RESUMO
NEW FINDINGS: What is the topic of this review? The review discusses how eosinophils can contribute to the function of perivascular adipose tissue and explores the mechanisms involved. What advances does it highlight? Understanding the communication between the cell populations that constitute perivascular adipose tissue function is important for exploring therapeutic options in the treatment of obesity-related cardiovascular complications. This article highlights that eosinophils are able to contribute directly to healthy perivascular adipose tissue function. These immune cells contribute to adrenergic signalling and nitric oxide- and adiponectin-dependent mechanisms in perivascular adipose tissue. ABSTRACT: Perivascular adipose tissue is a heterogeneous tissue that surrounds most blood vessels in the body. This review focuses on the contribution of eosinophils located within the adipose tissue to vascular contractility. A high-fat diet reduces the number of these immune cells within perivascular adipose tissue, and this loss is linked to an increase in vascular contractility and hypertension. We explored the mechanisms by which eosinophils contribute to this function using genetically modified mice, ex vivo assessment of contractility and pharmacological tools. We found that eosinophils contribute to adrenergic signalling and nitric oxide- and adiponectin-dependent mechanisms in perivascular adipose tissue. It is now important to explore whether manipulation of these pathways in obesity can alleviate cardiovascular complications, in order to determine whether eosinophils are a valid target for obesity-related disease.
Assuntos
Tecido Adiposo/metabolismo , Eosinófilos/metabolismo , Obesidade/metabolismo , Adiponectina/metabolismo , Animais , Dieta Hiperlipídica , Hipertensão/fisiopatologia , Camundongos , Óxido Nítrico/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Treatment response in late-life depression has been linked to cerebrovascular disease notably via the vascular depression hypothesis. This study investigated the relationship between endothelial function and atherosclerosis and treatment response to antidepressant monotherapy. METHODS: Twenty five patients with late-life depression were compared with 21 non-depressed control subjects in a case control study. Nine of the depressed subjects were responders to antidepressant monotherapy and 16 were not. Vascular measures included assessment of carotid intima media thickness (IMT) representing atherosclerosis and biopsied small artery dilatation to acetylcholine to assess endothelial function in a subset of subjects. RESULTS: There were no group differences in vascular risks or sociodemographic variables. There was a significant group difference (responders versus non-responders versus controls) on both IMT and endothelial function (p < 0.01 and p < 0.05, respectively) with a significant difference between controls and non-responders (p < 0.001) on IMT and between controls and responders (p < 0.05) and control versus non-responders (p < 0.05) on endothelial function but no significant difference between responders and non-responders. On both IMT and endothelial function, there was a gradient across groups, with control subjects having best vascular structure or function, non-responders worse and responders in-between. CONCLUSIONS: The results are consistent with a hypothesis that poorer antidepressant response in later life depressive disorder may be linked to an underlying vascular dysfunction and pathology. The study is small, and the results require replication but if confirmed, trials with vasoprotective medication aimed at improving vascular function in order to alter the prognosis of late-life depression would be a rational development.
Assuntos
Aterosclerose/fisiopatologia , Transtorno Depressivo/fisiopatologia , Endotélio Vascular/fisiopatologia , Acetilcolina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Antidepressivos/uso terapêutico , Artérias/efeitos dos fármacos , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Transtorno Depressivo/tratamento farmacológico , Feminino , Humanos , MasculinoRESUMO
Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure.
Assuntos
Canais de Cátion TRPC/fisiologia , Túnica Íntima/patologia , Doenças Vasculares/metabolismo , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Hiperplasia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Ratos , Ratos Endogâmicos WKY , Veia Safena/patologia , Suínos , Canais de Cátion TRPC/antagonistas & inibidores , Canais de Cátion TRPC/genética , Regulação para Cima , Doenças Vasculares/tratamento farmacológicoRESUMO
BACKGROUND: Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-beta1 on luminal loss after PTCA. METHODS AND RESULTS: Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-beta type II receptor (Ad5-RIIs), an adenovirus expressing beta-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs-injected arteries (1.71+/-0.12 mm(2)) than in the Ad5-lacZ (1.33+/-0.13 mm(2)) or vehicle-only (1.08+/-0.17 mm(2); P=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (P=0.013) and external (P=0.031) elastic laminae in Ad5-RIIs-treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (P=0.004). CONCLUSIONS: Adenovirus-mediated antagonism of TGF-beta1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-beta1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy-mediated antagonism of TGF-beta1 as prophylactic therapy for restenosis.
Assuntos
Adenoviridae/genética , Angioplastia Coronária com Balão/efeitos adversos , Colágeno/metabolismo , Reestenose Coronária/terapia , Terapia Genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Animais , Células Cultivadas , Constrição Patológica/metabolismo , Constrição Patológica/patologia , Constrição Patológica/terapia , Reestenose Coronária/etiologia , Reestenose Coronária/metabolismo , Reestenose Coronária/patologia , Vasos Coronários/metabolismo , Vasos Coronários/patologia , Meios de Cultivo Condicionados/farmacologia , Vetores Genéticos , Inflamação/etiologia , Músculo Liso Vascular/metabolismo , Proteínas Serina-Treonina Quinases , RNA Mensageiro/biossíntese , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Suínos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta1 , beta-Galactosidase/metabolismoRESUMO
OBJECTIVE: The aim was to determine whether regional differences in arterial responses to vasoconstrictor and vasorelaxant agonists exist within the minipig coronary vasculature. METHODS: Hearts were obtained from miniature pigs (20-40 kg) immediately after death. First and third order arterial branches of the left anterior descending artery were dissected from within the subepicardium and mounted as ring preparations in a small vessel myograph for measurement of isometric tension under standardised conditions. Contractile responses to acetylcholine, noradrenaline, and U46619, and the relaxation responses to noradrenaline, bradykinin, and substance P were measured. Arterial tone was increased with KCl or acetylcholine prior to addition of vasodilator agonists. RESULTS: First order branches were more sensitive to the constrictor influence of acetylcholine than third order branches [pD2 values 6.42(SEM 0.07), n = 13, and 6.26(0.07), n = 13, for first and third order respectively, p < 0.05]. U46619 did not induce contractile responses in arteries less than 210 microns in diameter. Noradrenaline only induced small contractile responses in the presence of propranolol following removal of the endothelium. In arteries preconstricted with 40 mM KCl, noradrenaline induced relaxation which was inhibited by propranolol and was uninfluenced by arterial calibre. In the presence of propranolol, noradrenaline-mediated relaxations of acetylcholine-preconstricted arteries were endothelium dependent and alpha 2 adrenoceptor mediated, and greater in first order than in third order branches [58(5)%, n = 9, and 26(8)%, n = 9, for first and third order branches respectively, p < 0.05]. Relaxations mediated by bradykinin and substance P were not influenced significantly by arterial calibre but were greater in arteries preconstricted with acetylcholine than with KCl. CONCLUSIONS: In isolated minipig coronary arteries the vasoconstrictor responses to acetylcholine and U46619, and the endothelium dependent, noradrenaline mediated relaxations, differ according to the branching order studied. These data provide further evidence for a regional heterogeneity of vascular responses in the porcine coronary vasculature.
Assuntos
Acetilcolina/farmacologia , Artérias/anatomia & histologia , Circulação Coronária/efeitos dos fármacos , Norepinefrina/farmacologia , Endoperóxidos Sintéticos de Prostaglandinas/farmacologia , Tromboxano A2/análogos & derivados , Sistema Vasomotor/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animais , Artérias/efeitos dos fármacos , Bradicinina/farmacologia , Feminino , Técnicas In Vitro , Masculino , Propranolol/farmacologia , Substância P/farmacologia , Suínos , Porco Miniatura , Tromboxano A2/farmacologiaRESUMO
OBJECTIVES: The proto-oncogenes c-fos, c-myc and H-ras have been shown to rise in a characteristic pattern in the left ventricle undergoing hypertrophy in the coarctation model of experimental hypertension and there is some evidence to suggest that they might play a role in the initiation of hypertrophic growth. However, in vivo studies do not discriminate between the direct effects of pressure and pressure-independent trophic stimuli such as angiotensin II. To examine these influences separately we studied isolated working hearts exposed to different afterloads in the presence or absence of angiotensin II. METHODS: Hearts from normotensive female Wistar rats were perfused with a modified Krebs-Henseleit solution, with and without angiotensin II (100 nmol/1) and exposed to low (60 mmHg) or high (140 mmHg) afterload (n > 17/group). Proto-oncogene mRNA induction in the left ventricle was assessed by Northern blot analysis. RESULTS: Aortic pressures were 101 +/- 14/63 +/- 6 mmHg (mean +/- s.d.) with low and 175 +/- 13/93 +/- 20 mmHg with high afterload; hearts in both groups maintained a stable cardiac output over 240 min, except for high afterload hearts not perfused with angiotensin II, which showed a 59% drop by the end of the experiment (P < 0.001). There was a 50% (32%, 72%) (geometric mean and 95% confidence interval) increase of c-myc and 54% (27%, 86%) increase in c-fos, but a 32% (25%, 40%) suppression of H-ras with high (140 mmHg) as compared with low (60 mmHg) afterloads (P < 0.0001 for each). There was no significant difference in c-myc and c-fos induction with different levels of high afterload (110, 120, 140 mmHg), but for H-ras suppression progressively increased with increasing afterload (P = 0.003). At high afterload, levels of c-fos rose at 30 min and peaked at 60 min, c-myc continued to rise up to 240 min, and H-ras was suppressed at all four time points. The addition of angiotensin II (100 nmol/l) to the perfusate resulted in 18% (6%, 28%; P = 0.006) lower c-myc levels, 12% (-6%, 28%; P = 0.18) lower c-fos levels and an 11% (-0.1%, 24%; P = 0.056) increase of H-ras. CONCLUSION: The isolated perfused working rat heart is capable of performing stably for a period of at least 240 min at high afterload pressures comparable to those encountered in hypertension. A proto-oncogene induction similar to that seen in the hypertrophying heart can be induced by increased pressure alone, without the mediating effects of circulating angiotensin II. Hearts perfused with angiotensin II showed a more stable performance at high levels of afterload which was associated with a minor attenuation of pressure-induced changes in proto-oncogene expression.
Assuntos
Angiotensina II/farmacologia , Cardiomegalia/metabolismo , Hipertensão/metabolismo , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/análise , Animais , Northern Blotting , Feminino , Expressão Gênica/efeitos dos fármacos , Perfusão , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Ratos , Ratos Wistar , Proteínas ras/genéticaRESUMO
To simulate in vivo conditions as closely as possible to in vitro conditions, we examined the morphological and functional characteristics of isolated human subcutaneous small arteries from 17 essential hypertensive patients and 14 normotensive control subjects using a perfusion myograph. Vessel segments were cannulated and exposed to conditions of constant flow and pressure. The ratio of media thickness to lumen diameter in arteries from hypertensive patients increased significantly. With the endothelium intact, sensitivity to extraluminally applied norepinephrine was not different, and this was not affected by inhibition of neuronal amine uptake with cocaine. After removal of the endothelium, sensitivity to norepinephrine was augmented in normotensive vessels to a greater extent than in hypertensive vessels. Endothelium-dependent relaxation to acetylcholine was significantly reduced in arteries from hypertensive patients, but endothelium-independent relaxation to sodium nitroprusside was not different from that observed in vessels from normotensive control subjects. These data demonstrate that sensitivity to exogenous norepinephrine is not different in essential hypertension but that there is defective endothelium-dependent dilatation, suggesting a contributory role for endothelium dysfunction in human essential hypertension.
Assuntos
Artérias/fisiopatologia , Hipertensão/fisiopatologia , Endotélio Vascular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Perfusão , Resistência Vascular , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
The sensitivity of the myofilaments to Ca2+ is increased during agonist-induced contraction of vascular smooth muscle. Given the important contribution of vascular tone to the elevation of peripheral resistance observed in genetic hypertension, we have investigated whether alterations in myofilament Ca2+ sensitivity occur in small arteries from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls during the developmental and established phases of hypertension. Segments of mesenteric, renal, and femoral artery with an average lumen diameter <300 microm from 5- or 20-week-old rats were mounted in a wire myograph. Morphological measurements were made and the vessels permeabilized with Staphylococcus aureus alpha-toxin. Dose-response curves to increasing concentrations of Ca2+ were obtained and the ability of 100 nmol/L endothelin-1 (ET-1) or 10 micromol/L norepinephrine (NE) in the presence of 10 micromol/L GTP to enhance tension in response to low Ca2+ (pCa6.7) was determined. Systolic, diastolic, and mean blood pressures were higher in SHR than in WKY at 5 and 20 weeks. The media thickness:lumen diameter ratio was increased in mesenteric and femoral arteries from SHR compared with WKY at 5 and 20 weeks. There was no difference in media thickness:lumen diameter ratio in renal arteries or between 5- and 20-week animals in any vascular bed. The pCa curves were not different in mesenteric, renal, or femoral arteries from hypertensive compared with normotensive rats or between age groups, except in femoral arteries at 20 weeks, which exhibited a greater sensitivity to Ca2+ in SHR. Tension developed in response to maximal Ca2+ (pCa5.0) was greater in permeabilized mesenteric arteries from SHR compared with WKY at 20 weeks of age only; media stress was again similar in both strains but increased in older animals compared with younger animals in mesenteric arteries from WKY. The submaximal contraction induced by pCa6.7 was greater in femoral and renal than mesenteric arteries. GTP (10 micromol/L) augmented the tension developed to pCa6.7 in mesenteric arteries at 5 and 20 weeks and in renal arteries at 20 weeks. Addition of 100 nmol/L ET-1 or 10 micromol/L NE in the continued presence of GTP markedly increased tension in mesenteric arteries at 5 and 20 weeks. In renal arteries, 10 micromol/L NE enhanced Ca2+ sensitivity in the presence of GTP in SHR at 5 and 20 weeks and WKY at 5 weeks. In femoral arteries, there was a tendency for ET-1 and NE to increase Ca2+ sensitivity, but this increase was significant in WKY at 20 weeks (ET-1) and SHR at 5 weeks (NE) only. We have demonstrated that the sensitivity of the myofilaments to Ca2+ and ET-1- or NE-induced Ca2+ sensitization is not different in permeabilized small mesenteric, renal, or femoral arteries from SHR compared with WKY controls. Only in SHR mesenteric arteries at 20 weeks of age was there evidence of increased active tension in response to maximal Ca2+, despite structural differences, consistent with increased muscle mass in femoral arteries from SHR. We conclude that it is unlikely that a ubiquitous abnormality of the sensitivity of the contractile apparatus to Ca2+ or agonist-induced Ca2+ sensitization in vascular smooth muscle underlies the elevated total peripheral resistance associated with hypertension.
Assuntos
Envelhecimento/fisiologia , Artérias/efeitos dos fármacos , Cálcio/agonistas , Cálcio/farmacologia , Hipertensão/fisiopatologia , Ratos Endogâmicos SHR/fisiologia , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/fisiologia , Artérias/patologia , Pressão Sanguínea , Resistência a Medicamentos , Endotelina-1/farmacologia , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/patologia , Guanosina Trifosfato/farmacologia , Hipertensão/patologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/patologia , Norepinefrina/farmacologia , Ratos , Ratos Endogâmicos WKY , Artéria Renal/efeitos dos fármacos , Artéria Renal/patologia , Vasoconstrição , Vasoconstritores/farmacologiaRESUMO
To investigate intracellular pH (pHi) in human resistance arteries in essential hypertension, vessels were obtained from small biopsies of skin and subcutaneous fat from 14 untreated patients, and the results were compared with those from 14 matched normotensive control volunteers. Segments of isolated resistance arteries were mounted in a myograph and loaded with the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Fluorescence signals were monitored using a series of barrier filters and chromatic beam splitters. In this way both resting pHi and the changes in pHi observed during isometric contractions initiated by agonists could be recorded. Resting pHi was not different in vessels from hypertensive patients (hypertensive, 7.24 +/- 0.06 versus control, 7.25 +/- 0.04 pH units). The application of ethylisopropylamiloride (EIPA) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) demonstrated that both Na(+)-H+ exchange and bicarbonate-dependent membrane mechanisms contributed to pHi homeostasis but that neither system was overactive in hypertension (pHi change with EIPA in vessels from hypertensive versus control subjects was -0.11 +/- 0.02 and 0.13 +/- 0.03 pH units, respectively, and pHi change with DIDS in vessels from hypertensive versus control subjects was -0.097 +/- 0.05 and -0.091 +/- 0.03 pH units, respectively). The application of norepinephrine or 125 mM K+ solution induced contraction in the arterial segments with an accompanying fall in pHi. With norepinephrine this fall was significantly attenuated in vessels from hypertensive patients. These results fail to provide evidence for raised pHi in resistance arteries in human essential hypertension, and contrary to previous reports in circulating blood cells, Na(+)-H+ exchange is not overactive in the vessels of such patients.
Assuntos
Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-dissulfônico/análogos & derivados , Amilorida/análogos & derivados , Artérias/fisiologia , Hipertensão/fisiopatologia , Resistência Vascular , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico , Ácido 4-Acetamido-4'-isotiocianatostilbeno-2,2'-dissulfônico/farmacologia , Tecido Adiposo/irrigação sanguínea , Amilorida/farmacologia , Antiarrítmicos/farmacologia , Bicarbonatos , Transporte Biológico , Calibragem , Proteínas de Transporte/fisiologia , Feminino , Fluoresceínas , Homeostase , Humanos , Concentração de Íons de Hidrogênio , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Potássio/farmacologia , Pele/irrigação sanguínea , Trocadores de Sódio-Hidrogênio , Resistência Vascular/efeitos dos fármacosRESUMO
Intramural sympathetic neuroeffector responses and presynaptic regulation of neurotransmission by amine uptake and alpha 2-adrenergic receptors were examined in young (5-week-old) and mature (12-week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar-Kyoto (WKY) control rats. Electrical field stimulation (20 V, 0.2-msec pulse width, 3-second pulse train each minute, 5-100 Hz) elicited contractile responses from isolated mesenteric arteries mounted in a myograph. There was a significant difference between the sensitivity of arteries to electrical field stimulation in the two age groups, with arteries from 12-week-old rats being more sensitive than arteries from 5-week-old animals. Also, there was a significant age-strain interaction: the sensitivity of arteries from SHR to electrical field stimulation increased dramatically with age compared with that of WKY rat arteries. Cocaine significantly increased the sensitivity to electrical field stimulation after inhibition of presynaptic alpha 2-adrenergic receptors, and had a significantly greater effect in arteries from 5-week-old SHR compared with WKY controls. This would reflect an overactive neuronal amine uptake mechanism in young SHR. At 12 weeks there was no significant interstrain difference in the effect of cocaine. Yohimbine increased the sensitivity to electrical field stimulation both before and after inhibition of neuronal amine uptake, but there was no difference in its effect with age or strain. Therefore, although sensitivity to sympathetic nerve stimulation varies with age in the SHR, there is no evidence that this can be ascribed to alpha 2-adrenergic receptor function.
Assuntos
Artérias/fisiopatologia , Hipertensão/fisiopatologia , Junção Neuroefetora/fisiologia , Animais , Cocaína/farmacologia , Estimulação Elétrica , Masculino , Prazosina/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Adrenérgicos alfa/fisiologia , Ioimbina/farmacologiaRESUMO
We investigated the morphological (wall-lumen ratio) and contractile characteristics of distal mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls at a distending pressure of 63% of the mean aortic pressure of each rat using a pressure arteriograph. The wall-lumen ratios obtained were compared with those obtained at a pressure of 100 mm Hg. Experiments were carried out at 5 and 20 weeks. Mean aortic pressure of SHR was significantly increased at 5 weeks compared with that of WKY and was further increased by 20 weeks. At 63% of mean aortic pressure, no difference in the wall-lumen ratio of the arteries was observed between strains at 5 weeks; at 20 weeks, the wall-lumen ratio of SHR arteries was significantly increased compared that in WKY arteries. The wall-lumen ratio of SHR vessels did not differ at 63% mean aortic pressure compared with 100 mm Hg at either 5 or 20 weeks, whereas this parameter was significantly reduced in WKY vessels at 100 mm Hg compared with 63% mean aortic pressure at 5 and 20 weeks. In the presence of spontaneous myogenic tone, there was a borderline reduction in the lumen diameter of SHR vessels compared with WKY vessels and with increasing norepinephrine concentrations at 5 weeks. At 20 weeks, lumen diameter between strains did not differ in the presence of myogenic tone nor with increasing norepinephrine concentrations. Similar results were obtained when vessels from both rat strains were pressurized to 80 mm Hg. Thus, the increased wall-lumen ratio in the distal mesenteric arteries from adult SHR compared with those from WKY is not associated with an increased contractility under isobaric conditions when studied at physiological distending pressure.
Assuntos
Hipertensão/patologia , Artérias Mesentéricas/patologia , Vasoconstrição , Animais , Hipertensão/fisiopatologia , Masculino , Artérias Mesentéricas/fisiopatologia , Norepinefrina/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasoconstrição/efeitos dos fármacosRESUMO
In order to investigate whether functional and morphological changes are present in the resistance vasculature before hypertension is established, isolated subcutaneous resistance vessels were studied from 21 young normotensive subjects with a family history of hypertension and 22 controls matched for age, sex, and weight. The vessels from the offspring of hypertensive patients displayed no morphological changes or differences in reactivity or sensitivity to the vasoconstrictor agonists norepinephrine, angiotensin II, serotonin, and vasopressin. In the presence of cocaine, however, vessels from offspring showed a significantly greater shift in sensitivity to norepinephrine, a phenomenon also observed in previous studies of vessels from hypertensive patients. The results suggest that in essential hypertension, while morphological and functional abnormalities of the resistance vasculature may develop as the blood pressure rises, a defect in neuroeffector activity is present before hypertension is established and may be a manifestation of abnormal sympathetic nervous system activity underlying the disease.
Assuntos
Vasos Sanguíneos/fisiopatologia , Hipertensão/fisiopatologia , Resistência Vascular , Adulto , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Cálcio/metabolismo , Cocaína/farmacologia , Resistência a Medicamentos , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Técnicas In Vitro , Masculino , Norepinefrina/farmacologiaRESUMO
The relationship between leukocyte ionized calcium concentration, sodium content, and blood pressure was studied in normotensive subjects with (n = 17) and without (n = 21) a family history of hypertension and in untreated patients with essential hypertension (n = 22). There was a highly significant correlation between intracellular ionized calcium and mean supine blood pressure (measured on the same occasion) in normal subjects with no family history of hypertension (r = +0.73, p less than 0.01). This relationship was lost in normal subjects with a family history of hypertension, and in hypertensive patients there was a nonsignificant negative correlation between intracellular ionized calcium and blood pressure (r = +0.08 and -0.31, respectively). Intracellular ionized calcium was similar in the normotensive groups (both, 126 +/- 7 nmol/L) and slightly but nonsignificantly elevated in hypertensive patients (143 +/- 10 nmol/L; p = 0.09). There was no correlation between intracellular ionized calcium and sodium content in any group (r less than 0.1). These results indicate that while leukocyte ionized calcium in normotensive subjects with no family history of hypertension may reflect smooth muscle contractility resulting in the positive correlation between leukocyte ionized calcium and blood pressure, this relationship is lost in hypertensive patients and subjects predisposed to hypertension. This may be due to an altered relationship between leukocyte and smooth muscle calcium handling in these subjects or to non-calcium-mediated influences on blood pressure.
Assuntos
Pressão Sanguínea , Cálcio/sangue , Hipertensão/sangue , Leucócitos/metabolismo , Sódio/sangue , Adulto , Citosol/metabolismo , Feminino , Humanos , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Contração Muscular , Músculo Liso Vascular/fisiologiaRESUMO
The effects of stress on leukocyte membrane sodium efflux rate constant and plasma norepinephrine levels were studied before and during cold pressor test in normotensive subjects with and without a family history of hypertension. After 20 minutes of supine rest, no significant differences in total, ouabain-resistant or ouabain-sensitive sodium efflux rate constants were apparent between the two groups. In normotensive subjects with no family history, there was no significant change in any efflux rate constant during cold pressor test, although there was a highly significant negative correlation between change in total efflux rate constant and change in norepinephrine levels (r = -0.82, p less than 0.01, n = 12). During cold pressor test in subjects with a family history of hypertension, there was a significant rise in the ouabain-resistant efflux rate constant (1.5 +/- 0.1 vs 1.0 +/- 0.1 hr-1; p less than 0.01, n = 10); this level was also significantly higher than that in control subjects (p less than 0.002). In this group, the ouabain-sensitive efflux rate constant fell slightly but not significantly (1.8 +/- 0.2 vs 2.1 +/- 0.2 hr-1; n = 10). These results suggest that stress in the form of a cold stimulus produces qualitative differences in leukocyte cation transport in normotensive offspring of hypertensive patients as compared with subjects without such a family history.
Assuntos
Temperatura Baixa , Hipertensão/genética , Canais Iônicos/metabolismo , Leucócitos/metabolismo , Norepinefrina/sangue , Pressorreceptores/fisiologia , Sódio/metabolismo , Adulto , Pressão Sanguínea , Feminino , Humanos , Hipertensão/metabolismo , MasculinoRESUMO
Left ventricular hypertrophy is a common clinical feature in hypertensive patients and may be associated with structural changes in vessel morphology. In an open prospective trial, we evaluated 14 patients with previously untreated hypertension (163 +/- 2/104 +/- 2 mm Hg) and an echocardiographically determined left ventricular mass index of 141.6 +/- 5.2 g/m2, indicating left ventricular hypertrophy. We obtained a gluteal skin biopsy sample before starting treatment to investigate subcutaneous small-artery (approximately 200 to 400 microns diameter) morphology and function. Patients then received antihypertensive treatment with a combination of spirapril (3 or 6 mg) and isradipine (2.5 or 5 mg). Echocardiographic recordings were made after 6 months and 1 year, and a final biopsy was taken after 1 year. After 1 year, blood pressure was significantly reduced to 142 +/- 3/ 90 +/- 1 mm Hg (P < .001), and left ventricular mass index decreased significantly to 105.3 +/- 5.8 g/m2 (P < .001). Baseline media-lumen ratio (7.64 +/- 0.48%) was not markedly reduced (7.21 +/- 0.55%), although a decrease occurred in 7 of 12 evaluable patients. Norepinephrine-induced vasoconstriction was markedly reduced after 1 year. In conclusion, a significant regression of left ventricular hypertrophy was obtained after 1 year of treatment with spirapril and isradipine, whereas a similar reduction in medial thickness relative to lumen diameter of subcutaneous small arteries could not be observed in all patients. Reversal of structural changes in resistance vessels may require a longer treatment period in patients with proven left ventricular hypertrophy.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Artérias/efeitos dos fármacos , Enalapril/análogos & derivados , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Isradipino/uso terapêutico , Resistência Vascular , Artérias/patologia , Artérias/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Combinação de Medicamentos , Ecocardiografia , Enalapril/uso terapêutico , Feminino , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Estudos ProspectivosRESUMO
In a double-blind randomized trial, the effects of treatment with an angiotensin-converting enzyme (ACE) inhibitor (perindopril) and a beta-blocker (atenolol) on small artery structure were compared in previously untreated essential hypertensive patients. Subjects (diastolic blood pressure > or = 100 and < or = 120 mm Hg) were randomly assigned to treatment for 12 months with either perindopril (n = 13, 4 to 8 mg/d) or atenolol (n = 12, 50 to 100 mg/d); the dosage was adjusted upward and in some cases combined (n = 5, perindopril; n = 2, atenolol) with thiazide diuretic to achieve target blood pressure (diastolic blood pressure below 90 mm Hg). Before and at the end of treatment, gluteal biopsies were taken under local anesthetic; from these biopsies, two small arteries were dissected and mounted on a myograph for morphometry. The reduction in blood pressure with atenolol (drop in mean blood pressure 28.4 +/- 1.8 mm Hg) was greater than with perindopril (20.6 +/- 1.8 mm Hg, P < .05). Perindopril treatment caused an increase in small artery diameter (231 +/- 14 to 274 +/- 13 microns, P < .05) and a reduction in the ratio of media thickness to lumen diameter (7.94 +/- 0.65% to 5.96 +/- 0.42%, P < .05), whereas atenolol had no effect (246 +/- 14 to 231 +/- 13 microns and 7.14 +/- 0.47% to 6.79 +/- 0.45%, respectively). The change in small artery morphology caused by perindopril was not accompanied by any change in media cross-sectional area, suggesting that the change was due to "remodeling."(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Artérias/efeitos dos fármacos , Atenolol/uso terapêutico , Hipertensão/tratamento farmacológico , Indóis/uso terapêutico , Adulto , Idoso , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PerindoprilRESUMO
The wide range of membrane electrolyte transport abnormalities associated with experimental, genetic, and essential hypertension may either reflect an underlying global change in the cell membrane or may be directly related to the underlying disturbance that causes hypertension or to changes in sodium balance. To investigate this further, we studied sodium transport and intracellular electrolyte composition in the thymocytes of normal rats undergoing salt loading or depletion, and in rats with renovascular, mineralocorticoid, or spontaneous hypertension compared to appropriate age-matched normotensive control rats. In normotensive rats, although there was no significant difference between the blood pressures at the two extremes of sodium balance, sodium loading caused a nonsignificant rise in sodium transport, whereas sodium depletion was associated with a significant fall in sodium transport and intracellular sodium. When cells from salt-loaded or normal animals were incubated in a medium containing their own serum, sodium transport was slightly stimulated in both, but there was no significant difference in the sodium efflux-rate constant of thymocytes obtained from rats on the normal as opposed to the high salt intake. Compared to normotensive rats, there was no significant change in the sodium efflux-rate constant in any of the hypertensive rat models studied. However, the sodium efflux-rate constant fell with age in both the spontaneously hypertensive and Wistar-Kyoto normotensive rats. The present studies show that dietary sodium intake and aging had considerable effects on rat thymocyte sodium transport, but neither of these changes was related to a change in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hipertensão/metabolismo , Sódio/metabolismo , Timo/metabolismo , Animais , Transporte Biológico , Pressão Sanguínea , Desoxicorticosterona , Feminino , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Membranas Intracelulares/metabolismo , Ratos , Ratos Endogâmicos , Cloreto de Sódio , Timo/patologiaRESUMO
It has been postulated that depressed membrane sodium transport is a necessary step in blood pressure elevation in essential hypertension. Accordingly, leucocyte sodium efflux-rate constants were estimated in 14 normotensive subjects who had one or more first-degree relatives with essential hypertension, and also in 14 matched control subjects with no such family history, before and after taking bendrofluazide for 7 days. Efflux rates in the controls did not change after the diuretic. However, in the relatives, mean total sodium efflux-rate constant was at first significantly depressed but later rose to normal with the diuretic. This was due almost entirely to an increase in glycoside-sensitive sodium pump activity. Blood pressure remained unchanged in both groups. Thus, assuming that perturbations in leucocytes reflect similar abnormalities in other cell lines, major changes in sodium transport in the normotensive individual without accompanying changes in blood pressure suggest that, while these changes may be a marker for later hypertension, they do not participate directly in blood pressure control.
Assuntos
Pressão Sanguínea , Hipertensão/sangue , Leucócitos/metabolismo , Sódio/sangue , Adulto , Transporte Biológico/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Creatinina/sangue , Diuréticos/farmacologia , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Potássio/sangue , Renina/sangue , Ureia/sangue , Ácido Úrico/sangueRESUMO
To examine the function of resistance-sized arteries in hypertension under in vitro conditions that approximate in vivo conditions as much as possible, we mounted segments of second-order mesenteric resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats aged 12 to 13 weeks in a perfusion myograph and exposed them to conditions of constant flow and pressure. The endothelial integrity was validated both functionally and histologically. Vascular sensitivity to norepinephrine was examined when the hormone was applied either intraluminally or extraluminally and before and after removal of the endothelium. Both endothelium-dependent and -independent dilatation was assessed by the intraluminal application of acetylcholine and sodium nitroprusside, respectively. Sodium nitroprusside was applied to arteries after endothelium removal. Arterial responses were measured by changes in intraluminal diameter recorded with a video camera and imaging system. Vessels from SHR demonstrated depressed endothelium-dependent relaxation but similar endothelium-independent relaxation and greater sensitivity to norepinephrine with both intraluminal and extraluminal application. Removal of the endothelium abolished the differences in sensitivity to norepinephrine between the two strains. The results demonstrate that resistance arteries from SHR when examined under in vitro perfusion display enhanced sensitivity to norepinephrine due to depressed endothelium-dependent dilatation, and the data suggest that functional modifications in the endothelium may play an important role in hypertensive vascular disease.
Assuntos
Artérias/fisiopatologia , Hipertensão/genética , Hipertensão/fisiopatologia , Resistência Vascular , Acetilcolina/farmacologia , Animais , Artérias/efeitos dos fármacos , Técnicas In Vitro , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Perfusão , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasoconstrição , VasodilataçãoRESUMO
The purpose of the present study was to determine the cellular basis for the increased ratio of media thickness to lumen diameter (media-lumen ratio) consistently found in the peripheral resistance arteries from patients with essential hypertension using an unbiased stereological principle (the "disector"). Segments of subcutaneous resistance arteries (approximately 200 microns internal diameter) were isolated from gluteal biopsies of skin and subcutaneous fat taken from 16 untreated patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. Measured under standardized conditions (ie, relaxed and under controlled mechanical conditions) on an isometric myograph, vessels from hypertensive patients had a significant (P < .05) reduction in lumen diameter and an increase in media-lumen ratio (P < .05) compared with vessels from normotensive control subjects. These changes were not associated with alterations in the estimated media volume per segment length. After these measurements had been made, the arteries were fixed, serial sectioned, and stained. The volume fraction of smooth muscle cells within the media was estimated by point counting on photomicrographs of the vessels. Using the disector principle, we determined the numerical density (number per unit volume) of smooth muscle cells within the media of each vessel and calculated the average smooth muscle cell volume (1775 +/- 122 [mean +/- SEM] and 1532 +/- 112 microns 3, hypertensive and normotensive, respectively, P > .05) on the basis of these measurements.(ABSTRACT TRUNCATED AT 250 WORDS)