RESUMO
The ω-hydroxylase CYP4A11 catalyzes the transformation of epoxyeicosatrienoic acids (EETs) to ω-hydroxylated EETs, endogenous peroxisome proliferator-activated receptor-α (PPARα) agonists. PPARα activation increases high-density lipoprotein cholesterol (HDL-C). A cytosine-for-thymidine (T8590C) variant of CYP4A11 encodes for an ω-hydroxylase with reduced activity. This study examined the relationship between CYP4A11 T8590C genotype and metabolic parameters in the Framingham Offspring Study and in a clinical practice-based biobank, BioVU. In women in the Framingham Offspring Study, the CYP4A11 8590C allele was associated with reduced HDL-C concentrations (52.1±0.5 mg dl(-1) in CYP4A11 CC- or CT-genotype women versus 54.8±0.5 mg dl(-1) in TT women at visit 2, P=0.02), and with an increased prevalence of low HDL-C, defined categorically as îº50 mg dl(-1) (odds ratio 1.39 (95% CI 1.02-1.90), P=0.04). In the BioVU cohort, the CYP4A11 8590C allele was also associated with low HDL-C in women (odds ratio 1.69 (95% CI 1.03-2.77, P=0.04)). There was no relationship between genotype and HDL-C in men in either cohort.
Assuntos
HDL-Colesterol/genética , HDL-Colesterol/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Adulto , Alelos , Estudos de Coortes , Citocromo P-450 CYP4A/genética , Citocromo P-450 CYP4A/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , MasculinoRESUMO
We examined the effect of -58 C/T and BE1 +9/-9 polymorphisms in the bradykinin B2 receptor gene on forearm vascular resistance (FVR) before and during intrabrachial artery infusion of the B2 receptor-, endothelium-dependent agonist bradykinin and the endothelium-independent agonist sodium nitroprusside in 228 normotensive subjects. In 166 white Americans, systolic blood pressure (SBP) and pulse pressure were highest in the BE1 +9/+9 group (118+/-2 and 51+/-2 mm Hg, respectively; P<0.05 versus -9/-9 for either), intermediate in the +9/-9 group (114+/-1 and 49+/-1 mm Hg, P<0.05 versus -9/-9 for pulse pressure), and lowest in the -9/-9 group (110+/-2 and 44+/-2 mm Hg). In 62 black Americans, FVR was 25% higher in the BE1 +9/+9 group compared with the BE1 +9/-9 and -9/-9 groups at baseline (P=0.038) or during bradykinin (P=0.03). Increased SBP or vascular resistance may contribute to increased left ventricular mass reported previously in individuals with the BE1+9/+9 genotype.
Assuntos
Negro ou Afro-Americano/genética , Pressão Sanguínea/genética , Antebraço/irrigação sanguínea , Polimorfismo Genético , Receptor B2 da Bradicinina/genética , Resistência Vascular/genética , População Branca/genética , Adulto , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Frequência do Gene , Genótipo , Humanos , Infusões Intra-Arteriais , Masculino , Nitroprussiato/administração & dosagem , Fenótipo , Receptor B2 da Bradicinina/agonistas , Fluxo Sanguíneo Regional/genética , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/administração & dosagemRESUMO
Studies in isolated vessels and rat models of hypertension suggest that angiotensin (Ang)-(1-7) potentiates the vasodilator effect of bradykinin, possibly through ACE inhibition. We therefore tested the hypothesis that Ang-(1-7) potentiates the vasodilator or tissue plasminogen activator (TPA) response to bradykinin in the human forearm vasculature. Graded doses of Ang-(1-7) (10, 100, and 300 pmol/min), bradykinin (47, 94, and 189 pmol/min), and Ang I (1, 10, and 30 pmol/min) were administered through the brachial artery to 8 normotensive subjects in random order. Thirty minutes after initiation of a constant infusion of Ang-(1-7) (100 pmol/min), bradykinin and Ang I infusions were repeated. There were no systemic hemodynamic effects of the agonists. Bradykinin significantly increased forearm blood flow (P<0.001, from 3.8+/-0.5 to 13.9+/-3.1 mL/min per 100 mL at 189 pmol/min) and net TPA release (P=0.007, from 1.1+/-1.0 to 23.6+/-6.2 ng/min per 100 mL at 189 pmol/min), whereas Ang I caused vasoconstriction (P=0.003, from 3.3+/-0.4 to 2.5+/-0.3 mL/min per 100 mL at 30-pmol/min dose). There was no effect of Ang-(1-7) on either forearm blood flow (P=0.62, 3.3+/-0.4 to 3.5+/-0.4 mL/min per 100 mL at 300 pmol/min) or TPA release (P=0.52, from 0.7+/-0.8 to 1.0+/-0.7 ng/min/100 mL at 300 pmol/min). Moreover, there was no effect of 100 pmol/min Ang-(1-7) on the vasodilator [P=0.46 for Ang-(1-7) effect] or TPA [P=0.82 for Ang-(1-7) effect] response to bradykinin or the vasoconstrictor response to Ang I [P=0.62 for Ang-(1-7) effect]. These data do not support a role of Ang-(1-7), given at supraphysiological doses, in the regulation of human peripheral vascular resistance or fibrinolysis.
Assuntos
Angiotensina I/farmacologia , Anti-Hipertensivos/farmacologia , Bradicinina/farmacologia , Fragmentos de Peptídeos/farmacologia , Ativador de Plasminogênio Tecidual/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Adulto , Sinergismo Farmacológico , Feminino , Antebraço/irrigação sanguínea , Humanos , Masculino , Fluxo Sanguíneo Regional/efeitos dos fármacos , Estatísticas não Paramétricas , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
Components of the kallikrein kinin system have been associated with the pathophysiology of hypertension in animal and human studies. In this study, we examined the distribution of four different polymorphisms of the kinin B1 and B2 receptor genes in a population of 120 normotensive and 77 hypertensive African-Americans. Allelic frequencies for three of the four polymorphisms were significantly different from those previously reported in Caucasian populations. Among the polymorphisms analyzed, a potentially functionally significant polymorphism in the core promoter of the kinin B2 receptor (C-58-->T transition) displayed an increased prevalence of the C-58 allele in the hypertensive patients as compared with the controls (0.75 v. 0.62, P = .009). Thus, this B2 receptor promoter polymorphism may represent a susceptibility marker for essential hypertension in African-Americans.
Assuntos
População Negra , Frequência do Gene , Hipertensão/etnologia , Hipertensão/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Receptores da Bradicinina/genética , Adulto , Negro ou Afro-Americano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor B2 da BradicininaRESUMO
BACKGROUND: Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium. Although bradykinin is known to cause vasodilation through B(2) receptor-dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown. METHODS AND RESULTS: We measured the effects of intra-arterial bradykinin (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 microg/min), and nitroprusside (0.8, 1.6, and 3.2 microg/min) on forearm vasodilation and tPA release in healthy volunteers in the presence and absence of (1) the B(2) receptor antagonist HOE 140 (100 microg/kg IV), (2) the NO synthase inhibitor L-N:(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min intra-arterially), and (3) the cyclooxygenase inhibitor indomethacin (50 mg PO TID). B(2) receptor antagonism attenuated vasodilator (P:=0.004) and tPA (P:=0.043) responses to bradykinin, without attenuating the vasodilator response to nitroprusside (P:=0.36). L-NMMA decreased basal forearm blood flow (from 2.35+/-0.31 to 1. 73+/-0.22 mL/min per 100 mL, P:=0.01) and blunted the vasodilator response to acetylcholine (P:=0.013) and bradykinin (P:=0.07, P:=0. 038 for forearm vascular resistance) but not that to nitroprusside (P:=0.47). However, there was no effect of L-NMMA on basal (P:=0.7) or bradykinin-stimulated tPA release (P:=0.45). Indomethacin decreased urinary excretion of the prostacyclin metabolite 2, 3-dinor-6-keto-prostaglandin F(1alpha) (P:=0.04). The vasodilator response to endothelium-dependent (P:=0.019 for bradykinin) and endothelium-independent (P:=0.019) vasodilators was enhanced during indomethacin administration. In contrast, there was no effect of indomethacin alone (P:=0.99) or indomethacin plus L-NMMA (P:=0.36) on bradykinin-stimulated tPA release. CONCLUSIONS: These data indicate that bradykinin stimulates tPA release from human endothelium through a B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Bradykinin-stimulated tPA release may represent a marker for the endothelial effects of endothelium-derived hyperpolarizing factor.
Assuntos
6-Cetoprostaglandina F1 alfa/análogos & derivados , Bradicinina/análogos & derivados , Bradicinina/administração & dosagem , Endotélio Vascular/metabolismo , Antebraço/irrigação sanguínea , Ativador de Plasminogênio Tecidual/metabolismo , 6-Cetoprostaglandina F1 alfa/urina , Acetilcolina/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Antagonistas dos Receptores da Bradicinina , Inibidores de Ciclo-Oxigenase/administração & dosagem , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Indometacina/administração & dosagem , Infusões Intra-Arteriais , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroprussiato/administração & dosagem , Pletismografia , Receptor B2 da Bradicinina , Fluxo Sanguíneo Regional/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , ômega-N-Metilarginina/administração & dosagemRESUMO
BACKGROUND: Bradykinin is a cardioprotective peptide metabolized by the angiotensin-converting enzyme (ACE). An insertion/deletion (I/D) polymorphism in the ACE gene determines plasma ACE levels. The D allele is associated with cardiovascular disease, which may relate to enhanced angiotensin II production or to increased bradykinin degradation to the inactive metabolite bradykinin 1-5 (BK1-5). Therefore, we determined the effect of the ACE I/D polymorphism on human bradykinin metabolism in vivo. METHODS AND RESULTS: Bradykinin (400 ng/min) was infused into the brachial artery of volunteers with ACE I/I, I/D, or D/D genotypes (n=9 each). The bradykinin and BK1-5 levels in forearm venous return were quantified by liquid chromatography-mass spectroscopy. Plasma ACE activity was highest in those with the D/D genotype (36.8+/-6.2 U/mL), intermediate in those with the I/D genotype (25.3+/-3.3 U/mL), and lowest in those with the I/I genotype (20.3+/-2.3 U/mL; P=0.017 for effect of number of D alleles). Bradykinin concentrations were 726+/-242, 469+/-50, and 545+/-104 fmol/mL in I/I, I/D, and D/D subjects, respectively (P>0. 10). Significant correlations existed between the number of D alleles and BK1-5 concentrations (1113+/-290, 1520+/-318, and 1887+/-388 fmol/mL in the I/I, I/D, and D/D groups, respectively; P=0.027) and the ratio of BK1-5 to bradykinin (1.87+/-0.35, 3.09+/-0. 40, and 4.31+/-0.97 in the I/I, I/D, and D/D volunteers, respectively; P=0.010). The venous blood BK1-5:bradykinin ratio correlated with plasma ACE activity (r(2)=0.16, P=0.039), and total kinin concentration correlated with net tissue plasminogen activator release across the forearm (r(2)=0.20, P=0.027). CONCLUSIONS: The ACE D allele has a significant effect on the in vivo degradation of bradykinin in humans. The ratio of BK1-5:bradykinin may serve as a marker for tissue ACE activity.
Assuntos
Bradicinina/sangue , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Alelos , Artéria Braquial , Bradicinina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Infusões Intra-Arteriais , Masculino , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: The most common polymorphisms of the human beta2-adrenergic receptor--Arg16-->Gly and Gln27-->Glu--are associated with alterations in beta2-adrenergic receptor responses, both in vitro and in vivo. beta2-Adrenergic receptor-mediated vascular responses are affected by ethnicity, blood pressure, and genotype. We tested the hypothesis that these two common beta2-adrenergic receptor genetic variants are associated with essential hypertension in black or white Americans. SUBJECTS AND METHODS: In a population-based case-control association study, the relationship between beta2-adrenergic receptor genotypes and hypertension was examined in 307 normotensive subjects (128 black and 179 white) and 356 hypertensive subjects (155 black and 201 white). A polymerase chain reaction-based single-stranded conformational polymorphism method with direct sequencing of the bands of interest was used to detect the two frequently occurring beta2-adrenergic receptor variants (Arg16-->Gly, Gln27-->Glu). RESULTS: No significant differences in the distributions of alleles and genotypes of the tested beta2-adrenergic receptor variants were found between normotensive and hypertensive groups from either black or white Americans (all P > .05). There was a marked interethnic difference in the frequency of the Gln27-->Glu beta2-adrenergic receptor polymorphism in both normotensive and hypertensive subjects. In normotensive white subjects, the variant Glu27 allele (35.2% versus 18.0%; P < .0001) and Glu27 homozygous genotype (14.0% versus 4.7%; P < .01) were more common than in black subjects. Similarly, in hypertensive white subjects, the variant Glu27 allele (35.8% versus 18.4%; P < .0001) and the Glu27 homozygous genotype (15.9% versus 2.6%; P < .0001) were more common than in black subjects. CONCLUSIONS: These data suggest that although there are marked ethnic differences in their distribution, the common genetic polymorphisms of the human beta2-adrenergic receptor gene do not cosegregate with the presence of hypertension in either black or white Americans.
Assuntos
População Negra/genética , Hipertensão/genética , Polimorfismo Conformacional de Fita Simples , Receptores Adrenérgicos beta 2/genética , População Branca/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
The alpha1-adrenergic receptor (alpha1-AR) mediates vasoconstriction and plays an important role in the regulation of vascular tone. Increased alpha1-AR-mediated vasoconstrictor sensitivity, increased vascular reactivity to stress, and an increased prevalence of hypertension occur in African-Americans. The human alpha1A-AR is the predominant alpha1-AR subtype in vascular smooth muscle. The potential relevance of alpha1A-AR genetic variation to ethnic differences in vascular response and to the pathogenesis of hypertension prompted us to determine the frequency distribution of a recently identified polymorphism (Arg492 to Cys) in the alpha1A-AR in normotensive and hypertensive black and white American individuals. Polymerase chain reaction-based PstI restriction fragment length polymorphisms in the human alpha1A-AR gene were determined in 231 African-American and 282 Caucasian individuals, both with and without hypertension. There were marked differences in the genotypic and allelic distributions of the Arg492 to Cys alpha1A-AR polymorphism between African-American and Caucasian individuals (Cys492/Cys492 genotype, normotensive: 7.6% versus 30.1%; hypertensive: 7.1% versus 26.2%; Cys492 allele, normotensive: 29.5% versus 53.8%; hypertensive: 28.8% versus 55.2%; blacks versus whites, P < 0.0001). The frequency of the variant Cys492 allele was similar in normotensive and hypertensive individuals, both in African-Americans (29.5% versus 28.8%) and Caucasians (53.8% versus 55.2%). There were no significant intergenotypic differences in blood pressure (all P > 0.05). The data indicate that this polymorphism is not associated with essential hypertension in black or white Americans, but that the frequency of the alpha1A-AR Arg492 allele occurs significantly more commonly in African-Americans than in Caucasians. The potential role of the Arg492 to Cys alpha1A-AR polymorphism in ethnic differences in vascular alpha1-adrenergic response requires further investigation.
Assuntos
População Negra/genética , Hipertensão/genética , Polimorfismo Genético , Receptores Adrenérgicos alfa 1/genética , População Branca/genética , Adulto , Idoso , Alelos , Feminino , Frequência do Gene , Genótipo , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Fragmento de Restrição , Receptores Adrenérgicos alfa 1/fisiologia , VasoconstriçãoRESUMO
Bradykinin stimulates tissue plasminogen activator (tPA) release in isolated perfused animal tissues. The present study tests the hypothesis that bradykinin increases tPA release in humans through local effects on the vasculature. Graded doses of sodium nitroprusside (0.8 to 3.2 micrograms/min), acetylcholine (ACh) (7.5 to 60 micrograms/min), and bradykinin (100 to 400 ng/min) were administered intra-arterially in random order in 10 salt-depleted (10 mmol/d of Na) normotensive volunteers. None of the drugs altered mean arterial pressure or heart rate. Forearm blood flow (FBF) was measured by strain-gauge plethysmography. All 3 drugs caused a dose-dependent increase in FBF, although ACh was less potent than either nitroprusside or bradykinin (maximum FBF 7.5+/-2.4 versus 10.0+/-1.5 and 11.9+/-2.1 mL. 100 mL-1. min-1, respectively). Bradykinin caused a significant, dose-dependent increase in venous (effect of dose F=9. 9, P=0.028 by ANOVA), but not arterial (F=0.154, P=0.92) tPA antigen in the infused arm. Thus, net tPA release increased significantly in response to bradykinin (50.6+/-13.3 at the highest dose versus 0. 9+/-0.4 ng. 100 mL-1. min -1 at baseline, P=0.014). In contrast, bradykinin did not affect plasminogen activator inhibitor antigen. Neither nitroprusside nor ACh altered plasma levels of tPA or plasminogen activator inhibitor antigen. Bradykinin increased tPA release across the forearm in the absence of systemic effects. This effect could not be attributed to changes in blood flow because doses of equivalent potency of the vasodilator nitroprusside did not increase tPA. These data demonstrate that bradykinin stimulates tPA release in the human vasculature.
Assuntos
Acetilcolina/farmacologia , Bradicinina/farmacologia , Hemodinâmica/efeitos dos fármacos , Nitroprussiato/farmacologia , Ativador de Plasminogênio Tecidual/sangue , Vasodilatadores/farmacologia , Acetilcolina/administração & dosagem , Análise de Variância , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/administração & dosagem , Dieta Hipossódica , Fibrinólise/efeitos dos fármacos , Fibrinólise/fisiologia , Antebraço/irrigação sanguínea , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Infusões Intra-Arteriais , Nitroprussiato/administração & dosagem , Inibidor 1 de Ativador de Plasminogênio/sangue , Valores de Referência , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
There are ethnic differences in the prevalence and severity of hypertension and asthma and in beta-2 adrenergic receptor (BAR2)-mediated vascular responses. Two common polymorphisms of the human BAR2, Arg16 to Gly and Gln27 to Glu, are associated with alterations in BAR2 response, both in vitro and in vivo. Ethnic differences in disease manifestations and responses to treatment may be explained by the altered frequency of BAR2 polymorphisms. To determine the relative frequencies of the Arg16 to Gly and Gln27 to Glu BAR2 polymorphisms in different ethnic groups we studied 415 (123 African-American, 188 Caucasian-American and 104 Chinese) healthy individuals. There was a marked interethnic difference in the frequency of the BAR2 polymorphisms among the ethnic groups. The Glu27 allele was more frequent in Caucasian-American (34.8%) than in African-American individuals (20.7%) (P = 0.0001) and much less frequent in Chinese individuals (7.2%) (P = 0.0001 versus African-American or Caucasian-American). The homozygous Glu27 genotype was more frequent in Caucasian-American (15.4%) than African-American individuals (4.9%) (P = 0.003) and was not observed in Chinese. The Gly16 allele (54.3% versus 41.3%) and homozygous genotype (35.1% versus 18.3%) were more common in Caucasian-American than Chinese individuals (P = 0.003 for both). There is a marked ethnic difference in the frequency of these two common BAR2 polymorphisms among African-American, Caucasian-American and Chinese individuals, with a markedly reduced frequency of the Glu27 polymorphism, the polymorphism associated with resistance to desensitization and increased BAR2 responses, in African-American and Chinese individuals. Such ethnic genotypic differences may explain previously observed alterations in the response to the BAR agonists in different ethnic groups.
Assuntos
Povo Asiático/genética , População Negra/genética , Polimorfismo Genético , Receptores Adrenérgicos beta 2/genética , População Branca/genética , Negro ou Afro-Americano , Sequência de Bases , China , Primers do DNA , Genótipo , HumanosRESUMO
BACKGROUND: Angiotensin-converting-enzyme (ACE) inhibitors not only decrease the production of angiotensin II but also decrease the degradation of bradykinin. In this study, a specific bradykinin-receptor antagonist, icatibant acetate (HOE 140), was used to determine the contribution of bradykinin to the short-term effects of ACE inhibition on blood pressure and plasma renin activity in both normotensive and hypertensive subjects. METHODS: We compared the hemodynamic, renal, and endocrine effects of captopril alone (25 mg), captopril plus icatibant (100 microg per kilogram of body weight), the angiotensin II subtype 1-receptor antagonist losartan (75 mg), and placebo in 20 subjects with normal blood pressure and 7 subjects with hypertension. The subjects were studied while they were salt depleted (i.e., in balance on a diet in which they were allowed 10 mmol of sodium per day). The drugs were administered on four separate study days in a single-blind, randomized fashion. RESULTS: The coadministration of icatibant significantly attenuated the hypotensive effect of captopril (maximal decrease in mean arterial pressure for all subjects combined, 10.5+/-1.0 mm Hg, as compared with 14.0+/-1.0 mm Hg for captopril alone; P=0.001), in such a way that the decrease in blood pressure after the administration of captopril plus icatibant was similar to that after the administration of losartan (maximal decrease in mean arterial pressure, 11.0+/-1.7 mm Hg). Icatibant did not alter the renal hemodynamic response to captopril, but it significantly altered the change in plasma renin activity in response to ACE inhibition (-0.4+/-0.4 ng of angiotensin I per milliliter per hour, as compared with 2.0+/-0.7 ng per milliliter per hour for captopril alone; P=0.007). The magnitude of these effects was similar in both the normotensive and the hypertensive subjects, as well as in both the black subjects and the white subjects. CONCLUSIONS: These data confirm that bradykinin contributes to the short-term effects of ACE inhibition on blood pressure in normotensive and hypertensive persons and suggest that bradykinin also contributes to the short-term effects of ACE inhibition on the renin-angiotensin system.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Antagonistas dos Receptores da Bradicinina , Bradicinina/análogos & derivados , Hipertensão/fisiopatologia , Anti-Hipertensivos/farmacologia , Bradicinina/farmacologia , Captopril/farmacologia , Dieta Hipossódica , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Rim/efeitos dos fármacos , Losartan/farmacologia , Masculino , Valores de Referência , Sistema Renina-Angiotensina/efeitos dos fármacos , Método Simples-CegoRESUMO
The C1166 variant, an A to C substitution polymorphism at the 1166 position of the angiotensin II type I (AT1) receptor, has been previously associated with hypertension in Caucasians. This study determines the frequency of the C1166 variant in an African American population. Normotensive African American (n = 99) and Caucasian (n = 100) subjects were genotyped to determine the frequency of the C1166 variant. This study establishes the frequency of the C1166 variant in African Americans (0.05 +/- 0.01) and demonstrates a significantly lower frequency in African Americans compared with Caucasians (0.05 vs. 0.25, respectively, chi 2 = 30.7, p < < 0.001, 1 df).
Assuntos
População Negra/genética , Polimorfismo Genético , Receptores de Angiotensina/genética , Adulto , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , População Branca/genéticaRESUMO
Angiotensin converting enzyme (ACE) inhibitors block degradation of bradykinin and bradykinin stimulates prostacyclin production. ACE inhibitors are reported to increase prostaglandins. Therefore, we set out to determine 1) the contribution of prostacyclin to the bradykinin-mediated vasodepressor effects of ACE inhibitors, 2) whether ACE inhibitors alter the effect of bradykinin on prostacyclin, and 3) whether the effects of ACE inhibitors on bradykinin and prostaglandins are class effects or dependent on ACE inhibitor structure. To address these questions, we compared the effects of captopril, quinapril and placebo on blood pressure, urinary excretion of 2,3-dinor-6-keto-PGF1 alpha, and the vasodepressor response to i.v. bradykinin in 21 salt-replete normal-to-high renin hypertensive patients. Captopril and quinapril doses were titrated to lower pressure similarly. Captopril, but not quinapril, increased excretion of prostacyclin metabolite (217 +/- 50 vs. 135 +/- 21 pg/mg Cr base line, P < .05). Both ACE inhibitors dramatically, equally potentiated the vasodepressor response to bradykinin; the bradykinin dose required to decrease mean arterial pressure 15 mm Hg or increase pulse 20 bpm was 50-fold lower in ACEI-treated than in placebo-treated subjects (10 +/- 0 and 12.1 +/- 2.1 ng/kg/min in captopril and quinapril groups vs. 567 +/- 109 ng/kg/min in the placebo group; P < .005). ACE inhibition significantly attenuated the prostacyclin response to bradykinin at any given level of hypotensive response. Indomethacin abolished the prostacyclin response to bradykinin but did not alter the vasodepressor response. These data demonstrate that ACE inhibitors potentiate bradykinin-mediated vasodepression through a prostaglandin-independent mechanism. They suggest that although ACE inhibitors increase prostaglandins by increasing bradykinin, ACE inhibitors may attenuate prostaglandin production through a second bradykinin-independent mechanism.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/farmacologia , Epoprostenol/metabolismo , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/urina , Adolescente , Adulto , Idoso , Feminino , Humanos , Hipertensão/tratamento farmacológico , Indometacina/farmacologia , Masculino , Pessoa de Meia-Idade , Pulso Arterial/efeitos dos fármacos , Método Simples-CegoRESUMO
BACKGROUND: Angioedema is a potentially life-threatening side effect of angiotensin-converting enzyme (ACE) inhibitors. Although the mechanism of angioedema is not certain, bradykinin has been implicated in its pathogenesis. Compared with Caucasians, African Americans are at an increased risk of ACE inhibitor-associated angioedema, independent of ACE inhibitor dose or concurrent medications. Because urinary kallikrein levels are decreased in African Americans with hypertension, we hypothesized that endogenous bradykinin levels may be decreased in African Americans and that they therefore may be more sensitive to ACE inhibitor-induced increases in bradykinin or to exogenous bradykinin. OBJECTIVE: To test this hypothesis, we measured the wheal response to intradermal injection of bradykinin in salt-replete hypertensive and normotensive African Americans and Caucasians. METHODS: Two doses of bradykinin, 1 microgram and 10 micrograms, were administered on separate days in a randomized, double-blind fashion. RESULTS: Higher bradykinin dose (analysis of variance: F = 38.33, p < 0.001), African American race (analysis of variance: F = 17.90, p < 0.001), and hypertension (analysis of variance: F = 4.37, p = 0.05) were all associated with an increased wheal response to bradykinin. CONCLUSION: These data provide additional support for racial differences in the kallikrein-kinin system and also implicate abnormalities of the tissue kallikrein-kinin system in essential hypertension.
Assuntos
Bradicinina/efeitos adversos , Hipersensibilidade a Drogas/etnologia , Hipersensibilidade a Drogas/epidemiologia , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Angioedema/induzido quimicamente , Angioedema/epidemiologia , Angioedema/etnologia , Bradicinina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/etnologia , Testes Intradérmicos , Masculino , Pessoa de Meia-IdadeAssuntos
Síndrome do Túnel Carpal/fisiopatologia , Nervo Mediano/fisiopatologia , Enfermagem Perioperatória , Adulto , Idoso , Síndrome do Túnel Carpal/diagnóstico , Síndrome do Túnel Carpal/cirurgia , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Avaliação em Enfermagem , Cuidados Pós-OperatóriosRESUMO
Mongrel dogs with experimental spinal cord injury were treated with the carotenoid compound crocetin. It has been shown that crocetin increases the diffusion speed of oxygen through plasma, and should provide a net increase in oxygen at the level of the capillary endothelial cell. The treated animals showed a significant improvement in recovery rates as compared to controls.
Assuntos
Carotenoides/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Dexametasona/farmacologia , Cães , Feminino , Masculino , Oxigênio/sangue , Traumatismos da Medula Espinal/fisiopatologia , Vitamina A/análogos & derivadosRESUMO
Analyzed are data on 430 operations in 326 patients for median nerve compression at the wrist. Follow-up data from a patient self-evaluation questionnaire were available for 71% of patients. Incidence was highest in the fifth and sixth decades of life, and 65% of patients were female. For most patients, symptoms were worse at night or with excessive hand use or both. Self-evaluation questionnaires showed total relief of symptoms after operation in 51% of cases, 75% or greater improvement in 31%, and 50% or greater improvement in 10%. The dominant hand was more severely involved in two thirds of the patients and 78% of patients had occupations involving considerable use of their hands, suggesting that an occupational factor might be involved in the genesis or aggravation of median nerve compression.
Assuntos
Síndrome do Túnel Carpal/cirurgia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Métodos , Pessoa de Meia-Idade , Ocupações , Infecção da Ferida Cirúrgica/epidemiologiaRESUMO
Mongrel cats with experimental cryogenic brain lesions were treated with the carotenoid compound crocetin. It has been shown that crocetin increases the diffusion speed of oxygen through plasma, and should provide a net increase in available oxygen to the capillary endothelial cell. The treated group of animals showed a significant reduction in edema as compared to a comparable control group. It is suggested that oxygen availability is an important factor in vasogenic edema.
Assuntos
Edema Encefálico/tratamento farmacológico , Carotenoides/uso terapêutico , Oxigênio/sangue , Animais , Edema Encefálico/metabolismo , Gatos , Dexametasona/uso terapêutico , Feminino , Masculino , Vitamina A/análogos & derivadosRESUMO
Four cases of cerebral fibrosarcomas occurring in two families are reported. To our knowledge, no similar cases have been reported. Evidence that a heritable factor is involved in the genesis of some brain tumors is suggested by these cases.
Assuntos
Neoplasias Encefálicas/genética , Fibrossarcoma/genética , Idoso , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Feminino , Fibrossarcoma/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
An unusual case of a choroid plexus papilloma which completely isolated the right temporal and occipital horns from the remainder of the ventricular system is presented. The tumor secreted large quantities of cerebrospinal fluid and also bled into this obstructed cavity. A gross total removal was accomplished.