RESUMO
Prolonged high-fat diet (HFD) accelerates the cardiovascular, renal, and metabolic dysfunction in hypertensive rats with altered renal development (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and metabolic function in settings of hypertension and obesity. This study examined whether 6 wk treatment with an SGLT2 inhibitor (empagliflozin, 7 mg/kg/day) enhances the cardiovascular, renal, and metabolic effects of a sGC stimulator (praliciguat, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat abdominal volume (FAV), insulin resistance, leptin and triglycerides levels, and intrarenal infiltration of inflammatory cells were higher, but cardiac output and creatinine clearance were lower in hypertensive rats (n = 15) than in normotensive rats (n = 7). Praliciguat administration (n = 10) to hypertensive rats reduced (P < 0.05) AP, FAV, plasma concentrations of leptin and triglycerides, and increased (P < 0.05) cardiac output and creatinine clearance. Empagliflozin administration (n = 8) only increased (P < 0.05) glucosuria and creatinine clearance and decreased (P < 0.05) plasma leptin and triglycerides concentrations in hypertensive rats. Simultaneous administration of praliciguat and empagliflozin (n = 10) accelerated the decrease in AP, improved glucose tolerance, reduced (P < 0.05) incremental body weight gain, and decreased (P < 0.05) insulin resistance index, RVR, and the infiltration of T-CD3 lymphocytes in renal cortex and renal medulla. In summary, the combined administration of praliciguat and empagliflozin leads to a greater improvement of the cardiovascular, renal, and metabolic dysfunction secondary to prolonged exposure to HFD in hypertensive rats with ARDev than the treatment with either praliciguat or empagliflozin alone.NEW & NOTEWORTHY This is the first study, to our knowledge, showing that SGLT2 inhibition potentiates the beneficial cardiovascular, renal, and metabolic effects elicited by sGC stimulation in hypertensive rats with prolonged high-fat diet. The effects of the simultaneous administration of praliciguat and empagliflozin are greater than those elicited by either one alone. The effects of the simultaneous treatment may be related to a greater reduction in the inflammatory status.
Assuntos
Hipertensão , Resistência à Insulina , Animais , Compostos Benzidrílicos/farmacologia , Creatinina , Dieta Hiperlipídica/efeitos adversos , Glucose , Leptina , Ratos , Transportador 2 de Glucose-Sódio , Guanilil Ciclase Solúvel , TriglicerídeosRESUMO
The mechanisms involved in renal dysfunction induced by high-fat diet (HFD) in subjects with altered renal development (ARDev) are understudied. The objective of this study is to examine whether there are sex-dependent differences in the mechanisms involved in the hypertension and deterioration of renal function in SD rats with prolonged HFD and ARDev. The role of angiotensin II (Ang II) in the arterial pressure (AP) increments, the renal hemodynamic sensitivity to Ang II, glomerular damage and changes in fat abdominal volume, plasma adipokine levels, renal NADPHp67phox expression, and renal infiltration of immune cells were examined. Hypertension and deterioration of renal function were enhanced (P < 0.05) in both sexes of rats with HFD and ARDev. The decrease (P < 0.05) of AP elicited by candesartan in hypertensive rats was similar to that induced by the simultaneous administration of candesartan and apocynin. The greater (P < 0.05) renal vasoconstriction induced by Ang II in both sexes of rats with HFD and ARDev was accompanied by an enhanced (P < 0.05) infiltration of CD-3 cells and macrophages in the renal cortex and renal medulla. The increments (P < 0.05) in the renal expression of NADPHp67phox and glomeruloesclerosis were greater (P < 0.05) in males than in females with HFD and ARDev. Our results suggest that the hypertension and deterioration of renal function induced by HFD in rats with ARDev are Ang II-dependent and mediated by increments in oxidative stress and immune system activation. Sex-dependent increments in oxidative stress and glomerular damage may contribute to the deterioration of renal function in these rats.
Assuntos
Dieta Hiperlipídica , Hipertensão/fisiopatologia , Nefropatias/fisiopatologia , Rim , Fatores Sexuais , Animais , Feminino , Rim/fisiopatologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To examine whether the cardiac, renal and uterine physiological hemodynamic changes during gestation are altered in rats with an early and prolonged exposure to a high fat diet (HFD). METHODS: Arterial pressure and cardiac, renal, uterine and radial arteries hemodynamic changes during gestation were examined in adult SD rats exposed to normal (13%) (n = 8) or high (60%) (n = 8) fat diets from weaning. Plethysmography, high-resolution high-frequency ultrasonography and clearance of an inulin analog were used to evaluate the arterial pressure and hemodynamic changes before and at days 7, 14 and 19 of gestation. RESULTS: Arterial pressure was higher (P<0.05) in rats with high than in those with normal (NFD) fat diet before pregnancy (123 ±3 and 110 ±3 mmHg, respectively) and only decreased at day 14 of gestation in rats with NFD (98±4 mmHg, P<0.05). A significant increment in stroke volume (42 ±10%) and cardiac output (51 ±12%) was found at day 19 of pregnancy in rats with NFD. The changes in stroke volume and cardiac output were similar in rats with NFD and HFD. When compared to the values obtained before pregnancy, a transitory elevation in renal blood flow was found at day 14 of pregnancy in both groups. However, glomerular filtration rate only increased (P<0.05) in rats with NFD at days 14 (20 ±7%) and 19 (27 ±8%) of gestation. The significant elevations of mean velocity, and velocity time integral throughout gestation in radial (127 ±26% and 111 ±23%, respectively) and uterine (91 ±16% and 111 ±25%, respectively) arteries of rats with NFD were not found in rats with an early and prolonged HFD. SUMMARY: This study reports novel findings showing that the early and prolonged exposure to a HFD leads to a significant impairment in the renal, uterine and radial arteries hemodynamic changes associated to gestation.
Assuntos
Artérias/fisiopatologia , Vasos Coronários/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Fenômenos Fisiológicos da Nutrição Animal , Animais , Artérias/diagnóstico por imagem , Pressão Sanguínea/fisiologia , Vasos Coronários/diagnóstico por imagem , Feminino , Taxa de Filtração Glomerular/fisiologia , Rim/irrigação sanguínea , Modelos Animais , Gravidez , Ratos , Fluxo Sanguíneo Regional/fisiologia , Volume Sistólico/fisiologia , Ultrassonografia , Útero/irrigação sanguínea , Útero/diagnóstico por imagemRESUMO
Regulation of medullary blood flow (MBF) is essential in maintaining renal function and blood pressure. However, it is unknown whether outer MBF (OMBF) and papillary blood flow (PBF) are regulated independently when extracellular volume (ECV) is enhanced. The aim of this study was to determine whether OMBF and PBF are differently regulated and whether there is an interaction between nitric oxide (NO), prostaglandins (PGs) and angiotensin II (Ang II) in regulating OMBF and PBF when ECV is enhanced. To achieve these goals, OMBF and PBF were measured by laser-Doppler in volume-expanded rats treated with a cyclooxygenase inhibitor (meclofenamate, 3 mg/kg) and/or a NO synthesis inhibitor (L-nitro-arginine methyl ester (L-NAME), 3 µg/kg/min) and/or Ang II (10 ng/kg/min). OMBF was unchanged by NO or PGs synthesis inhibition but decreased by 36 % (P < 0.05) when L-NAME and meclofenamate were infused simultaneously. PBF was similarly reduced by L-NAME (12 %), meclofenamate (17 %) or L-NAME + meclofenamate (19 %). Ang II did not modify OMBF, but it led to a similar decrease (P < 0.05) in OMBF when it was administered to rats with reduced NO (32 %), PGs (36 %) or NO and PGs (37 %) synthesis. In contrast, the fall in PBF induced by Ang II (12 %) was enhanced (P < 0.05) by the simultaneous PGs (30 %) or PGs and NO (31 %) synthesis inhibition but not in L-NAME-treated rats (20 %). This study presents novel findings suggesting that blood flows to the outer medulla and renal papilla are differently regulated and showing that there is a complex interaction between NO, PGs and Ang II in regulating OMBF and PBF when ECV is enhanced.
Assuntos
Angiotensina II/fisiologia , Medula Renal/irrigação sanguínea , Óxido Nítrico/fisiologia , Prostaglandinas/fisiologia , Fluxo Sanguíneo Regional/fisiologia , Animais , Taxa de Filtração Glomerular , Masculino , Ratos , Ratos WistarRESUMO
Numerous studies have evaluated blood pressure (BP) and renal changes in several models of developmental programming of hypertension. The present study examined to what extent BP, renal hemodynamic, and renal structure are affected at an old age in male and female animals with altered renal development. It also evaluated whether renal damage is associated with changes in cyclooxygenase (COX)-2 and neuronal nitric oxide synthase (NOS1) expression and immunoreactivity. Experiments were carried out in rats at 10-11 and 16-17 mo of age treated with vehicle or an ANG II type 1 receptor antagonist during the nephrogenic period (ARAnp). A progressive increment in BP and a deterioration of renal hemodynamics were found in both sexes of ARAnp-treated rats, with these changes being greater (P < 0.05) in male rats. The decrease in glomerular filtration rate at the oldest age was greater (P < 0.05) in male (74%) than female (32%) ARAnp-treated rats. Sex-dependent deterioration of renal structure was demonstrated in optical and electron microscopic experiments. COX-2 and NOS1 immunoreactivity were enhanced in the macula densa of male but not female ARAnp-treated rats. The present study reports novel findings suggesting that stimuli that induce a decrease of ANG II effects during renal development lead to a progressive increment in BP and renal damage at an old age in both sexes, but these BP and renal changes are greater in males than in females. The renal damage is associated with an increase of COX-2 and NOS1 in the macula densa of males but not females with altered renal development.
Assuntos
Envelhecimento/fisiologia , Hipertensão/fisiopatologia , Óxido Nítrico Sintase Tipo I/biossíntese , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Ciclo-Oxigenase 2/metabolismo , Feminino , Taxa de Filtração Glomerular/fisiologia , Hipertensão/etiologia , Imidazóis/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Tetrazóis/farmacologiaRESUMO
The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na(+) intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na(+) intake (NSI) or low Na(+) intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg·kg(-1)·day(-1) PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg·kg(-1)·day(-1)) reduced RBF (P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease (P < 0.05) in PGE2 and an increase (P < 0.05) in 6-keto-PGF1α. The administration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na(+) intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors.
Assuntos
Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/metabolismo , Rim/fisiologia , Circulação Renal/fisiologia , Sódio/farmacologia , Aldosterona/sangue , Animais , Benzoxazóis/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Cães , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Oxirredutases Intramoleculares/genética , Rim/efeitos dos fármacos , Piperidinas/farmacologia , Potássio/urina , Prostaglandina-E Sintases , Circulação Renal/efeitos dos fármacos , Sódio/administração & dosagem , Sódio/urina , Tromboxano B2/sangueRESUMO
It is known that cyclooxygenase-2 (COX-2) inhibition elicits significant renal hemodynamics alterations when sodium intake is low. However, the mechanisms involved in these renal changes are not well known. Our objective was to evaluate the role of angiotensin II and 5-lipooxygenase-derived metabolites in the renal effects induced by prolonged COX-2 inhibition when sodium intake is low. Conscious dogs were treated during 7 days with a COX-2 inhibitor (1 mg·kg·d, SC75416), and either a vehicle, an AT1 receptor antagonist (0.4 mg · kg · d, candesartan) or a selective 5-lipooxygenase inhibitor (PF-150, 20 and 60 mg · kg · d). The administration of SC75416 alone induced significant changes in renal blood flow (219 ± 14 to 160 ± 10 mL/min), glomerular filtration rate (51 ± 2 to 42 ± 3 mL/min), and plasma potassium (pK) (4.3 ± 0.1 to 4.6 ± 0.1 mEq/L). Similar decrements in renal blood flow (27%) and glomerular filtration rate (20%) and a similar increment in pK (7%) were found when SC75416 was administered in candesartan-pretreated dogs. However, SC75416 administration did not elicit significant changes in renal hemodynamics and pK in dogs pretreated with each dose of PF-150. Our data suggest that leukotrienes but not angiotensin II are involved in the renal effects induced by COX-2 inhibition when sodium intake is low.
Assuntos
Angiotensina II/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dieta Hipossódica , Leucotrienos/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Benzopiranos/farmacologia , Compostos de Bifenilo , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Cães , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/metabolismo , Inibidores de Lipoxigenase/administração & dosagem , Inibidores de Lipoxigenase/farmacologia , Piranos/administração & dosagem , Piranos/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Circulação Renal/efeitos dos fármacos , Tetrazóis/farmacologiaRESUMO
BACKGROUND: An elevated plasma level of homocysteine (hyperhomocysteinemia) is thought to be an important risk factor for a variety of cardiovascular diseases including preeclampsia. Although clinical studies have reported a two- to threefold elevation in plasma levels of homocysteine in women who developed preeclampsia, the importance of hyperhomocysteinemia in causing endothelial dysfunction and increases in arterial pressure during pregnancy is unknown. METHODS: Therefore, the purpose of this study was to determine the effects of a two- to threefold elevation in plasma homocysteine levels on arterial pressure, chronic pressure-natriuresis relationship, and endothelial factors during pregnancy in the rat. Homocysteine treatment for 4 weeks increased plasma homocysteine levels in pregnant rats from 7.1 +/- 1.9 to 16.7 +/- 2.3 micromol/l. RESULTS: Homocysteine treatment decreased urinary nitrate/nitrite levels from 53 +/- 7 vs. 39 +/- 5 (micromol/24 h/kg body weight) in pregnant rats whereas having no effect on urinary excretion of endothelin. Homocysteine treatment had no effect on mean arterial pressure (MAP) in pregnant rats (104 +/- 2 vs. 107 +/- 3 mm Hg) nor on the chronic pressure-natriuresis relationship. CONCLUSIONS: These results suggest that although hyperhomocysteinemia decreases nitric oxide (NO) production in pregnant rats, hyperhomocysteinemia does not affect MAP, the chronic pressure-natriuresis relationship, or urinary excretion of endothelin in pregnant rats. Moreover, the reported two- to threefold elevation in plasma level of homocysteine in women with preeclampsia is unlikely to contribute to the hypertension of preeclampsia.
Assuntos
Pressão Sanguínea , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/fisiopatologia , Óxido Nítrico/metabolismo , Complicações Cardiovasculares na Gravidez/metabolismo , Complicações Cardiovasculares na Gravidez/fisiopatologia , Animais , Feminino , Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Pré-Eclâmpsia/etiologia , Gravidez , RatosRESUMO
Several studies have proposed that cyclooxygenase-2 (COX2) is involved in the regulation of nephrogenesis and that an impaired nephrogenesis may induce the development of hypertension. This study was designed to test the hypothesis that the decrease of COX2 activity leads to a reduction in nephron number, an increase in arterial pressure, and age-dependent renal alterations that are greater in male than in female rats. Arterial pressure was measured from the first to the 16th month of life in rats treated with vehicle or a COX2 inhibitor during the nephrogenic period. Stereological and histological evaluations and renal function studies were performed at different ages. Arterial pressure increased (14%; P<0.05) and nephron number decreased (17%; P<0.05) to similar levels in male and female COX2-treated rats. However, glomerular filtration rate (31%) and renal plasma flow (25%) decreased (P<0.05) in male but not in female COX2-treated rats. A greater (P<0.05) age-dependent elevation in glomerular hypertrophy was also found in male COX2-treated rats compared with their female littermates. Glomerulosclerosis and tubulointerstitial damage in renal cortex and medulla were also significantly enhanced in male but not in female aged COX2-treated rats. Our results demonstrate that the decrease in COX2 activity during renal development leads to a reduction in nephron number and to an elevation in arterial pressure that are similar in males and females. However, the consequent age-dependent deterioration of the renal structure and renal function is only significantly enhanced in male rats.
Assuntos
Envelhecimento/metabolismo , Ciclo-Oxigenase 2/metabolismo , Hipertensão/enzimologia , Glomérulos Renais/enzimologia , Néfrons/embriologia , Néfrons/enzimologia , Caracteres Sexuais , Envelhecimento/patologia , Animais , Pressão Sanguínea/fisiologia , Peso Corporal , Feminino , Taxa de Filtração Glomerular/fisiologia , Hipertensão/etiologia , Hipertensão/patologia , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/patologia , Masculino , Néfrons/patologia , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/fisiologiaRESUMO
A chronic reduction in uterine perfusion pressure in the pregnant rat is associated with significant elevations in mean arterial pressure, proteinuria, and reductions in kidney function as is chronic nitric oxide blockade, suggesting that nitric oxide deficiency may contribute to the clinical manifestations of preeclampsia. The purpose of this study was to determine whether supplementation with L-arginine, the precursor for nitric oxide, attenuates the hypertension produced in response to a chronic reduction in uterine perfusion pressure in the pregnant rat. Reduced uterine perfusion was initiated at day 14 of gestation with arterial pressure determined at day 19 of gestation in conscious, chronically instrumented rats. Arterial pressure was significantly elevated in pregnant rats with chronic reductions in uterine perfusion as compared with pregnant control rats (132+/-2 versus 109+/-2 mm Hg, P<0.01, respectively). Treatment with L-arginine (2%) in the drinking water was initiated at day 10 of gestation. l-arginine supplementation resulted in a significant decrease in arterial pressure in both pregnant rats with reduced uterine perfusion pressure (113+/-2 mm Hg treated, P<0.01 versus untreated pregnant with reduced uterine perfusion pressure) and pregnant control (97+/-3 mm Hg treated, P<0.01 versus untreated pregnant) rats. However, supplementation with L-arginine decreased blood pressure by 19 mm Hg in pregnant with reduced uterine perfusion pressure (untreated versus treated) as compared with 12 mm Hg in pregnant (untreated versus treated) rats. Thus, these results suggest that l-arginine supplementation may be beneficial in attenuating the hypertension in preeclampsia.
Assuntos
Arginina/uso terapêutico , Hipertensão/tratamento farmacológico , Doadores de Óxido Nítrico/uso terapêutico , Óxido Nítrico/fisiologia , Pré-Eclâmpsia/prevenção & controle , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Útero/irrigação sanguínea , Animais , Arginina/farmacologia , Constrição , Endotélio Vascular/fisiopatologia , Feminino , Hipertensão/fisiopatologia , Óxido Nítrico/deficiência , Doadores de Óxido Nítrico/farmacologia , Pré-Eclâmpsia/etiologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Complicações Cardiovasculares na Gravidez/fisiopatologia , Pressão , Ratos , Ratos Sprague-Dawley , Sistema Vasomotor/fisiopatologiaRESUMO
The present study tested the hypothesis that cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) are involved in mediating hypertension and renal vasoconstriction during chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats. 1-aminobenzotriazole (ABT), a CYP enzyme inhibitor (25 mg/kg per day), or vehicle (saline 0.9%) was administered for 7 days to normal pregnant (NP) rats and to pregnant rats with chronic RUPP. RUPP rats infused with vehicle showed significantly (P<0.01) higher mean arterial pressure (MAP) (130+/-2 versus 106+/-1 mm Hg), renal vascular resistance (RVR) (22.6+/-1.8 versus 16.3+/-1.1 mm Hg/mL per minute) and lower (P<0.05) glomerular filtration rate (GFR) (1.6+/-0.1 versus 2.3+/-0.1 mL/min) than NP rats. ABT decreased (P<0.01) MAP in RUPP rats (111+/-1 mm Hg), whereas it had no effect in NP rats (108+/-2 mm Hg). CYP inhibition also attenuated the differences in renal hemodynamics observed between NP and RUPP rats. After treatment with ABT, RVR and GFR were similar in RUPP rats (19.3+/-1.5 mm Hg/mL per minute and 2.0+/-0.2 mL/min, respectively) and NP rats (16.3+/-2.4 mm Hg/mL per minute and 2.4+/-0.2 mL/min). The effects of CYP enzymes inhibitor in RUPP rats were associated with a reduction (P<0.05) of 20-HETE formation (32%) and a decreased (P<0.05) expression (33%) of CYP4A protein in renal cortex. In contrast, renal epoxygenase activity did not change in these animals. These results suggest that 20-HETE contributes to hypertension and renal vasoconstriction induced by chronic RUPP in pregnant rats.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Pré-Eclâmpsia/etiologia , Útero/irrigação sanguínea , Animais , Ácidos Araquidônicos/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP4A/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Hemodinâmica/efeitos dos fármacos , Hipertensão/etiologia , Rim/fisiopatologia , Córtex Renal/metabolismo , Pré-Eclâmpsia/enzimologia , Pré-Eclâmpsia/fisiopatologia , Gravidez , Ratos , Ratos Sprague-Dawley , Triazóis/farmacologiaRESUMO
Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1-treated rats was 141+/-3 mm Hg, compared with 125+/-2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3+/-2.5 versus 10+/-1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5+/-0.9 versus 8.7+/-0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F2alpha excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127+/-4 versus 127+/-4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F2alpha in the endothelin-1-treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.
Assuntos
Dinoprosta/análogos & derivados , Endotelina-1/toxicidade , Hipertensão/induzido quimicamente , Espécies Reativas de Oxigênio/metabolismo , Vasoconstritores/toxicidade , Animais , Células Cultivadas , Doença Crônica , Óxidos N-Cíclicos/farmacologia , Endotelina-1/farmacologia , F2-Isoprostanos/urina , Sequestradores de Radicais Livres/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Músculo Liso Vascular/metabolismo , Ratos , Ratos Sprague-Dawley , Marcadores de Spin , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Vasoconstritores/farmacologiaRESUMO
We have reported that the renal hemodynamic effects of norepinephrine (NE) are modulated by cyclooxygenase-2 (COX-2)-derived metabolites. Our main objective was to examine whether there is an interaction between nitric oxide (NO) and COX-2 in modulating the renal hemodynamic effects of NE. NE was infused at three doses to anesthetized dogs pretreated with vehicle (n = 8), a selective COX-2 inhibitor (nimesulide) (n = 6), an NO synthesis inhibitor [NG-nitro-l-arginine methyl ester; l-NAME] (n = 8), or with nimesulide and l-NAME (n = 5). During NE infusion, PGE2 excretion increased (125%) in the control group and did not change in the l-NAME-treated dogs. The simultaneous inhibition of NO and COX-2 potentiated to a greater extent the NE-induced renal vasoconstriction than inhibition of either NO or COX-2. The NE-induced renal vasoconstriction during NO and COX-2 inhibition was reduced (P < 0.05) by infusing an AT1 receptor antagonist (n = 6). These results suggest that there is an interaction between NO and COX-2 in protecting the renal vasculature from the NE effects and that angiotensin II partly mediates the NE-induced renal vasoconstriction when NO synthesis and COX-2 activity are reduced.
Assuntos
Hemodinâmica/efeitos dos fármacos , Isoenzimas/metabolismo , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Óxido Nítrico/metabolismo , Norepinefrina/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/enzimologia , Rim/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Circulação Renal/efeitos dos fármacos , Sulfonamidas/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
The role of cyclooxygenase-2 (COX-2) in the prolonged regulation of renal function was evaluated during changes in sodium intake and reduction of NO synthesis. It was evaluated in conscious dogs by administering a selective inhibitor (nimesulide) during 8 consecutive days. Nimesulide administration to dogs with normal or high sodium load did not modify glomerular filtration rate but reduced renal blood flow (16%; P<0.05). The vasoconstriction elicited by COX-2 inhibition was greater when NO production was inhibited because glomerular filtration rate decreased by >25% when nimesulide was administered to dogs with a reduced NO synthesis. During low sodium intake, COX-2 inhibition elicited a decrease (P<0.05) of both glomerular filtration rate (34%) and renal blood flow (31%). Sodium excretion only decreased (P<0.05) during the first day of COX-2 inhibition in dogs with normal or high sodium load. The increase in plasma potassium levels elicited by COX-2 inhibition was greater in dogs with low sodium intake and was enhanced when NO production was inhibited. This change in potassium was not secondary to a decrease in plasma aldosterone levels. The results of this study suggest that COX-2-derived metabolites (1) play a more important role in the long-term regulation of renal hemodynamic when sodium intake is low, (2) protect the renal vasculature from the vasoconstriction secondary to a reduction in NO, (3) are only acutely involved in regulating urinary sodium excretion, and (4) play a more important role in regulating plasma potassium concentration when NO synthesis is reduced.
Assuntos
Isoenzimas/metabolismo , Rim/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Aldosterona/sangue , Animais , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Infusões Intravenosas , Isoenzimas/antagonistas & inibidores , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Testes de Função Renal , Modelos Animais , Óxido Nítrico/metabolismo , Potássio/sangue , Prostaglandinas/urina , Circulação Renal/efeitos dos fármacos , Renina/sangue , Sódio/sangue , Sódio/metabolismo , Sódio/urina , Cloreto de Sódio/administração & dosagem , Sódio na Dieta/farmacologia , Sulfonamidas/farmacologia , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
BACKGROUND: The purpose of this study was to determine the role of thromboxane A2 (TXA2) in a conscious, chronically instrumented rat model of pregnancy-induced hypertension (PIH) produced by chronic reductions in uterine perfusion pressure (RUPP). METHODS: Mean arterial pressure (MAP), glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and 24-h urinary excretion of TXB2 (metabolite of TXA2) were determined in normal pregnant rats and RUPP pregnant rats. RESULTS: At day 20 of pregnancy, RUPP rats showed a significantly (P < .05) higher MAP (125 +/- 3 mm Hg v 100 +/- 2 mm Hg) as compared with normal pregnant controls. The elevation in arterial pressure in RUPP group was associated with a marked increase (P < .05) in the urinary concentration of TXB2 compared with normal pregnant group (3663 +/- 488 v 2646 +/- 257 pg/24 h). Baseline GFR (1.74 +/- 0.13 v 2.40 +/- 0.20 mL/min, respectively, P < .05) and ERPF (5.13 +/- 0.44 v 6.44 +/- 0.58 mL/min, respectively) were decreased in RUPP rats relative to pregnant controls. Infusion of a TX receptor antagonist, SQ 29,548 (2 mg/kg bolus plus 2 mg/kg per h infusion) had no significant effect on increased MAP in RUPP pregnant rats. Similarly, ERPF and GFR did not change during acute blockade of TXA2 receptors in this group. CONCLUSION: These findings suggest that enhanced production of TXA2 does not play a major role in mediating the hypertension and renal vasoconstriction produced by chronic RUPP in pregnant rats.
Assuntos
Pré-Eclâmpsia/fisiopatologia , Circulação Renal/fisiologia , Tromboxano A2/biossíntese , Útero/irrigação sanguínea , Animais , Compostos Bicíclicos Heterocíclicos com Pontes , Modelos Animais de Doenças , Ácidos Graxos Insaturados , Feminino , Hidrazinas/farmacologia , Hipertensão/fisiopatologia , Gravidez , Complicações Cardiovasculares na Gravidez/fisiopatologia , Ratos , Circulação Renal/efeitos dos fármacos , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/fisiologiaRESUMO
Studies during the past decade have provided a better understanding of the potential mechanisms responsible for the pathogenesis of preeclampsia. The initiating event in preeclampsia has been postulated to be reduced uteroplacental perfusion as a result of abnormal cytotrophoblast invasion of spiral arterioles. Placental ischemia/hypoxia is thought to lead to widespread activation/dysfunction of the maternal vascular endothelium which results in enhanced formation of endothelin, thromboxane, and superoxide, increased vascular sensitivity to angiotensin II, and decreased formation of vasodilators such as nitric oxide and prostacyclin. These endothelial abnormalities, in turn, cause hypertension by impairing renal function and increasing total peripheral resistance. While recent studies support a role for cytokines and other factors such as lipid peroxides and reactive oxygen intermediates as potential mediators of endothelial dysfunction, finding the link between placental ischemia/hypoxia and maternal endothelial and vascular abnormalities remains an important area of investigation. The quantitative importance of the various endothelial and humoral factors in mediating the vasoconstriction and elevation in arterial pressure during preeclampsia has also not been completely elucidated.
Assuntos
Hipóxia/fisiopatologia , Isquemia/fisiopatologia , Placenta/irrigação sanguínea , Pré-Eclâmpsia/fisiopatologia , Vasos Sanguíneos/fisiopatologia , Feminino , Humanos , Microcirculação , GravidezRESUMO
The aim of this study was to assess the effects of acute or prolonged increases of ANG II on nitric oxide synthase (NOS) activities and protein expression in mesenteric resistance vessels, left ventricle, renal cortex, and renal medulla. The response of NOS activities to ANG II is compared with that induced by phenylephrine. ANG II or phenylephrine were infused over either 3 h or 3 days to conscious rats. NOS activity was examined by measuring the rate of conversion of L-[14C]arginine to L-[14C]citrulline. Protein levels of endothelial (e) and neuronal (n) NOS were determined by Western blot analysis. Arterial pressure (AP) increased (P < 0.05) during acute and prolonged ANG II infusion. Ca2+-dependent NOS activity values (pmol of citrulline x min(-1) x g wet wt(-1)) for control rats were 21 +/- 9 in mesenteric arteries, 13 +/- 7 in left ventricle, 14 +/- 8 in renal cortex, and 411 +/- 70 in renal medulla. Acute ANG II infusion increased (P < 0.05) Ca2+-dependent NOS activity in renal cortex and renal medulla (81 +/- 18 and 611 +/- 48, respectively), but no differences were found in mesenteric arteries and left ventricle with respect to control rats. In contrast to the renal changes in NOS activity, acute ANG II infusion did not modify eNOS or nNOS expression in any of the tissues examined. Prolonged ANG II infusion increased (P < 0.05) Ca2+-dependent NOS activity in mesenteric arteries (70 +/- 17), renal cortex (104 +/- 31), and left ventricle (49 +/- 8) and did not elicit changes in renal medulla. After a prolonged ANG II infusion, eNOS and nNOS levels increased in all tissues examined with the exception of eNOS in the mesenteric arteries and nNOS in the left ventricle, which were not altered. Acute and prolonged phenylephrine infusion elevated AP to a similar extent as ANG II but only elicited significant increments of Ca2+-dependent NOS activity in renal cortex. These data indicate that acute and prolonged elevations in ANG II upregulate Ca2+-dependent NOS activity and protein expression in different tissues related to the control of blood pressure. However, these ANG II effects are heterogeneous with respect to the tissue implicated, the time course of the stimulation, and the NOS isoform involved. Phenylephrine only induces a significant elevation of Ca2+-dependent NOS activity in renal cortex.
Assuntos
Angiotensina II/farmacologia , Óxido Nítrico Sintase/metabolismo , Vasoconstritores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Córtex Renal/enzimologia , Medula Renal/enzimologia , Masculino , Artérias Mesentéricas/enzimologia , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo I , Óxido Nítrico Sintase Tipo III , Fenilefrina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
-It has been reported that bradykinin (BK) can induce or activate both cyclooxygenase (COX) isoforms and that the renal effects of BK seem to be mediated by prostaglandins and NO. The first objective of this study was to evaluate the relative contribution of both COX isoforms in mediating the renal response to BK in anesthetized dogs. The second objective was to examine whether COX-2 inhibition potentiates the renal effects induced by NO reduction during BK administration. Intrarenal BK infusion (8 ng. kg(-1). min(-1), n=6) elicited a significant increment in renal blood flow, sodium excretion, urine volume, and the fractional excretion of lithium. COX-2 inhibition (nimesulide, 5 µg. kg(-1). min(-1), n=6) reduced the renal vasodilatation but did not significantly modify the natriuresis or diuresis secondary to BK. Administration of a nonspecific isozyme COX inhibitor (meclofenamate, 5 µg. kg(-1). min(-1); n=6) did not induce greater effects than those produced by nimesulide. NO synthesis reduction (N:(G)-nitro-L-arginine methyl ester [L-NAME], 3 µg. kg(-1). min(-1)) prevented the renal vasodilatation and the increment in the fractional excretion of lithium induced by BK but did not affect the natriuretic or diuretic response. Simultaneous nimesulide infusion did not modify the renal effects of L-NAME during BK infusion (n=6). Finally, inhibition of both COX isoforms with meclofenamate, in dogs treated with L-NAME (n=6), completely prevented the vasodilator and excretory actions of BK. The results of this study suggest that (1) NO and prostanoids dependent on COX-2 seem to be involved in the renal vasodilatation induced by BK, and (2) there is an interaction between NO and COX-1-derived metabolites in mediating the natriuretic and diuretic response to BK.