RESUMEN
Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.
Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Diuréticos/uso terapéutico , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Losartán/uso terapéutico , Factores de Edad , Anciano , Anciano de 80 o más Años , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Diuréticos/efectos adversos , Combinación de Medicamentos , Femenino , Humanos , Hidroclorotiazida/efectos adversos , Riñón/efectos de los fármacos , Riñón/fisiología , Losartán/administración & dosificación , Losartán/efectos adversos , Masculino , Persona de Mediana Edad , Potasio/sangre , Factores de Tiempo , Resultado del TratamientoRESUMEN
The molecular mechanisms of endothelial dysfunction and vascular calcification have been considered independently and potential links are currently unknown in chronic kidney disease (CKD). Bone morphogenetic protein (BMP) receptor signaling mediates calcification of atherosclerotic plaques. Here we tested whether BMP receptor signaling contributes to endothelial dysfunction, as well as to osteogenic differentiation of vascular smooth muscle cells (VSMCs), in a model of short-term CKD. In C57BL/6 mice, subtotal nephrectomy activated BMP receptor and increased phosphatase-and-tensin homolog (PTEN) protein in the endothelial cells and medial VSMCs without vascular remodeling in the aorta. In the endothelial cells, PTEN induction led to inhibition of the Akt-endothelial nitric oxide synthase (eNOS) pathway and endothelial dysfunction. In VSMCs, the PTEN increase induced early osteogenic differentiation. CKD-induced inhibition of eNOS phosphorylation and the resultant endothelial dysfunction were inhibited in mice with endothelial cell-specific PTEN ablation. Knockout of the BMP type I receptor abolished endothelial dysfunction, the inhibition of eNOS phosphorylation, and VSMC osteogenic differentiation in mice with CKD. A small molecule inhibitor of BMP type I receptor, LDN-193189, prevented endothelial dysfunction and osteogenic differentiation in CKD mice. Thus, BMP receptor activation is a mechanism for endothelial dysfunction in addition to vascular osteogenic differentiation in a short-term CKD model. PTEN may be key in linking BMP receptor activation and endothelial dysfunction in CKD.
Asunto(s)
Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/antagonistas & inhibidores , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/fisiología , Células Endoteliales/fisiología , Insuficiencia Renal Crónica/fisiopatología , Animales , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo III/fisiología , OsteogénesisRESUMEN
Morning hypertension is an established risk factor for cardiovascular events. In the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy (MAPPY) study, a 50-mg losartan/12.5-mg hydrochlorothiazide combination (Los/HCTZ) lowered morning blood pressure (BP) more effectively than 100-mg losartan (High-Los) in treated hypertensive patients with morning hypertension. The aim of this MAPPY study sub-analysis was to determine whether Los/HCTZ was effective for controlling isolated morning hypertension (morning BP ≥ 135/85 mmHg and evening BP < 135/85 mmHg), sustained hypertension (morning and evening BP ≥ 135/85 mmHg), or both. Of the 110 patients studied, 25 (22.7%) had isolated morning hypertension, and 85 (77.3%) had sustained hypertension at baseline. After 3-month treatment, isolated morning hypertension developed into controlled hypertension (morning and evening BP < 135/85 mmHg) in 9 of 11 Los/HCTZ patients (81.8%) and 3 of 14 High-Los patients (21.4%) (p = 0.003, chi-square test). Sustained hypertension developed into controlled hypertension in 21 of 44 Los/HCTZ patients (47.7%) and 13 of 41 High-Los patients (31.7%)(NS). The rates of achievement of SBP < 135 mmHg both in the morning and evening were: 81.8% and 21.4% in Los/HCTZ- and High-Los-treated isolated morning hypertension (p = 0.003), respectively; and 61.4% and 36.6% in Los/HCTX- and High-Los-treated sustained hypertension (p = 0.022), respectively. In conclusion, Los/HCTZ was effective for controlling both types of morning hypertension, especially isolated morning hypertension. Los/HCTZ was superior to High-Los in treating both types of morning hypertension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hidroclorotiazida/administración & dosificación , Hipertensión/tratamiento farmacológico , Losartán/administración & dosificación , Anciano , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Estudios Prospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: It has been shown that increased short-term blood pressure (BP) variability (BPV) aggravates hypertensive cardiac remodeling in spontaneously hypertensive rats (SHRs) through a cardiac angiotensin II (angII) system. However, little was known about the renal damage induced by large BPV. Thus, histological changes in the kidney were investigated and candesartan, an angII type 1 receptor blocker (ARB), was also examined to see whether it would prevent renal damage in SHRs with large BPV. METHODSâANDâRESULTS: Bilateral sinoaortic denervation (SAD) was performed in SHRs to create a model of a combination of hypertension and large BPV. SAD increased BPV without changing mean BP. Seven weeks later, SAD induced patchy, wedge-shaped, focal sclerotic lesions accompanied by interstitial fibrosis and ischemic changes of glomeruli and tubules in the cortex. The pre-glomerular arterioles adjacent to the sclerotic lesions showed arteriolosclerotic changes associated with vascular smooth muscle cell proliferation and extracellular matrix deposition, leading to the luminal narrowing and occlusion. Chronic treatment with a subdepressor dose of candesartan prevented not only arteriolosclerotic changes but also cortical sclerotic lesions in SHRs with SAD without changing BPV. CONCLUSIONS: Large BPV aggravates pre-glomerular arteriolosclerosis, which results in the cortical sclerotic changes in SHRs through a local angII-mediated mechanism. This study raised the possibility that ARB is useful for renal protection in patients who have a combination of hypertension and increased BPV.
Asunto(s)
Arteriosclerosis , Presión Sanguínea , Hipertensión , Isquemia , Corteza Renal , Animales , Arteriosclerosis/patología , Arteriosclerosis/fisiopatología , Hipertensión/patología , Hipertensión/fisiopatología , Isquemia/patología , Isquemia/fisiopatología , Corteza Renal/irrigación sanguínea , Corteza Renal/patología , Corteza Renal/fisiopatología , Conejos , Ratas Endogámicas SHRRESUMEN
BACKGROUND: Hypertensive patients with large blood pressure variability (BPV) have aggravated target organ damage. Because the aldosterone/mineralocorticoid receptor (MR) system is a possible mechanism of hypertensive organ damage, we investigated in spontaneously hypertensive rats (SHRs) whether a specific MR blocker, eplerenone, would prevent BPV-induced aggravation of hypertensive cardiac remodeling. METHODS AND RESULTS: A rat model of a combination of hypertension and large BPV was created by performing bilateral sinoaortic denervation (SAD) in SHRs. SAD increased BPV without changing mean BP. SAD induced perivascular macrophage infiltration and aggravated myocardial fibrosis and cardiac hypertrophy, resulting in LV systolic dysfunction. Immunohistostaining revealed SAD-induced translocation of MRs into the nuclei (ie, MR activation) of the intramyocardial arterial medial cells and cardiac myocytes. SAD increased phosphorylation of p21-activated kinase1 (PAK1), a regulator of MR nuclear translocation. Chronic administration of a subdepressor dose of eplerenone prevented MR translocation, macrophage infiltration, myocardial fibrosis, cardiac hypertrophy, and LV dysfunction, while not affecting BPV. Circulating levels of aldosterone and cortisol were not changed by SAD. CONCLUSIONS: Eplerenone inhibited the aggravation of cardiac inflammation and hypertensive cardiac remodeling, and thereby prevented progression of LV dysfunction in SHRs with large BPV. This suggests that the PAK1-MR pathway plays a role in cardiac inflammation and remodeling induced by large BPV superimposed on hypertension, independent of circulating aldosterone.
Asunto(s)
Presión Sanguínea , Cardiomegalia/metabolismo , Núcleo Celular/metabolismo , Hipertensión/metabolismo , Proteínas Musculares/metabolismo , Miocardio/metabolismo , Receptores de Mineralocorticoides/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Aldosterona/sangre , Animales , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Núcleo Celular/patología , Eplerenona , Humanos , Hidrocortisona/sangre , Hipertensión/patología , Hipertensión/fisiopatología , Macrófagos/metabolismo , Macrófagos/patología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Proteínas Musculares/antagonistas & inhibidores , Miocarditis/metabolismo , Miocarditis/patología , Miocarditis/fisiopatología , Miocardio/patología , Fosforilación/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Espironolactona/análogos & derivados , Espironolactona/farmacología , Remodelación Ventricular/efectos de los fármacos , Quinasas p21 Activadas/metabolismoRESUMEN
Patients with chronic kidney disease have elevated circulating asymmetric dimethylarginine (ADMA). Recent studies have suggested that ADMA impairs endothelial nitric oxide synthase (eNOS) by effects other than competition with the substrate L-arginine. Here, we sought to identify the molecular mechanism by which increased ADMA causes endothelial dysfunction in a chronic kidney disease model. In wild-type mice with remnant kidney disease, blood urea nitrogen, serum creatinine, and ADMA were increased by 2.5-, 2-, and 1.2-fold, respectively, without any change in blood pressure. Nephrectomy reduced endothelium-dependent relaxation and eNOS phosphorylation at Ser1177 in isolated aortic rings. In transgenic mice overexpressing dimethylarginine dimethylaminohydrolase-1, the enzyme that metabolizes ADMA, circulating ADMA was not increased by nephrectomy and was decreased to half that of wild-type mice. These mice did not exhibit the nephrectomy-induced inhibition of both endothelium-dependent relaxation and eNOS phosphorylation. In cultured human endothelial cells, agonist-induced eNOS phosphorylation and nitric oxide production were decreased by ADMA at concentrations less than that of L-arginine in the media. Thus, elevated circulating ADMA may be a cause, not an epiphenomenon, of endothelial dysfunction in chronic kidney disease. This effect may be attributable to inhibition of eNOS phosphorylation.
Asunto(s)
Arginina/análogos & derivados , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Insuficiencia Renal Crónica/fisiopatología , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Animales , Arginina/sangre , Arginina/farmacología , Modelos Animales de Enfermedad , Endotelio Vascular/fisiopatología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Óxido Nítrico Sintasa de Tipo III/fisiología , Fosforilación , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
We report on transoral carotid ultrasonography using a micro convex probe with B-flow imaging for determining spontaneous extracranial internal carotid artery dissection just below the petrous portion. A 49-year-old man suffered cortical and subcortical infarction in the region of the right middle cerebral artery. Magnetic resonance angiography on the third day of admission revealed spontaneous recanalization of the right internal carotid artery associated with an intimal flap-like structure at the petrous portion. Transoral carotid ultrasonography using a micro convex probe revealed right extracranial internal carotid artery dissection, showing an increased diameter of the right extracranial internal carotid artery with double lumen formation, stenosis of the true lumen, and a mobile intimal flap in B-flow imaging. Transoral carotid ultrasonography using a micro convex probe was helpful to attempt a self-expanding stent for recanalizing right extracranial internal carotid artery dissection. The patient recovered and was discharged ambulatory. The size of the micro convex probe was optimum for transoral carotid ultrasonography in our patient. Micro convex probe is more commonly used than the standard transoral carotid ultrasonography probe, which lacks versatility. We consider that transoral carotid ultrasonography using a micro convex probe could be routinely used for ultrasonographic evaluation of extracranial internal carotid artery dissection.
Asunto(s)
Disección de la Arteria Carótida Interna/diagnóstico por imagen , Estenosis Carotídea/diagnóstico por imagen , Ultrasonografía Doppler en Color/instrumentación , Disección de la Arteria Carótida Interna/complicaciones , Disección de la Arteria Carótida Interna/terapia , Estenosis Carotídea/complicaciones , Estenosis Carotídea/terapia , Procedimientos Endovasculares/instrumentación , Diseño de Equipo , Humanos , Infarto de la Arteria Cerebral Media/diagnóstico , Infarto de la Arteria Cerebral Media/etiología , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Stents , Resultado del TratamientoAsunto(s)
Puente de Arteria Coronaria , Mecánica Respiratoria , Síndrome del Robo de la Subclavia , Anciano , Velocidad del Flujo Sanguíneo , Femenino , Humanos , Radiografía , Síndrome del Robo de la Subclavia/diagnóstico por imagen , Síndrome del Robo de la Subclavia/fisiopatología , UltrasonografíaRESUMEN
Diastolic dysfunction is more prevalent in individuals with hypertension, particularly postmenopausal women; however, the pathogenesis of diastolic dysfunction remains unknown. Pressure overload activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction in rats with a suprarenal aortic constriction (AC). Therefore, we examined the effects of bilateral ovariectomy (OVX) on left ventricle (LV) remodeling, diastolic dysfunction and cardiac inflammation in hypertensive female rats. Rats were randomized to OVX+AC, OVX and AC groups as well as a Control group receiving sham operations for both the procedures. Rats underwent OVX at 6 weeks and AC at 10 weeks (Day 0). At Day 28, OVX did not appear to affect arterial pressure, cardiac hypertrophy or LV fractional shortening in AC rats. However, OVX increased myocardial fibrosis, elevated LV end-diastolic pressure and reduced the transmitral Doppler spectra early to late filling velocity ratio in AC rats. AC-induced transient myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration, both of which peaked at Day 3 and were augmented and prolonged by OVX. At Day 28, dihydroethidium staining revealed superoxide generation in the intramyocardial arterioles in the OVX+AC group but not in the AC group. NOX1, a functional subunit of nicotinamide adenine dinucleotide phosphate oxidase, was upregulated only in the OVX+AC group at Day 28. Chronic 17ß-estradiol replacement prevented the increases in macrophage infiltration, NOX1 upregulation, myocardial fibrosis and diastolic dysfunction in OVX+AC rats. In conclusion, we suggest that estrogen deficiency augments cardiac inflammation and oxidative stress and thereby aggravates myocardial fibrosis and diastolic dysfunction in hypertensive female rats. The findings provide insight into the mechanism underlying diastolic dysfunction in hypertensive postmenopausal women.
Asunto(s)
Fibrosis Endomiocárdica/fisiopatología , Estrógenos/deficiencia , Hipertensión/fisiopatología , Miocarditis/fisiopatología , Ovariectomía , Posmenopausia/fisiología , Disfunción Ventricular Izquierda/fisiopatología , Animales , Diástole/fisiología , Modelos Animales de Enfermedad , Fibrosis Endomiocárdica/metabolismo , Fibrosis Endomiocárdica/prevención & control , Estradiol/uso terapéutico , Femenino , Humanos , Hipertensión/metabolismo , Miocarditis/metabolismo , Miocarditis/prevención & control , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Superóxidos/metabolismo , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/prevención & control , Remodelación Ventricular/fisiologíaRESUMEN
Pronounced variability in blood pressure (BP) is an aggravating factor of hypertensive end-organ damage. However, its pathogenesis remains unknown. Statins have various protective effects on the cardiovascular system. Thus, we determined whether simvastatin would attenuate the aggravation of hypertensive cardiac remodeling in a rat model of hypertension with large BP variability, and also investigated the signaling mechanism involved in its effect. A model of hypertension with large BP variability was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). A SAD or sham operation was performed in 12-week-old rats. Thereafter, simvastatin (0.2 mgkg(-1) per day) or vehicle was intraperitoneally administered every day. After 6 weeks , telemetric recordings revealed that SAD enhanced BP variability without changing the mean BP. SAD increased myocyte hypertrophy, myocardial fibrosis and macrophage infiltration associated with the upregulation of brain natriuretic peptide (BNP), type I procollagen, transforming growth factor (TGF)-ß and monocyte chemoattractant protein (MCP)-1, and activation of RhoA, Ras and ERK1/2. Simvastatin did not change the mean BP or BP variability in SAD-operated SHRs. In SAD-operated SHRs, simvastatin attenuated myocyte hypertrophy and BNP expression, as well as RhoA, Ras and ERK1/2 activities. In contrast, simvastatin did not change myocardial fibrosis, macrophage infiltration, or the expression of procollagen and TGF-ß or MCP-1 in SAD-operated SHRs. Simvastatin did not affect serum lipid levels. In conclusion, simvastatin attenuated the large BP variability-induced aggravation of cardiac hypertrophy, but not myocardial fibrosis, in SHRs. The activation of RhoA/Ras-ERK pathways may contribute to the aggravation of cardiac hypertrophy by a combination of hypertension and large BP variability.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Cardiomegalia/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/tratamiento farmacológico , Simvastatina/uso terapéutico , Animales , Cardiomegalia/patología , Seno Carotídeo/inervación , Aumento de la Célula/efectos de los fármacos , Colesterol/sangre , Desnervación , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Frecuencia Cardíaca/efectos de los fármacos , Lipoproteínas HDL/sangre , Masculino , Proteínas de Unión al GTP Monoméricas/antagonistas & inhibidores , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Ratas , Ratas Endogámicas SHR , Resultado del Tratamiento , Triglicéridos/sangre , Remodelación Ventricular/efectos de los fármacos , Proteína de Unión al GTP rhoA/antagonistas & inhibidoresRESUMEN
Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.