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Beta-adrenergic receptors (ß-AR) are expressed on the membranes of various cell types and their activation affects body water balance by modulating renal sodium and water excretion, cardiovascular function and metabolic processes. However, ß-AR-associated body fluid imbalance has not been well characterised. In the present study, we hypothesized that chronic ß-AR stimulation increases electrolyte and water content at the tissue level. We evaluated the effects of isoproterenol, a non-selective ß-AR agonist, on electrolyte and water balance at the tissue level. Continuous isoproterenol administration for 14 days induced cardiac hypertrophy, associated with sodium-driven water retention in the heart, increased the total body sodium, potassium and water contents at the tissue level, and increased the water intake and blood pressure of the mice. There was greater urine output in response to the isoproterenol-induced body water retention. These isoproterenol-induced changes were reduced by propranolol, a non-selective beta-receptor inhibitor. Isoproterenol-treated mice even without excessive water intake had higher total body electrolyte and water contents, and this tissue water retention was associated with lower dry body mass, suggesting that ß-AR stimulation in the absence of excess water intake induces catabolism and water retention. These findings suggest that ß-AR activation induces tissue sodium and potassium retention, leading to body fluid retention, with or without excess water intake. This characterisation of ß-AR-induced electrolyte and fluid abnormalities improves our understanding of the pharmacological effects of ß-AR inhibitors. Significance Statement We have shown that chronic ß-AR stimulation causes cardiac hypertrophy associated with sodium-driven water retention in the heart and increases the accumulation of body sodium, potassium and water at the tissue level. This characterisation of the ß-AR-induced abnormalities in electrolyte and water balance at the tissue level improves our understanding of the roles of ß-AR in physiology and pathophysiology and the pharmacological effects of ß-AR inhibitors.
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We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2 receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.
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Líquidos Corporales , Conservación de los Recursos Hídricos , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Benzazepinas/farmacología , Ratas , Tolvaptán , Urea , AguaRESUMEN
BACKGROUND: The nonsteroidal mineralocorticoid receptor blocker esaxerenone is effective in reducing blood pressure (BP). OBJECTIVE: In this study, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. METHODS: In the different experimental setups, we evaluated BP by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a low-salt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. RESULTS: HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone- and furosemide-treated rats compared with their HSD-fed counterparts. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. Histological evaluation showed that esaxerenone, but not furosemide, treatment attenuated glomerulosclerosis, tubulointerstitial fibrosis, and urinary protein excretion induced by high salt loading. CONCLUSIONS: Collectively, these findings suggest that an esaxerenone treatment-induced reduction in BP and renoprotection are associated with body sodium homeostasis in salt-loaded DSS rats.
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Hipertensión , Enfermedades Renales , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Presión Sanguínea , Furosemida/farmacología , Enfermedades Renales/patología , Pirroles , Ratas , Ratas Endogámicas Dahl , Sodio/metabolismo , Cloruro de Sodio/farmacología , Cloruro de Sodio Dietético/farmacología , SulfonasRESUMEN
The aim of the present study is to investigate whether a disruption of the dipping pattern of blood pressure (BP) is associated with the progression of renal injury in Dahl salt-sensitive (DSS) hypertensive rats. Seven-week-old DSS rats were fed a high salt diet (HSD; 8% NaCl) for 10 weeks, followed by a transition to a normal salt diet (NSD; 0.3% NaCl) for 4 weeks. At baseline, NSD-fed DSS rats showed a dipper-type circadian rhythm of BP. By contrast, HSD for 5 days caused a significant increase in the difference between the active and inactive periods of BP with an extreme dipper type of BP, while proteinuria and renal tissue injury were not observed. Interestingly, HSD feeding for 10 weeks developed hypertension with a non-dipper pattern of BP, which was associated with obvious proteinuria and renal tissue injury. Four weeks after switching to an NSD, BP and proteinuria were significantly decreased, and the BP circadian rhythm returned to the normal dipper pattern. These data suggest that the non-dipper pattern of BP is associated with the progression of renal injury during the development of salt-dependent hypertension.
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Lesión Renal Aguda/etiología , Presión Sanguínea , Ritmo Circadiano , Hipertensión/complicaciones , Proteinuria/etiología , Lesión Renal Aguda/fisiopatología , Animales , Hipertensión/etiología , Hipertensión/fisiopatología , Riñón/patología , Riñón/fisiopatología , Proteinuria/fisiopatología , Ratas , Ratas Endogámicas Dahl , Sodio en la Dieta/toxicidadRESUMEN
NEW FINDINGS: What is the central question of this study? Can chymase inhibition prevent angiotensin I-induced hypertension through inhibiting the conversion of angiotensin I to angiotensin II in the kidney? What is the main finding and its importance? Treatment with TEI-F00806 decreased angiotensin II content of the kidney, renal cortical angiotensinogen protein levels and chymase mRNA expression, and attenuated the development of hypertension. ABSTRACT: The effects of the selective chymase inhibitor TEI-F00806 were examined on angiotensin I (Ang I)-induced hypertension and intrarenal angiotensin II (Ang II) production in salt-treated mice. Twelve-week-old C57BL male mice were given a high-salt diet (4% NaCl + saline (0.9% NaCl)), and divided into three groups: (1) sham + vehicle (5% acetic acid in saline), (2) Ang I (1 µg kg-1 min-1 , s.c.) + vehicle, and (3) Ang I + TEI-F00806 (100 mg kg-1 day-1 , p.o.) (n = 8-10 per group). Systolic blood pressure was measured weekly using a tail-cuff method. Kidney Ang II content was measured by radioimmunoassay. Chronic infusion of Ang I resulted in the development of hypertension (P < 0.001), and augmented intrarenal chymase gene expression (P < 0.05), angiotensinogen protein level (P < 0.001) and Ang II content (P < 0.01) in salt-treated mice. Treatment with TEI-F00806 attenuated the development of hypertension (P < 0.001) and decreased Ang II content of the kidney (P < 0.05), which was associated with reductions in renal cortical angiotensinogen protein levels (P < 0.001) and chymase mRNA expression (P < 0.05). These data suggest that a chymase inhibitor decreases intrarenal renin-angiotensin activity, thereby reducing salt-dependent hypertension.
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Presión Sanguínea/efectos de los fármacos , Quimasas/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Angiotensina I , Angiotensina II/metabolismo , Animales , Quimasas/metabolismo , Hipertensión/inducido químicamente , Hipertensión/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Ratones , Peptidil-Dipeptidasa A/metabolismoRESUMEN
Metabolic syndrome is often associated with disruption of circadian rhythm of systemic haemodynamics and cardiovascular disease. Experiments were conducted to investigate the effects of luseogliflozin, a selective SGLT2 inhibitor, on circadian rhythm of sympathetic nervous function and locomotor activity (LA) in metabolic syndrome rats. The difference in the low frequency component of systolic blood pressure between the dark and light period significantly increased in the luseogliflozin-treated SHRcp. LA also increased in the dark period compared with the light period following luseogliflozin treatment. These data suggest that circadian rhythm of sympathetic nervous function and LA is improved by luseogliflozin in metabolic syndrome rats, which may contribute to SGLT2 inhibitor-induced improvement of cardiovascular outcomes.
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Ritmo Circadiano/efectos de los fármacos , Locomoción/efectos de los fármacos , Síndrome Metabólico/fisiopatología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Sorbitol/análogos & derivados , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Animales , Masculino , Ratas , Sorbitol/farmacologíaRESUMEN
AIMS/HYPOTHESIS: Recent clinical studies have shown that renal sympathetic denervation (RDX) improves glucose metabolism in patients with resistant hypertension. We aimed to elucidate the potential contribution of the renal sympathetic nervous system to glucose metabolism during the development of type 2 diabetes. METHODS: Uninephrectomised diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats underwent RDX at 25 weeks of age and were followed up to 46 weeks of age. RESULTS: RDX decreased plasma and renal tissue noradrenaline (norepinephrine) levels and BP. RDX also improved glucose metabolism and insulin sensitivity, which was associated with increased in vivo glucose uptake by peripheral tissues. Furthermore, RDX suppressed overexpression of sodium-glucose cotransporter 2 (Sglt2 [also known as Slc5a2]) in renal tissues, which was followed by an augmentation of glycosuria in type 2 diabetic OLETF rats. Similar improvements in glucose metabolism after RDX were observed in young OLETF rats at the prediabetic stage (21 weeks of age) without changing BP. CONCLUSIONS/INTERPRETATION: Here, we propose the new concept of a connection between renal glucose metabolism and the renal sympathetic nervous system during the development of type 2 diabetes. Our data demonstrate that RDX exerts beneficial effects on glucose metabolism by an increase in tissue glucose uptake and glycosuria induced by Sglt2 suppression. These data have provided a new insight not only into the treatment of hypertensive type 2 diabetic patients, but also the pathophysiology of insulin resistance manifested by sympathetic hyperactivity.
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Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Riñón/inervación , Riñón/metabolismo , Sistema Nervioso Simpático/fisiopatología , Animales , Presión Sanguínea , Diabetes Mellitus Tipo 2/patología , Técnica de Clampeo de la Glucosa , Glucosuria/metabolismo , Humanos , Riñón/patología , Nefrectomía , Norepinefrina/sangre , Estado Prediabético/metabolismo , Ratas , Ratas Endogámicas OLETF , Transportador 2 de Sodio-Glucosa/metabolismo , SimpatectomíaRESUMEN
Renal denervation (RDN) has emerged as a novel therapy for drug-resistant hypertension. We here examined the effects of RDN at early versus advanced stages of hypertension on blood pressure and organ pathology in rats with salt-sensitive hypertension. Dahl salt-sensitive (DahlS) rats fed an 8% NaCl diet from 6 weeks of age were subjected to RDN (surgical ablation and application of 10% phenol in ethanol) or sham surgery at 7 (early stage) or 9 (advanced stage) weeks and were studied at 12 weeks. RDN at early or advanced stages resulted in a moderate lowering of blood pressure. Although RDN at neither stage affected left ventricular (LV) and cardiomyocyte hypertrophy, it ameliorated LV diastolic dysfunction, fibrosis, and inflammation at both stages. Intervention at both stages also attenuated renal injury as well as downregulated the expression of angiotensinogen and angiotensin-converting enzyme (ACE) genes and angiotensin II type 1 receptor protein in the kidney. Furthermore, RDN at both stages inhibited proinflammatory gene expression in adipose tissue. The early intervention reduced both visceral fat mass and adipocyte size in association with downregulation of angiotensinogen and ACE gene expression. In contrast, the late intervention increased fat mass without affecting adipocyte size as well as attenuated angiotensinogen and ACE gene expression. Our results thus indicate that RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated cardiac and renal injury and adipose tissue inflammation in DahlS rats. They also suggest that cross talk among the kidney, cardiovascular system, and adipose tissue may contribute to salt-sensitive hypertension. Supposed mechanism for the beneficial effects of RDN on hypertension and target organ damage in DahlS rats. RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated renal injury in DahlS rats. Cross talk among the kidney, cardiovascular system, and adipose tissue possibly mediated by circulating RAS may contribute to salt-sensitive hypertension. LV; left ventricular, NE; norepinephrine, RAS; renin-angiotensin system, RDN; renal denervation.
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BACKGROUND: The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure. However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by coactivating the sympathetic nervous system and renin-angiotensin system in the kidney. We also examined the therapeutic potential of renal denervation and renin-angiotensin system inhibition to suppress renal injury in chronic heart failure. METHODS AND RESULTS: Sprague-Dawley rats underwent aortic regurgitation and were treated for 6 months with vehicle, olmesartan (an angiotensin II receptor blocker), or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in aortic regurgitation rats. These changes were associated with increased urinary angiotensinogen excretion, kidney angiotensin II and norepinephrine (NE) levels, and enhanced angiotensinogen and angiotensin type 1a receptor gene expression and oxidative stress in renal cortical tissues. Aortic regurgitation rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, angiotensin II, and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by aortic regurgitation. CONCLUSIONS: In this chronic cardiac volume-overload animal model, activation of the sympathetic nervous system augments kidney renin-angiotensin system and oxidative stress, which act as crucial cardiorenal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardiorenal syndrome.
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Albuminuria/prevención & control , Insuficiencia de la Válvula Aórtica/prevención & control , Riñón/inervación , Podocitos/patología , Simpatectomía , Albuminuria/complicaciones , Albuminuria/patología , Animales , Insuficiencia de la Válvula Aórtica/complicaciones , Insuficiencia de la Válvula Aórtica/patología , Línea Celular Transformada , Humanos , Riñón/patología , Riñón/fisiología , Masculino , Podocitos/fisiología , Ratas , Ratas Sprague-Dawley , Simpatectomía/métodosRESUMEN
We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.
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Conservación de los Recursos Hídricos , Hipertensión , Ratas , Animales , Ratas Endogámicas SHR , Presión Sanguínea , Ratas Endogámicas WKY , Agua , Riñón , SodioRESUMEN
We recently demonstrated that cilnidipine, an L/N-type calcium channel blocker, elicits protective effects against glomerular podocyte injury, in particular, in obese hypertensive rats that express the N-type calcium channel (N-CC). Since the N-CC is known to be expressed in sympathetic nerve endings, we evaluated the reno-protective effects of cilnidipine in innervated and denervated spontaneously hypertensive rats (SHR). Male SHR were uninephrectomized and fed 4% high-salt diet (HS-UNX-SHR). Animals were divided into groups, as follows, and observed from 9 to 27 weeks of age: 1) vehicle (n = 14), 2) vehicle plus renal-denervation (n = 15), 3) cilnidipine (50 mg/kg per day, p.o.; n = 10), and 4) cilnidipine plus renal-denervation (n = 15). Renal denervation attenuated elevations in blood pressure, but failed to suppress urinary protein excretion and podocyte injury in HS-UNX-SHR. Cilnidipine in both innervated and denervated HS-UNX-SHR similarly induced significant antihypertensive effects, as well as suppressing the urinary protein excretion and podocyte injury, compared to vehicle-treated HS-UNX-SHR. These data indicate that renal nerves have a limited contribution to the cilnidipine-induced reno-protective effects in HS-UNX-SHR.
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Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/fisiología , Dihidropiridinas/farmacología , Podocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Angiotensina II/metabolismo , Animales , Bloqueadores de los Canales de Calcio/uso terapéutico , Línea Celular , Desmina/metabolismo , Dihidropiridinas/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Hipertensión/fisiopatología , Masculino , Ratones , Podocitos/patología , Podocitos/fisiología , Sustancias Protectoras/uso terapéutico , Proteinuria/tratamiento farmacológico , Proteinuria/patología , Proteinuria/fisiopatología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
A growing body of evidence suggests the potential role of chymase in organ injury in diabetes. We investigated blood glucose levels and survival in transgenic mice carrying the human chymase gene (Tg). Intraperitoneal injections of streptozotocin (STZ) (200, 100, 75 and 50 mg/kg in total, i.p.) were given to uninephrectomized Tg mice and wild-type C57BL/6 (BL) mice. Before STZ injection, the Tg mice had significantly lower body weights and slightly higher systolic blood pressure as compared with the BL mice. STZ-treated Tg mice showed significantly higher postprandial blood glucose levels as compared with the STZ-treated BL mice. The survival prevalence of STZ-treated Tg mice was zero, whereas BL mice showed a value of 40% until 42 days. STZ (100, 75 or 50 mg/kg, i.p.)-treated Tg mice also showed a similar pattern as compared with the STZ-treated BL mice. These data suggest that human chymase contributes to blood glucose levels and mortality during the progression of diabetes.
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Glucemia/metabolismo , Quimasas/genética , Quimasas/metabolismo , Diabetes Mellitus Experimental , Animales , Presión Sanguínea/fisiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/mortalidad , Diabetes Mellitus Experimental/fisiopatología , Modelos Animales de Enfermedad , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/mortalidad , Hiperglucemia/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , FenotipoRESUMEN
The glucose-lowering effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors is reduced in patients with diabetes who have chronic kidney disease (CKD). In the present study, we examined the effect of an SGLT2 inhibitor on the salt sensitivity of blood pressure (BP), circadian rhythm of BP, and sympathetic nerve activity (SNA) in nondiabetic CKD rats. Uninephrectomized Wistar rats were treated with adenine (200 mg/kg/day) for 14 days. After stabilization with a normal-salt diet (NSD, 0.3% NaCl), a high-salt diet (HSD, 8% NaCl) was administered. Mean arterial pressure (MAP) was continuously monitored using a telemetry system. We also analyzed the low frequency (LF) of systolic arterial pressure (SAP), which reflects SNA. In adenine-induced CKD rats, HSD consumption for 5 days significantly increased the mean MAP from 106 ± 2 to 148 ± 3 mmHg. However, MAP was decreased to 96 ± 3 mmHg within 24 h after switching back to a NSD (n = 7). Treatment with an SGLT2 inhibitor, luseogliflozin (10 mg/kg/day, p.o., n = 7), significantly attenuated the HSD-induced elevation of MAP, which was associated with a reduction in LF of SAP. These data suggest that treatment with an SGLT2 inhibitor attenuates the salt sensitivity of BP, which is associated with SNA inhibition in nondiabetic CKD rats.
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Presión Sanguínea/efectos de los fármacos , Insuficiencia Renal Crónica/fisiopatología , Cloruro de Sodio Dietético , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Animales , Presión Sanguínea/fisiología , Ritmo Circadiano/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
We recently reported that a 4% high-salt diet + saline for drinking (HS + saline) leads to a catabolic state, reduced heart rate, and suppression of cardiovascular energy expenditure in mice. We suggested that HS + saline reduces heart rate via the suppression of the sympathetic nervous system to compensate for the high salt intake-induced catabolic state. To test this hypothesis, we directly measured renal sympathetic nerve activity (RSNA) in conscious Sprague-Dawley (SD) rats using a radiotelemetry system. We confirmed that HS + saline induced a catabolic state. HS + saline decreased heart rate, while also reducing RSNA in SD rats. In contrast, Dahl salt-sensitive (DSS) rats exhibited no change in heart rate and increased RSNA during high salt intake. Renal denervation significantly decreased heart rate and attenuated the catabolic state independent of blood pressure in DSS rats fed HS + saline, suggesting that salt-sensitive animals were unable to decrease cardiovascular energy consumption due to abnormal renal sympathetic nerve activation during high salt intake. These findings support the hypothesis that RSNA mediates heart rate during high salt intake in SD rats. However, the insensitivity of heart rate and enhanced RSNA observed in DSS rats may be additional critical diagnostic factors for salt-sensitive hypertension. Renal denervation may benefit salt-sensitive hypertension by reducing its effects on catabolism and cardiovascular energy expenditure.
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Presión Sanguínea/fisiología , Fenómenos Fisiológicos Cardiovasculares , Metabolismo Energético/fisiología , Frecuencia Cardíaca/fisiología , Riñón/inervación , Sodio en la Dieta , Sistema Nervioso Simpático/fisiología , Animales , Sistema Cardiovascular , Masculino , Ratas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , TelemetríaRESUMEN
(Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.
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Adenosina Trifosfatasas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Superficie Celular/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo , Adenosina Trifosfatasas/genética , Animales , Carcinoma Ductal Pancreático/genética , Línea Celular , Transformación Celular Neoplásica , Ensamble y Desensamble de Cromatina , Proteínas Cromosómicas no Histona/genética , Regulación Neoplásica de la Expresión Génica , Inestabilidad Genómica , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias Pancreáticas/genética , Regulación hacia Arriba , Secuenciación Completa del GenomaRESUMEN
Recent studies have shown that blocking non-proteolytically activated prorenin with a decoy peptide for the handle region of the prorenin prosegment (HRP) inhibits the development of microvascular complications in diabetic animals. In the present study, we investigated whether non-proteolytic activation of prorenin contributes to the development of fructose-induced insulin resistance. Rats were fed a standard diet (n = 10), a 60% high fructose diet (n = 16), or a high fructose diet + HRP (0.1 mg kg(-1) day(-1), n = 16) for 10 weeks. Fructose-fed rats showed higher systolic blood pressure (SBP), fasting plasma triglycerides, total cholesterol and insulin levels; which, except for SBP, were suppressed by HRP. The responses of plasma glucose and insulin levels to oral glucose loading were significantly greater in fructose-fed rats than in standard diet-fed rats. The HRP normalized the enhanced responses of plasma glucose and insulin levels that were observed in fructose-fed rats. Moreover, HRP suppressed the enhanced prorenin activation and angiotensin II formation in the soleus muscle of fructose-fed rats. These data suggest that local angiotensin II generation in skeletal muscle, induced by non-proteolytic activation of prorenin, contributes to the development of insulin resistance induced by a high fructose diet.
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Carbohidratos de la Dieta/administración & dosificación , Fructosa/administración & dosificación , Resistencia a la Insulina/fisiología , Renina/metabolismo , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adiponectina/genética , Angiotensina II/biosíntesis , Animales , Secuencia de Bases , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Tamaño de la Célula/efectos de los fármacos , Colesterol/sangre , Carbohidratos de la Dieta/efectos adversos , Activación Enzimática/efectos de los fármacos , Ácidos Grasos no Esterificados/sangre , Fructosa/efectos adversos , Insulina/sangre , Resistencia a la Insulina/genética , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Oligopéptidos/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/genética , Triglicéridos/sangre , Receptor de ProreninaRESUMEN
Cases of Clostridium perfringens septicemia, such as liver abscess, often develop a rapidly progressive intravascular hemolysis and coagulation; the mortality rate with current standard care including antibiotics and surgery is high. Herein, we firstly investigated the effects of gas gangrene antitoxin (GGA) (antitoxin against C. perfringens) and recombinant human soluble thrombomodulin (rTM) on the hemolysis, coagulation status, inflammatory process, and mortality in α-toxin-treated rats. Male 11-week-old Sprague Dawley rats were randomly divided into five groups: control group, α-toxin group, GGA group, rTM group, and combined GGA and rTM (combination group). After α-toxin injection, mortality and platelet counts, and hemolysis were observed for 6 h. The fibrin/fibrinogen degradation products (FDP), and plasma high-mobility group box 1 (HMGB1) were also measured at 6 h. The combination group demonstrated 100% survival compared with 50% survival in the α-toxin group and demonstrated significantly improved hemolysis, platelet counts, and lactate levels compared with those in the α-toxin group (p < .01). The FDP and HMGB1 levels in the combination therapy group were significantly lower than those in the α-toxin group (p < .05). Combination therapy with GGA and rTM administration is applicable as adjunct therapy for fatal C. perfringens sepsis.
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Antitoxinas/farmacología , Clostridium perfringens/patogenicidad , Gangrena Gaseosa/inmunología , Sepsis/tratamiento farmacológico , Trombomodulina/uso terapéutico , Animales , Toxinas Bacterianas , Productos de Degradación de Fibrina-Fibrinógeno , Proteína HMGB1 , Hemólisis/efectos de los fármacos , Masculino , Recuento de Plaquetas , Ratas Sprague-Dawley , Proteínas Recombinantes , Sepsis/inmunologíaRESUMEN
In sleep apnea syndrome (SAS), chronic intermittent hypoxia (CIH) is believed to activate the sympathetic nerve system, and is thus involved in cardiovascular diseases (CVD). However, since patients with SAS are often already obese, and have diabetes and/or hypertension (HT), the effects of CIH alone on sympathetic nerve activation and its impacts on CVD are largely unknown. We, therefore, examined the effects of CIH on sympathetic nerve activation in non-obese mice to determine whether renal sympathetic nerve denervation (RD) could ameliorate CIH-mediated cardiovascular effects. Male C57BL/6 (WT) mice were exposed to normal (FiO2 21%) or CIH (10% O2, 12 times/h, 8 h/day) conditions for 4 weeks with or without RD treatment. Increased urinary norepinephrine (NE), 8-OHdG, and angiotensinogen levels and elevated serum asymmetric dimethyl arginine levels were observed in the CIH model. Concomitant with these changes, blood pressure levels were significantly elevated by CIH treatment. However, these deleterious effects by CIH were completely blocked by RD treatment. The present study demonstrated that CIH-mediated renal sympathetic nerve activation is involved in increased systemic oxidative stress, endothelial dysfunction, and renin-angiotensin system activation, thereby contributing to the development of HT and CVD, thus could be an important therapeutic target in patients with SAS.
Asunto(s)
Enfermedades Cardiovasculares/prevención & control , Hipertensión/prevención & control , Hipoxia/complicaciones , Simpatectomía/métodos , Sistema Nervioso Simpático/cirugía , 8-Hidroxi-2'-Desoxicoguanosina , Angiotensinas/orina , Animales , Arginina/análogos & derivados , Arginina/sangre , Desoxiguanosina/análogos & derivados , Desoxiguanosina/orina , Modelos Animales de Enfermedad , Humanos , Hipoxia/sangre , Hipoxia/orina , Riñón/inervación , Masculino , Ratones , Ratones Endogámicos C57BL , Norepinefrina/orina , Estrés OxidativoRESUMEN
The present study aimed to assess the effects of rat adrenomedullin 2 on systemic and regional hemodynamics in conscious Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Intravenous infusion of rat adrenomedullin 2 (0.25-5 micro g/kg/min) decreased blood pressure, and increased heart rate in a dose-dependent manner in both types of rats. Rat adrenomedullin 2 (5 micro g/kg/min) increased heart rate and cardiac output. As a result, total peripheral resistance significantly decreased. In SHRs, adrenomedullin 2 significantly increased regional blood flow in the heart, liver, spleen, kidneys, and adrenal glands. Especially, effects on heart, liver, and kidneys were remarkable. Regional hemodynamic changes were reproduced in WKY rats, and there was no qualitative difference in regional responses to rat adrenomedullin 2 between SHRs and WKY rats. Thus, rat adrenomedullin 2 predominantly increased flow rates in organs that were richly blood-supplied from cardiac output. Rat adrenomedullin 2 may contribute to the regulation of the cardiovascular system, by acting as a local vasodilatory hormone as well as a circulatory hormone.
Asunto(s)
Adrenomedulina/farmacología , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Neuropéptidos/farmacología , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Flujo Sanguíneo Regional/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
The aim of this study is to examine the effects of acute administration of luseogliflozin, the sodium-glucose cotransporter 2 (SGLT2) inhibitor, on renal hemodynamics and tubular functions in anesthetized non-diabetic Sprague Dawley (SD) rats and 5/6 nephrectomized (Nx) SD rats. Renal blood flow (RBF), mean arterial pressure (MAP), and heart rate (HR) were continuously measured and urine was collected directly from the left ureter. Intraperitoneal injection of luseogliflozin (0.9 mg kg-1) did not change MAP, HR, RBF, or creatinine clearance (CrCl) in SD rats (n = 7). Luseogliflozin significantly increased urine volume, which was associated with significantly increased urinary glucose excretion rates (P < 0.001). Similarly, luseogliflozin significantly increased urinary sodium excretion (from 0.07 ± 0.01 µmol min-1 at baseline to 0.76 ± 0.08 µmol min-1 at 120 min; P < 0.001). Furthermore, luseogliflozin resulted in significantly increased urinary pH (P < 0.001) and decreased urinary osmolality and urea concentration (P < 0.001) in SD rats. Similarly, in Nx SD rats (n = 5-6), luseogliflozin significantly increased urine volume and urinary glucose excretion (P < 0.001) without altering MAP, HR, RBF, or CrCl. Luseogliflozin did not elicit any significant effects on the other urinary parameters in Nx SD rats. These data indicate that SGLT2 inhibitor elicits direct tubular effects in non-diabetic rats with normal renal functions.