea/fisiologia , DNA/metabolismo , Feminino , Hipertensão/etiologia , Hipertensão/fisiopatologia , Gravidez , Complicações Cardiovasculares na Gravidez/etiologia , Proteínas/metabolismo , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina/fisiologiaRESUMO
Some reports have stated that central norepinephrine (NE) depletion inhibited the development of hypertension in the rat. On the other hand, this pharmacological treatment induces changes on the central renin-angiotensin system. The present study was designed to follow the development of 2 kidney-2 clip (2k-2c) renovascular hypertension in rats depleted of central NE and to analyze the central and peripheral renin-angiotensin system. Male Wistar rats (n = 40) were used. Half of the animals was injected, intracisternally, with 6-hydroxydopamine (6-OHDA), the remaining rats only received the vehicle. One week later a silver clip was placed on each renal artery on half of the 6-OHDA treated rats and on half of the vehicle treated animals. A sham operation was performed on the remaining rats. Blood pressure was measured weekly during 7 weeks. Then, blood and cerebrospinal fluid (CSF) samples were obtained. The brain was dissected in several areas. NE and angiotensinogen concentration (AoC) were determined in tissue samples. AoC was evaluated in plasma and CSF; plasma renin activity was also measured. Hypertension development was not prevented by central NE depletion, which was significant in all central areas (p < 0.001). Other significant results showed that renal ischemia and/or NE depletion induced a significant increase in angiotensinogen concentration in the hypothalamus (p < 0.01) and in CSF (p < 0.05). In summary: central NE depletion was not able to modify the development of 2 k - 2 c hypertension. Treatment and renal ischemia induced an increase of central AoC.
Assuntos
Hipertensão Renovascular/etiologia , Norepinefrina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea , Encéfalo/metabolismo , Hipertensão Renovascular/fisiopatologia , Masculino , Oxidopamina , Ratos , Ratos Wistar , Renina/metabolismo , Simpatectomia Química , Sistema Nervoso Simpático/metabolismoRESUMO
The participation of the central serotonergic system in the development of two-kidney, two clip (2K2C) Goldblatt renovascular hypertension in the rat has been examined. Half of the rats were treated with desmethylimipramine intraperitoneally and 5,7-dihydroxytryptamine intracisternally; the other half received only desmethylimipramine and the 5,7-dihydroxytryptamine vehicle. Two days later, a silver clip was placed in both renal arteries in half of the rats of each group. A sham operation was performed in the remaining rats. Blood pressure was recorded during the 5 weeks after treatment. At the end of the experiment, blood and cerebrospinal fluid samples were obtained. The brain was dissected into several areas and kept frozen. Norepinephrine, serotonin, angiotensinogen, and renin-like concentration were evaluated in the brain areas. Plasma renin activity and angiotensinogen concentration in the plasma and cerebrospinal fluid were estimated. In the sham-operated groups, blood pressure was lower in the treated than in the control rats. The curve of blood pressure increase, as well as the final blood pressure, was similar in the treated and control 2K2C rats. Serotonin was significantly depleted by the 5,7-dihydroxytryptamine treatment in all brain areas. Treatment did not induce any changes in central norepinephrine concentration. Plasma renin activity was diminished in the treated sham-operated rats. These data indicate that the central serotonin depletion does not prevent the development of hypertension and confirm the role of the amine in normal blood pressure regulation. On the other hand, the peripheral renin-angiotensin system might participate in the development of high blood pressure in serotonin-depleted animals.
Assuntos
Encéfalo/metabolismo , Hipertensão Renovascular/etiologia , Serotonina/deficiência , 5,7-Di-Hidroxitriptamina/farmacologia , Angiotensinogênio/líquido cefalorraquidiano , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea , Desipramina/farmacologia , Hipertensão Renovascular/sangue , Hipertensão Renovascular/fisiopatologia , Masculino , Norepinefrina/metabolismo , Concentração Osmolar , Ratos , Ratos Endogâmicos , Renina/sangue , Serotonina/metabolismoRESUMO
Previous investigations have shown that depletion of brain norepinephrine (NE) induced by chemical sympathectomy resulted in significant changes in the central renin-angiotensin system. The purpose of the present work was to increase the NE concentration in the central nervous system (CNS) in order to analyze its effect on the peptidergic complex and on the blood pressure (BP) levels. Treated rats were given the following drugs in the drinking water: 1-dopa (12 mg/rat/day), carbidopa (6 mg/rat/day) and pargyline (10 mg/rat/day) during 25 days. BP was determined, blood and cerebrospinal fluid (CSF) samples were obtained. The CNS was dissected into several areas. NE, angiotensinogen (AoC) and renin concentration (RC) were determined in the brain parenchyma; AoC was evaluated in CSF and plasma samples. Pharmacological treatment resulted in an hypotensive effect and, at the same time, an increase of NE in the CNS (about 100%; p less than 0.0005). These changes were accompanied by a significant decrease in the peripheral and central AoC. These results add new evidence to the postulated relationship between these two important regulatory systems involved in cardiovascular control.
Assuntos
Encéfalo/fisiologia , Norepinefrina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Angiotensinogênio/metabolismo , Animais , Pressão Sanguínea , Sistema Nervoso Central/metabolismo , Epinefrina/metabolismo , Masculino , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos , Renina/metabolismoRESUMO
The aim of this study was to evaluate the components of the renin-angiotensin system in the periphery and in the central nervous system (CNS) of the spontaneous hypertensive rats (SHR). On the other hand, the norepinephrine (NE) content of the different areas and of the mesenteric artery were also measured. Sixteen SHR and 9 Wistar Kyoto (WKY) control animals were used at about 6 months of age. Blood and cerebrospinal fluid (CSF) samples were collected. The brain was dissected into several areas and the mesenteric artery was excised. Plasma renin activity (PRA), plasma angiotensinogen concentration (P1AoC), brain renin (RC) and angiotensinogen concentrations (AoC) were evaluated by radioimmunoassay. NE was determined in all the tissues by a fluorimetric technique. PRA, P1AoC and NE concentration in the mesenteric artery were similar in both groups. An increase in the NE content of the cerebellum was detected in the SHR without changes in the other areas of the CNS. AoC was decreased in the CSF and in the brain stem of the SHR animals. RC was evaluated in the hypothalamus, brain stem, cerebral cortex and cerebellum of the same strain of rats. These results seem to indicate the some alteration of the peptidergic system in the CNS is present in the hypertensive animals.
Assuntos
Hipertensão/metabolismo , Norepinefrina/metabolismo , Sistema Renina-Angiotensina , Animais , Encéfalo/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Distribuição TecidualRESUMO
In the present study we examined the effect of depletion of central nervous system serotonin by 5,7-dihydroxytryptamine on blood pressure in male Wistar rats. We also analyzed the relationship between the serotonergic and renin-angiotensin systems. Blood pressure was determined before and after intracisternal administration of 5,7-dihydroxytryptamine, 200 micrograms in saline with 1 mg/ml ascorbic acid (n = 9). Control rats (n = 8) received intracisternal vehicle. Before sacrifice, blood and cerebrospinal fluid samples were obtained. The brain was dissected in several areas. Serotonin, norepinephrine, angiotensinogen, and reninlike concentrations were determined in the brain parenchyma; angiotensinogen concentration was evaluated in cerebrospinal fluid and plasma samples; plasma renin activity was also measured. Treatment produced a significant decrease in blood pressure (-10 mm Hg; p less than 0.025) and, simultaneously, a high depletion of serotonin stores in the studied central areas (p less than 0.001), except in the cerebral cortex. Reninlike concentration was increased in the medulla oblongata (p less than 0.005) and the brainstem (p less than 0.02) after 5,7-dihydroxytryptamine treatment. Angiotensinogen concentration was decreased in the hypothalamus and elevated in the spinal cord. Angiotensinogen concentration in cerebrospinal fluid, plasma angiotensinogen concentration, and plasma renin activity did not change with treatment. Serotonin concentration in the cerebrospinal fluid remained unchanged, while the 5-hydroxyindoleacetic acid level was diminished (-47%; p less than 0.001). Intracisternal administration of 5,7-dihydroxytryptamine produced a hypotensive effect in normal rats and several modifications of the renin-angiotensin complex, suggesting a relationship between the monoaminergic and peptidergic systems.
Assuntos
Pressão Sanguínea , Sistema Renina-Angiotensina , Serotonina/fisiologia , 5,7-Di-Hidroxitriptamina/farmacologia , Angiotensinogênio/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Ratos , Ratos EndogâmicosRESUMO
The effect of ketanserin (Kt) has been analyzed during the development of two-kidney-two-clip (2k-2c) renovascular hypertension in the rat. Male Wistar rats were divided into four experimental groups: (1) clip Kt (ClKt) (n = 12)--A silver clip (0.25 mm width) was placed in each renal artery 3 days after beginning the administration of Kt (10 mg/kg/day) in the drinking water; (2) sham Kt (ShKt) (n = 13)--Similar to group 1, but the clips were placed in, and immediately removed from, the renal arteries; (3) untreated clip (UCl) (n = 10)--Similar to group 1, but the rats drank water; (4) untreated sham (USh) (n = 10)--Similar to group 2, but the rats drank water. Blood pressure (BP) was measured before surgery and was followed weekly for 7 weeks. At the end of this period, blood and cerebrospinal fluid (CSF) samples were obtained in all the animals. Plasma renin activity (PRA) and plasma and CSF angiotensinogen concentration (AoC) were evaluated. The results have shown that Kt partially inhibited the increase in BP induced by bilateral renal ischemia (BP: UCl rats 180.5 +/- 12.4 versus ClKt rats 149.8 +/- 5.1 mm Hg; p less than 0.01; USh rats 116.7 +/- 3.7; ShKt rats 114.4 +/- 5.0 mm Hg). PRA was similar in hypertensive and control rats whether or not they had received Kt. AoC in plasma was decreased in clipped treated and untreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)