RESUMEN

OBJECTIVES: Endothelial dysfunction occurs in hypoxia-related states such as ischemic heart disease or heart surgery. Intermediate- and small-conductance calcium-activated potassium channels (IKCa and SKCa) are closely related to endothelium-dependent hyperpolarizing factor-mediated endothelial function. However, the status of these KCa under hypoxia is unknown. We investigated whether endothelial dysfunction under hypoxic state is related to the alterations of IKCa and SKCa and whether use of IKCa/SKCa activator may protect endothelium from hypoxia-reoxygenation injury. METHODS: Isometric tension measurement, patch-clamp technique, intracellular membrane potential recording, and molecular methods were used to study porcine coronary arteries and endothelial cells. RESULTS: Hypoxia-reoxygenation (60-30 minutes) decreased endothelium-dependent hyperpolarizing factor-mediated relaxation at normothermia in Krebs solution (43.3%±6.3% vs 82.3%±2.9%) and in St Thomas' Hospital cardioplegic solution (28.9%±1.8% vs 78.1%±3.0%) (P<.001) as well as at hypothermia in St Thomas' Hospital solution (43.1%±2.6%, P<.001). Hypoxia-reoxygenation markedly reduced endothelial IKCa (2.8±0.6 vs 6.9±0.6 pA/pF) and SKCa currents (1.5±0.3 vs 4.3±0.4 pA/pF) (P<.05) and downregulated endothelial IKCa expression. IKCa/SKCa activator 1-ethyl-2-benzimidazolinone enhanced K+ current in endothelial cells that was blunted by hypoxia. Further, 1-ethyl-2-benzimidazolinone restored (P<.001) endothelium-dependent hyperpolarizing factor-mediated relaxation with hyperpolarization recovered from 6.0±0.3 to 7.8±0.4 mV (P<.05). CONCLUSIONS: In porcine coronary arteries, hypoxia markedly reduced endothelial K+ currents related to IKCa and SKCa with downregulation of protein expression and endothelium-derived hyperpolarizing factor function. IKCa/SKCa activator may preserve endothelium-dependent hyperpolarizing factor-mediated relaxation with enhancement of K+ current in endothelial cells and cellular membrane potential hyperpolarization in smooth muscle cells and may become a new strategy to protect coronary endothelium in cardiac surgery or transplantation.

Asunto(s)

Bencimidazoles/farmacología , Vasos Coronarios/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/agonistas , Daño por Reperfusión Miocárdica/prevención & control , Potasio/metabolismo , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/agonistas , Animales , Factores Biológicos/metabolismo , Hipoxia de la Célula , Células Cultivadas , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Relación Dosis-Respuesta a Droga , Células Endoteliales/metabolismo , Femenino , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/metabolismo , Masculino , Potenciales de la Membrana , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/fisiopatología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Pequeña Conductancia Activados por el Calcio/metabolismo , Porcinos , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología

RESUMEN

TRPC1 (transient receptor potential canonical 1) is a Ca(2+)-permeable cation channel involved in diverse physiological function. TRPC1 may associate with other proteins to form a signaling complex, which is crucial for channel function. In the present study, we investigated the interaction between TRPC1 and large conductance Ca(2+)-sensitive K(+) channel (BK(Ca)). With the use of potentiometric fluorescence dye DiBAC(4)(3), we found that store-operated Ca(2+) influx resulted in membrane hyperpolarization of vascular smooth muscle cells (VSMCs). The hyperpolarization was inhibited by an anti-TRPC1 blocking antibody T1E3 and 2 BK(Ca) channel blockers, charybdotoxin and iberiotoxin. These data were confirmed by sharp microelectrode measurement of membrane potential in VSMCs of intact arteries. Furthermore, T1E3 treatment markedly enhanced the membrane depolarization and contraction of VSMCs in response to several contractile agonists including phenylephrine, endothelin-1, and U-46619. In coimmunoprecipitation experiments, an antibody against BK(Ca) alpha-subunit [BK(Ca)(alpha)] could pull down TRPC1, and moreover an anti-TRPC1 antibody could reciprocally pull down BK(Ca)(alpha). Double-labeling immunocytochemistry showed that TRPC1 and BK(Ca) were colocalized in the same subcellular regions, mainly on the plasma membrane, in VSMCs. These data suggest that, TRPC1 physically associates with BK(Ca) in VSMCs and that Ca(2+) influx through TRPC1 activates BK(Ca) to induce membrane hyperpolarization. The hyperpolarizing effect of TRPC1-BK(Ca) coupling could serve to reduce agonist-induced membrane depolarization, thereby preventing excessive contraction of VSMCs to contractile agonists.

Asunto(s)

Señalización del Calcio , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Canales de Potasio/metabolismo , Canales Catiónicos TRPC/metabolismo , Animales , Barbitúricos , Membrana Celular/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Colorantes Fluorescentes , Humanos , Inmunohistoquímica , Isoxazoles , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/antagonistas & inhibidores , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Masculino , Potenciales de la Membrana , Microelectrodos , Microscopía Confocal , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/genética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Canales Catiónicos TRPC/genética , Transfección , Vasoconstricción , Vasoconstrictores/farmacología

RESUMEN

Fibrinogen, an acute phase protein, is an important inflammatory marker that is associated with cardiovascular diseases. We studied the association of three common human fibrinogen-beta gene (FGB) variants, -455G>A, -249C>T, and -148C>T with glycemic parameters in 265 non-diabetic Hong Kong Chinese subjects. Both FGB variants, -455G>A and -148C>T were in complete linkage disequilibrium and were associated with higher levels of plasma fibrinogen and 2-h glucose after a 75-g oral glucose load (p<0.01). Carriers of FGB AC-haplotype, comprising the two nucleotide variants at positions -455 and -249, had higher fibrinogen level (2.64 +/- 0.65 vs 2.42 +/- 0.52 g/L, p=0.002) and 2-h glucose after a 75-g oral glucose load (5.87 +/- 1.14 vs 5.47 +/- 1.22 g/L, p=0.006). The associations were significant in men, but not women. In stepwise multiple regression analysis, AC-haplotype was independently associated with plasma fibrinogen level and 2-h glucose (p=0.002 and 0.010 respectively). This suggests that fibrinogen may play a role in the development of impaired glucose tolerance.

Asunto(s)

Glucemia/análisis , Fibrinógeno/genética , Prueba de Tolerancia a la Glucosa , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Genotipo , Hong Kong , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión

RESUMEN

OBJECTIVE: Adenosine is a cAMP-elevating vasodilator that induces both endothelium-dependent and -independent vasorelaxation. An increase in cytosolic Ca(2+) ([Ca(2+)](i)) is a crucial early signal in the endothelium-dependent relaxation elicited by adenosine. This study explored the molecular identity of channels that mediate adenosine-induced Ca(2+) influx in vascular endothelial cells. METHODS AND RESULTS: Adenosine-induced Ca(2+) influx was markedly reduced by L-cis-diltiazem and LY-83583, two selective inhibitors for cyclic nucleotide-gated (CNG) channels, in H5V endothelial cells and primary cultured bovine aortic endothelial cells (BAECs). The Ca(2+) influx was also inhibited by 2 adenylyl cyclase inhibitors MDL-12330A and SQ-22536, and by 2 A(2B) receptor inhibitors MRS-1754 and 8-SPT, but not by an A(2A) receptor inhibitor SCH-58261 or a guanylyl cyclase inhibitor ODQ. Patch clamp experiments recorded an adenosine-induced current that could be inhibited by L-cis-diltiazem and LY-83583. A CNGA2-specific siRNA markedly decreased the Ca(2+) influx and the cation current in H5V cells. Furthermore, L-cis-diltiazem inhibited the endothelial Ca(2+) influx in mouse aortic strips, and it also reduced 5-N-ethylcarboxamidoadenosine (NECA, an A(2) adenosine receptor agonist)-induced vasorelaxation. CONCLUSIONS: CNGA2 channels play a key role in adenosine-induced endothelial Ca(2+) influx and vasorelaxation. It is likely that adenosine acts through A(2B) receptors and adenylyl cyclases to stimulate CNGA2.

Asunto(s)

Adenosina/farmacología , Calcio/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Células Endoteliales/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Adenilil Ciclasas/metabolismo , Aminoquinolinas/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Bovinos , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Placa-Clamp , Pirimidinas/farmacología , Receptor de Adenosina A2B/metabolismo , Triazoles/farmacología

RESUMEN

OBJECTIVE: We investigated the association of the metabolic syndrome with new-onset diabetes in the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort. RESEARCH DESIGN AND METHODS: We followed up on 1,679 subjects without diabetes at baseline. Those with a previous diagnosis of diabetes or those who were receiving drug treatment were considered to be diabetic. The remaining subjects underwent a 75-g oral glucose tolerance test (OGTT). Diabetes was defined by plasma glucose > or =7.0 mmol/l with fasting and/or > or =11.1 mmol/l at 2 h. RESULTS: The prevalences of the metabolic syndrome at baseline were 14.5 and 11.4%, respectively, according to U.S. National Cholesterol Education Program (NCEP) and International Diabetes Federation (IDF) criteria. After a median of 6.4 years, there were 66 and 54 new cases of diabetes in men and women, respectively. The metabolic syndrome at baseline predicted incident diabetes. Hazard ratios (HRs) for the NCEP and IDF definitions of the syndrome were 4.1 [95% CI 2.8-6.0] and 3.5 [2.3-5.2], respectively. HRs for fasting plasma glucose (FPG) > or =6.1 or 5.6 mmol/l were 6.9 [4.1-11.5] and 4.1 [2.8-6.0], respectively. The NCEP and IDF criteria had 41.9 and 31.7% sensitivity and 87.5 and 90.2% specificity, respectively. Their positive predictive values were low, approximately 20%, but their negative predictive values were approximately 95%. CONCLUSIONS: The metabolic syndrome, particularly its component, elevated FPG, predicts diabetes in Chinese. An individual without the metabolic syndrome is unlikely to develop diabetes, but one who has it should practice therapeutic lifestyle changes and have periodic FPG measurements to detect new-onset diabetes.

Asunto(s)

Diabetes Mellitus/epidemiología , Síndrome Metabólico/epidemiología , Adulto , Enfermedades Cardiovasculares/epidemiología , China/epidemiología , Femenino , Humanos , Masculino , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Prevalencia , Factores de Riesgo

RESUMEN

Detection of hypertension and blood pressure control are critically important for reducing the risk of heart attacks and strokes. We analyzed the trends in the prevalence, awareness, treatment, and control of hypertension in the United States in the period 1999-2004. We used the National Health and Nutrition Examination Survey 1999-2004 database. Blood pressure information on 14 653 individuals (4749 in 1999-2000, 5032 in 2001-2002, and 4872 in 2003-2004) aged >or=18 years was used. Hypertension was defined as blood pressure >or=140/90 mm Hg or taking antihypertensive medications. The prevalence of hypertension in 2003-2004 was 7.3+/-0.9%, 32.6+/-2.0%, and 66.3+/-1.8% in the 18 to 39, 40 to 59, and >or=60 age groups, respectively. The overall prevalence was 29.3%. When compared with 1999-2000, there were nonsignificant increases in the overall prevalence, awareness, and treatment rates of hypertension. The blood pressure control rate was 29.2+/-2.3% in 1999-2000 and 36.8+/-2.3% in 2003-2004. The age-adjusted increase in control rate was 8.1% (95% CI: 2.4 to 13.8%; P=0.006). The control rates increased significantly in both sexes, non-Hispanic blacks, and Mexican Americans. Among the >or=60 age group, the awareness, treatment, and control rates of hypertension had all increased significantly (P

Asunto(s)

Conocimientos, Actitudes y Práctica en Salud , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Adulto , Envejecimiento , Población Negra/estadística & datos numéricos , Presión Sanguínea/efectos de los fármacos , Femenino , Objetivos , Humanos , Hipertensión/fisiopatología , Masculino , Americanos Mexicanos/estadística & datos numéricos , Persona de Mediana Edad , Encuestas Nutricionales , Prevalencia , Estados Unidos/epidemiología

RESUMEN

The authors studied the prevalence of the metabolic syndrome in the 1999-2002 National Health and Nutrition Examination Survey (NHANES) according to the World Health Organization, National Cholesterol Education Program (NCEP), and International Diabetes Federation (IDF) definitions. There was 92.9% agreement between the NCEP and IDF definitions. The IDF prevalence was higher (p = 0.001) due to more men fulfilling its criteria than the NCEP's (39.9 +/- 1.7% vs. 33.6 +/- 1.6%; p = 0.007). If central obesity were not a prerequisite, the IDF prevalence would increase slightly to 40.3 +/- 1.1%. Subjects categorized as having the metabolic syndrome under IDF but not NCEP tended to be men, younger, and leaner. Their prevalence of self-reported coronary heart disease was not significantly different from that of other metabolic syndrome patients. Whether waist circumference is a prerequisite does not affect the diagnosis of the metabolic syndrome in the United States. The IDF definition identifies additional individuals at risk for cardiovascular disease.

Asunto(s)

Síndrome Metabólico/epidemiología , Encuestas Nutricionales , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Estudios Retrospectivos , Estados Unidos/epidemiología

RESUMEN

We studied single nucleotide polymorphisms (SNPs) and haplotypes in the urotensin-II (UTS2) and urotensin-II receptor gene (UTS2R) in Hong Kong Chinese (224 hypertensive and 306 normotensive unrelated subjects) and their relation to hypertension and the metabolic syndrome. For UTS2, the GGT haplotype (-605G, 143G and 3836T) was associated with higher plasma level of U-II and insulin, and higher homeostasis model assessment of insulin resistance index and beta-cell function. For UTS2R, the AC haplotype (-11640A and -8515C) was associated with higher 2 h plasma glucose after a 75 g oral glucose load. Therefore, U-II and its receptor may play a role in insulin resistance.

Asunto(s)

Haplotipos , Hipertensión/genética , Resistencia a la Insulina , Receptores Acoplados a Proteínas G/genética , Urotensinas/genética , Alelos , Secuencia de Bases , Femenino , Frecuencia de los Genes , Genotipo , Prueba de Tolerancia a la Glucosa , Humanos , Hipertensión/sangre , Desequilibrio de Ligamiento , Masculino , Modelos Genéticos , Datos de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Urotensinas/metabolismo

RESUMEN

The prevalence, awareness, treatment, and control of hypertension in the United States are analyzed using the National Health and Nutrition Examination Survey (NHANES) database covering the period 1988-2002. Mean body mass index was 26.1+/-0.1 kg/m2 in 1988-1991 and 27.9+/-0.2 kg/m2 in 2001-2002 (p < 0.001). In the same period, the prevalence of diabetes mellitus increased from 5.0% to 6.5% (p = 0.03). Diastolic blood pressure was 73.3+/-0.2 mm Hg in 1988-1991 and 71.6+/-0.4 mm Hg in 2001-2002 (p < 0.001). Among the 18-39 years and 60 years and older age groups, the prevalence of hypertension increased significantly since 1988-1991. Multiple regression shows age, body mass index, and being non-Hispanic black were significantly associated with hypertension. In the period 1988-2002, the percentage receiving treatment and the percentage with blood pressure controlled increased significantly. In 2001-2002, significantly more people with hypertension and diabetes reached a blood pressure target of <130/85 mm Hg. Overall, the control rates were low, especially among middle-aged Mexican-American men (8%).

Asunto(s)

Concienciación , Conocimientos, Actitudes y Práctica en Salud , Hipertensión/epidemiología , Hipertensión/terapia , Adolescente , Adulto , Factores de Edad , Anciano , Antihipertensivos , Presión Sanguínea , Índice de Masa Corporal , Femenino , Encuestas Epidemiológicas , Humanos , Hipertensión/prevención & control , Masculino , Persona de Mediana Edad , Encuestas Nutricionales , Prevalencia , Análisis de Regresión , Factores de Riesgo , Estados Unidos/epidemiología

RESUMEN

Control of glycemia and other risk factors in people with diabetes has a critical bearing on clinical outcome. Using data from the US National Health and Nutrition Examination Survey 1999-2002, the authors compared the characteristics and control among diabetic subjects in different antidiabetic treatment groups. Among diagnosed diabetic subjects (n=827), 18.3%, 15.2%, 56.6%, and 9.6% used diet therapy alone, insulin therapy alone, oral antidiabetic drugs alone, or both insulin and oral antidiabetic drugs, respectively. The pattern of antidiabetic treatment differed by age and race/ethnicity, but not sex and status of the cardiometabolic syndrome. Only a minority of patients had satisfactory control of glycemia (38.8%), low-density lipoprotein cholesterol (35.0%), and blood pressure (42.5%). Patients taking only insulin had the poorest glycemic control (15.2%), while patients using diet treatment alone (65.9%) had the best glycemic control. There is a need to improve glycemic control. Better patient education, intensive lifestyle changes, and newer therapies need to be explored.

Asunto(s)

Diabetes Mellitus/dietoterapia , Diabetes Mellitus/tratamiento farmacológico , Dietoterapia , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Síndrome Metabólico/epidemiología , Administración Oral , Adulto , Factores de Edad , Glucemia/efectos de los fármacos , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus/sangre , Diabetes Mellitus/epidemiología , Diabetes Mellitus/etnología , Femenino , Encuestas Epidemiológicas , Humanos , Hipercolesterolemia/epidemiología , Hipertensión/epidemiología , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Masculino , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/etnología , Persona de Mediana Edad , Encuestas Nutricionales , Prevalencia , Resultado del Tratamiento , Estados Unidos/epidemiología

RESUMEN

OBJECTIVES: Urotensin II is the most potent vasoconstrictor known. Its role in hypertension has not been investigated. Here, we studied the plasma levels in hypertensive and normotensive human subjects. DESIGN: A cross-sectional case-control study. SETTING: Hypertension clinic and research clinic of a university teaching hospital. PARTICIPANTS: Sixty-two hypertensive outpatient subjects (52% male, aged 57 +/- 13 years) and 62 normotensive controls (45% male, aged 54 +/- 13 years) recruited from the general population. MAIN OUTCOME MEASURES: Plasma urotensin II levels measured by radioimmunoassay, systolic and diastolic blood pressure. RESULTS: Plasma urotensin II was 8.8 +/- 0.9 pmol/l in normotensive controls and 13.6 +/- 1.4 pmol/l in hypertensive subjects (P = 0.005). In multiple regression analysis, systolic blood pressure was related to plasma urotensin II (beta = 0.31, P < 0.001) and age (beta = 0.28, P = 0.001), accounting for 10 and 8%, respectively, of the variance in systolic blood pressure. There was no significant correlation with gender, renal function or diabetes. CONCLUSIONS: Plasma urotensin II was raised in hypertensive patients compared to normotensive controls, and was directly related to systolic blood pressure. Our findings raise the possibility that urotensin II may have an aetiological role in hypertension and its complications.

Asunto(s)

Hipertensión/sangre , Urotensinas/sangre , Anciano , Antihipertensivos/uso terapéutico , Presión Sanguínea , Estudios de Casos y Controles , Estudios Transversales , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Masculino , Persona de Mediana Edad