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1.
J Pharmacol Sci ; 152(1): 22-29, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37059488

RESUMEN

PURPOSE: Oral administration of 5-aminolevulinic acid hydrochloride (5-ALA-HCl) has been reported to enhance the hypotensive effects associated with anesthetics, especially in elderly hypertensive patients treated with antihypertensive agents. The present study aimed to clarify the effects of antihypertensive-agent- and anesthesia-induced hypotension by 5-ALA-HCl in spontaneously hypertensive rats (SHRs). METHODS: We measured blood pressure (BP) of SHRs and normotensive Wistar Kyoto (WKY) rats treated with amlodipine or candesartan before and after administration of 5-ALA-HCl. We also investigated the change in BP following intravenous infusion of propofol and intrathecal injection of bupivacaine in relation to 5-ALA-HCl administration. FINDINGS: Oral administration of 5-ALA-HCl significantly reduced BP in SHRs and WKY rats with amlodipine and candesartan. Infusion of propofol significantly reduced BP in SHRs treated with 5-ALA-HCl. Intrathecal injection of bupivacaine significantly declined SBP and DBP in both SHRs and WKY rats treated with 5-ALA-HCl. The bupivacaine-induced decline in SBP was significantly larger in SHRs compared with WKY rats. CONCLUSION: These findings suggest that 5-ALA-HCl does not affect the antihypertensive agents-induced hypotensive effect, but enhances the bupivacaine-induced hypotensive effect, especially in SHRs, indicating that 5-ALA may contribute to anesthesia-induced hypotension via suppression of sympathetic nerve activity in patients with hypertension.


Asunto(s)
Hipertensión , Hipotensión Controlada , Hipotensión , Propofol , Ratas , Animales , Ratas Endogámicas SHR , Antihipertensivos/efectos adversos , Ratas Endogámicas WKY , Ácido Aminolevulínico/efectos adversos , Bupivacaína , Propofol/farmacología , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Presión Sanguínea , Hipotensión/inducido químicamente , Hipotensión/tratamiento farmacológico , Amlodipino/efectos adversos
2.
Am J Physiol Renal Physiol ; 315(6): F1747-F1758, 2018 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-30256128

RESUMEN

We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR.


Asunto(s)
Presión Sanguínea , Complemento C3/metabolismo , Hipertensión/metabolismo , Riñón/metabolismo , Sistema Renina-Angiotensina , Cloruro de Sodio Dietético , Angiotensinógeno/genética , Angiotensinógeno/metabolismo , Animales , Presión Sanguínea/genética , Cadherinas/genética , Cadherinas/metabolismo , Desdiferenciación Celular , Proliferación Celular , Células Cultivadas , Complemento C3/genética , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Hipertensión/genética , Hipertensión/patología , Hipertensión/fisiopatología , Riñón/patología , Riñón/fisiopatología , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Masculino , Fenotipo , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Transgénicas , Renina/genética , Renina/metabolismo , Sistema Renina-Angiotensina/genética , Transducción de Señal
3.
Hypertens Res ; 39(12): 848-856, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27412799

RESUMEN

Endothelial damage is repaired by endothelial progenitor cells (EPCs), which are pivotal in preventing cardiovascular diseases and prolonging lifespan. The WHO Cardiovascular Diseases and Alimentary Comparison Study demonstrated that dietary taurine and magnesium (Mg) intake suppresses cardiovascular diseases. We herein evaluate the effects of taurine and Mg supplementation on EPC function and oxidative stress in healthy men and spontaneously hypertensive rats (SHRs). Healthy men received taurine (3 g per day) or Mg (340 mg per day) for 2 weeks. SHRs and Wistar-Kyoto (WKY) rats were housed with high-salt drinking water (1% NaCl). The SHRs received 3% taurine solution and/or a high-Mg (600 mg per 100 g) diet for 4 weeks. Their peripheral blood mononuclear cells were separated to quantify EPC colony formation. Oxidative stress markers in their peripheral blood were evaluated using a free radical analytical system and a thiobarbituric acid reactive substance (TBARS) assay. Taurine and Mg supplementation significantly increased EPC colony numbers and significantly decreased free radical levels and TBARS scores in healthy men. Taurine and Mg supplementation significantly increased EPC colony numbers and significantly decreased TBARS scores and free radical levels in SHRs. Nicotinamide adenine dinucleotide phosphate oxidase component mRNA expression was significantly higher in the renal cortex of salt-loaded SHRs than in WKY rats, in which it was suppressed by taurine and Mg supplementation. Taurine and Mg supplementation increased EPC colony formation in healthy men and improved impaired EPC function in SHRs through antioxidation, indicating that the dietary intake of taurine and Mg may prolong lifespan by preventing the progression of cardiovascular diseases.


Asunto(s)
Antioxidantes/farmacología , Células Progenitoras Endoteliales/efectos de los fármacos , Magnesio/farmacología , Estrés Oxidativo/efectos de los fármacos , Taurina/farmacología , Adolescente , Adulto , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Células Progenitoras Endoteliales/metabolismo , Humanos , Masculino , Ratas , Ratas Endogámicas SHR , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismo , Adulto Joven
4.
Am J Hypertens ; 27(5): 695-701, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24200748

RESUMEN

BACKGROUND: Endothelial progenitor cells (EPCs) induce neovascularization and repair vascular damage. We have demonstrated that EPC function is impaired in hypertensive rats with increases in oxidative stress and that angiotensin II receptor blockers improved the impaired function of EPCs. In this study, we investigated basal EPC functions in normotensive control subjects and patients with essential hypertension and the effect of losartan on EPC function in hypertensive patients. METHODS: Eighteen normotensive control subjects and 36 patients with essential hypertension who were undergoing treatment participated in the study. Hypertensive patients were randomly selected to receive 50mg of losartan or 4 mg of trichlormethiazide daily for 4 weeks. Peripheral blood mononuclear cells were isolated and cultured to assay EPC colony formation. Blood pressure, biological examination, and oxidative stress were evaluated in all subjects. RESULTS: The number of EPC colonies was significantly lower in patients with essential hypertension than in normotensive control subjects. EPC colony number was significantly and inversely correlated with systolic and diastolic blood pressure in all subjects. EPC colony number was significantly increased by treatment with losartan in patients with essential hypertension but not affected by treatment with trichlormethiazide. CONCLUSIONS: EPC function was inversely correlated with blood pressure and was impaired in essential hypertension. Losartan significantly improved the impaired EPC function in hypertensive patients. Impaired EPC function may determine the cardiovascular complications in essential hypertension. The improvement of EPC function with the administration of angiotensin II receptor blockers is considered to be one of the cardiovascular protective effects.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Células Endoteliales/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Losartán/uso terapéutico , Células Madre/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Estudios Cruzados , Diuréticos/uso terapéutico , Células Endoteliales/metabolismo , Células Endoteliales/patología , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/metabolismo , Hipertensión/patología , Hipertensión/fisiopatología , Japón , Masculino , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , Estudios Prospectivos , Células Madre/metabolismo , Células Madre/patología , Factores de Tiempo , Resultado del Tratamiento , Triclormetiazida/uso terapéutico
5.
Kidney Int ; 79(1): 46-56, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20861821

RESUMEN

Pyrrole-imidazole (PI) polyamides are small synthetic molecules that recognize and attach to the minor groove of DNA, thereby inhibiting gene transcription by blocking transcription factor binding. These derivatives can act as gene silencers inhibiting target gene expression under stimulatory conditions such as disease. To evaluate PI polyamides as treatments for the progression of renal diseases, we examined morphological effects, pharmacological properties, and the specificity of PI polyamides targeted to the transforming growth factor (TGF)-ß1 promoter during salt-induced hypertensive nephrosclerosis in Dahl salt-sensitive rats. The targeted PI polyamide markedly reduced glomerulosclerosis and interstitial fibrosis without side effects. PI polyamide significantly decreased expression of TGF-ß1 and extracellular matrix in the renal cortex. Microarray analysis found that only 3% of the transcripts were affected by PI polyamide, but this included decreased expression of extracellular matrix, TGF-ß1-related cytokines, angiogenic, and cell stabilizing factors, proteinases, and renal injury-related factors. Thus, targeted PI polyamides are potential gene silencers for diseases not treatable by current remedies.


Asunto(s)
Aminoácidos/farmacología , Regulación de la Expresión Génica , Silenciador del Gen , Imidazoles/farmacología , Glomérulos Renales/patología , Nylons/farmacología , Pirroles/farmacología , Transcripción Genética/efectos de los fármacos , Factor de Crecimiento Transformador beta1/genética , Animales , Fibrosis/genética , Fibrosis/patología , Fibrosis/prevención & control , Terapia Genética/métodos , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/prevención & control , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Masculino , Regiones Promotoras Genéticas/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas Dahl
6.
Am J Hypertens ; 21(9): 1062-8, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18636069

RESUMEN

BACKGROUND: Endothelial progenitor cells (EPCs) derived from bone marrow migrate to areas of endothelial damage and repair them. EPC function is impaired by oxidative stress. We examined the effects of an antioxidative beta1-adrenoceptor blocker on the number and function of EPCs in hypertensive rats. METHODS: Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were fed diets loaded with high salt. The SHRs were treated with celiprolol or atenolol for 2 weeks. Peripheral blood mononuclear cells (MNCs) were separated, subjected to flow cytometric analysis to determine the number of circulating EPCs, and cultured to quantify EPC colony formation. EPC migration was evaluated in migration assay chambers. EPC senescence was evaluated using beta-galactosidase assay. Oxidative stress of EPCs was evaluated using thiobarbituric acid-reactive substance (TBARS) assay. The expression of nicotinamine adenine dinucleotide phosphate (NAD(P)H) oxidase component mRNAs in the renal cortex, aorta, and heart were evaluated by real-time PCR. RESULTS: The number, colony formation, and migration of EPCs in SHRs were significantly lower than those in WKY rats. TBARS scores in EPCs from SHRs were significantly higher than those from WKY rats. Celiprolol increased the number of circulating EPCs and stimulated EPC colony formation and migration, while decreasing EPC senescence. Celiprolol inhibited oxidation in EPCs from SHRs, and decreased the expression of NAD(P)H oxidase component mRNAs in the renal cortex, aorta, and heart. CONCLUSION: EPCs are impaired in SHRs in response to oxidative stress. Celiprolol decreases oxidative stress in hypertension in vivo and improves EPC numbers and function. It appears, therefore, that celiprolol may exert beneficial cardiovascular effects through its antioxidative properties.


Asunto(s)
Antagonistas Adrenérgicos beta/farmacología , Antioxidantes/farmacología , Celiprolol/farmacología , Células Endoteliales/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Células Madre/efectos de los fármacos , Animales , Movimiento Celular , Células Cultivadas , Masculino , NADPH Oxidasas/análisis , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/análisis , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY
7.
Hypertens Res ; 30(11): 1119-28, 2007 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18250561

RESUMEN

We evaluated the effects of the angiotensin II (Ang II) receptor blocker (ARB) losartan on the formation and number of endothelial progenitor cells (EPCs) in hypertensive rats. Wistar-Kyoto (WKY) rats and stroke-prone, spontaneously hypertensive rats (SHR-SP) were salt-loaded and then treated with losartan (10 mg/kg/day), trichlormethiazide (TCM; 1.6 mg/kg/day), or tempol (1 mmol/L) for 2 weeks. Peripheral blood mononuclear cells were isolated, subjected to flow cytometric analysis to determine the number of circulating EPCs, cultured to assay EPC colony formation, and subjected to a migration chamber assay to evaluate EPC migration. Oxidative stress in EPCs was evaluated by thiobarbituric acid reactive substance (TBARS) assay. The results showed that the number, colony formation, and migration of EPCs were markedly decreased in SHR-SP compared to those in WKY rats. The TBARS scores were significantly greater in SHR-SP than in WKY rats. Losartan and TCM decreased systolic blood pressure in SHR-SP to similar levels. Losartan and tempol increased the number of circulating EPCs and colony formation, and inhibited oxidation in SHR-SP. TCM did not affect the EPC number, colony formation, or oxidation. Both losartan and TCM stimulated EPC migration. Expression of gp91(phox), p22(phox), and p47(phox) mRNA in tissues was significantly decreased by losartan but not by TCM. These results indicate that the formation and function of EPCs are impaired by oxidative stress in SHR-SP. This is the first report to show that losartan improves the proliferation and function of EPCs in hypertension, suggesting that ARBs are useful to repair hypertensive vascular injuries.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antioxidantes/farmacología , Endotelio Vascular/citología , Hipertensión/tratamiento farmacológico , Losartán/farmacología , Células Madre/efectos de los fármacos , Animales , Óxidos N-Cíclicos/farmacología , Endotelio Vascular/fisiología , Hipertensión/fisiopatología , Masculino , NADPH Oxidasas/genética , ARN Mensajero/análisis , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Cloruro de Sodio Dietético/administración & dosificación , Marcadores de Spin , Células Madre/fisiología
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