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1.
Clin Exp Pharmacol Physiol ; 29(10): 898-904, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12207569

RESUMO

1. Chronic antihypertensive treatment lowers cardiovascular morbidity and mortality. The beneficial effect on the blood vessel wall may be due to the lowering of blood pressure (BP) and, hence, wall stress (WS), or to a treatment-induced change in wall structure. 2. We have previously shown that, when evaluated at the same level of BP and WS, the stiffness of the aortic wall of old spontaneously hypertensive rats (SHR) is higher than that of young and adult SHR and that of age-matched Wistar-Kyoto (WKY) rats. In the present study, we tested the hypothesis that the intrinsic changes in wall composition and mechanics in old SHR can be modulated by long-term treatment with an angiotensin I-converting enzyme inhibitor (captopril; 40 mg/kg per day) combined with a diuretic (hydrochlorothiazide; 20 mg/kg per day) and that treatment withdrawal would reveal whether such changes are maintained when BP and WS return to pretreatment levels. 3. We evaluated aortic structure and mechanics in SHR following 1 week withdrawal of oral antihypertensive treatment from 3 to 15 months of age (n = 8). Results were compared with age-matched SHR that were maintained on treatment (n = 12) or were not treated (n = 13) and with WKY rats (no treatment n = 11; maintained n = 11; withdrawn n = 10). 4. Isobaric aortic wall stiffness was estimated from the ratio of baseline aortic pulse wave velocity (PWV) to BP and the slope relating aortic PWV to BP following sodium nitroprusside-induced hypotension. Relative wall stiffening was estimated as the ratio of elastic modulus (EM) to WS. We argued that if treatment produced a change in wall elastin or collagen content, with a subsequent decrease in isobaric wall stiffness, then this would be maintained when BP increased following withdrawal of treatment. 5. In old SHR, treatment lowered isobaric wall stiffness (baseline PWV/BP 4.6 +/- 0.3 cm/s per mmHg; slope relating PWV to BP 6.7 +/- 0.4 x 10-3 cm/s per mmHg and EM/WS 4.1 +/- 0.4 vs 6.1 +/- 0.4 cm/s per mmHg, 9.7 +/- 0.9 x 10-3 cm/s per mmHg and 8.9 +/- 1.1, respectively, without treatment; all P < 0.05). After 1 weeks treatment withdrawal, the indices (5.7 +/- 0.2 cm/s per mmHg, 9.1 +/- 0.2 x 10-3 cm/s per mmHg and 7.2 +/- 0.6) increased in parallel with the increase in WS to levels similar to those observed in untreated SHR. There were no significant differences among the WKY rat groups. 6. Treatment increased the elastin and collagen contents of the aortic wall in both SHR (196 +/- 13 and 128 +/- 5 vs 111 +/- 9 and 86 +/- 4 mg/g wet weight, respectively, in untreated; P < 0.05) and WKY rats (190 +/- 19 and 135 +/- 4 vs 115 +/- 7 and 114 +/- 5 mg/g wet weight, respectively, in untreated; P < 0.05). This increase remained following withdrawal (213 +/- 26 and 118 +/- 4 vs 161 +/- 14 and 127 +/- 4 mg/g wet weight in SHR and WKY rats, respectively). 7. In summary, 1 year of treatment with captopril plus hydrochlorothiazide increases wall elastin content and reduces WS and stiffness in old SHR. Following withdrawal, elastin content remains high, but wall stiffness parallels WS in a manner similar to that in untreated SHR.


Assuntos
Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Anti-Hipertensivos/farmacologia , Aorta Abdominal/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Síndrome de Abstinência a Substâncias/patologia , Animais , Anti-Hipertensivos/uso terapêutico , Aorta Abdominal/patologia , Aorta Torácica/patologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Captopril/farmacologia , Captopril/uso terapêutico , Esquema de Medicação , Elasticidade/efeitos dos fármacos , Hipertensão/patologia , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Síndrome de Abstinência a Substâncias/fisiopatologia
2.
Cell Calcium ; 29(6): 409-15, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11352506

RESUMO

Neutrophil-like HL-60 cells reacted to N -formyl- l -Methionyl- l -Leucyl- l -P henylalanine (f MLP) with a rise in the intracellular calcium concentration ([Ca2]i), NADPH oxidase activation, and increased superoxide anion (O2-) production. [Ca2+]i mobilization and superoxide production were largely dependent on extracellular calcium (Ca2+]e) and a capacitative calcium entry. The monomeric G-protein, Rac-1, regulates NADPH oxidase activity. We tested the effect of removal of Ca2+]e on Rac-1 plasma membrane sequestration and activation of NADPH oxidase using immunodetection and a double labelling fluorescent method. Results showed that Rac-1 activation is mediated via a pertussis toxin (PTX)-sensitive heteromeric G-protein pathway, and that Rac-1 membrane sequestration was preceded by [Ca2+]i mobilization following entry of Ca2+ e. Therefore, we propose that O2- production is dependent on activation of PTX-sensitive G-proteins and sequestration of Rac-1 in the plasma membrane, following entry of Ca2+ e.


Assuntos
Cálcio/metabolismo , Membrana Celular/metabolismo , N-Formilmetionina Leucil-Fenilalanina/metabolismo , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Cálcio/agonistas , Cálcio/antagonistas & inibidores , Espaço Extracelular/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Células HL-60/metabolismo , Humanos , Fosfatos de Inositol/agonistas , N-Formilmetionina Leucil-Fenilalanina/farmacologia , NADPH Oxidases/efeitos dos fármacos , Toxina Pertussis , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fatores de Virulência de Bordetella/farmacologia , Proteínas rac1 de Ligação ao GTP/efeitos dos fármacos
3.
Biochem Pharmacol ; 61(9): 1169-75, 2001 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-11301051

RESUMO

We showed, in rat de-endothelialised tail artery, that pertussis toxin (PTX) (1 microg/mL, 2 hr) attenuated norepinephrine (NE)-induced vasoconstriction without modifying intracellular calcium concentration [Ca2+](i) mobilisation. We suggested the existence of two NE-induced intracellular pathways: a first, which would be insensitive to PTX and lead to [Ca2+](i) mobilisation, and a second sensitive to PTX and involved in the [Ca2+](i) sensitivity of NE-induced contraction. The aim of this study was to demonstrate the existence of the second intracellular pathway. PTX-sensitive G(i/o)-proteins in rat tail artery SMC membrane were identified by immunoblot and ADP-ribosylation. [(32)P]ADP-ribosylation of alpha(i/o)-subunits was demonstrated in situ by perfusing rat de-endothelialised tail artery segments with PTX (1 microg/mL, 2 hr), which suggested that G(i/o)-protein inactivation was involved in the reduction by PTX of the [Ca2+](i) sensitivity of NE-induced contraction. Coupling between G(i/o)-proteins and NE receptors was confirmed by the NE-induced increase in G(i/o)-specific GTPase activity (24.1 +/- 1.9 vs 8.8 +/- 0.4 pmol P(i)/mg protein at 5 min; P < 0.05 vs basal). [(3)H]Prazosin-binding data showed the presence of a heterogeneous alpha(1)-AR population in rat tail artery smooth muscle cells. We demonstrated the in vitro coupling between alpha(1A)-AR subtype and alpha(i)-subunits. In conclusion, we identified, in rat de-endothelialised tail artery, a PTX-sensitive G(i/o)-protein-modulated pathway that is coupled to NE receptors via alpha(1A)-AR. We suggest that NE stimulates two alpha(1)-AR-mediated intracellular pathways: a first, which is mediated by a G(q)-protein and leads to [Ca2+](i) mobilisation and contraction, and a second, which is mediated by a G(i)-protein and is involved in the amplification of the [Ca2+](i) sensitivity of NE-induced tension.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Músculo Liso Vascular/fisiologia , Norepinefrina/fisiologia , Vasoconstrição/fisiologia , Análise de Variância , Animais , Artérias/citologia , Transporte Biológico , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Toxina Pertussis , Prazosina/metabolismo , Ratos , Ratos Wistar , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos alfa 1/análise , Transdução de Sinais , Cauda , Trítio , Vasoconstrição/efeitos dos fármacos , Fatores de Virulência de Bordetella/farmacologia
4.
Biochem Pharmacol ; 61(4): 485-91, 2001 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11226383

RESUMO

Several studies have shown that stimulation of pertussis toxin (PTX)-sensitive G-proteins amplified alpha-adrenoceptor (alpha-AR) agonist-induced vasoconstriction in small muscular and resistance arteries. The aim of this study was to assess the potential involvement of PTX-sensitive G-proteins in norepinephrine (NE)-induced constriction in a large diameter artery, the rat aorta. PTX (1 microg/mL, 2 hr; 3 microg/mL, 4 hr) did not modify concentration-response curves to NE in endothelium-denuded aortic rings. However, several lines of evidence suggested that aortic smooth muscle cells (SMC) had a PTX-sensitive G-protein pathway. [alpha-(32)P]ADP-ribosylation of G(i/o)-proteins by PTX (3 microg/mL, 4 hr) was demonstrated in situ in the intact aorta without endothelium. alpha(i/o) subunits were identified in vitro by both immunoblotting and ADP-ribosylation experiments in rat aorta SMC membranes. The measurement of G(i/o)-specific GTPase activity evidenced an effective coupling between NE receptors and G(i/o)-proteins, as NE induced an increase in basal G(i/o)-specific GTPase activity (20.7 +/- 2.8 vs 7.2 +/- 2.2 pmol P(i)/mg protein at 5 min; P < 0.05 vs basal). Co-immunoprecipitation revealed the in vitro coupling between alpha(1D)-ARs and G(i)-protein in rat aorta SMC membranes. In conclusion, we identified a PTX-sensitive G(i/o)-protein pathway in rat endothelium-denuded aorta. We showed an effective coupling between NE receptors and G(i)-proteins via alpha(1D)-ARs. Since PTX has no effect on NE-induced vasoconstriction, the PTX-sensitive G(i)-protein pathway does not play a predominant role in NE-induced responses in rat aorta SMC in contrast to small diameter muscular and resistance arteries.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/fisiologia , Proteínas Heterotriméricas de Ligação ao GTP/fisiologia , Músculo Liso Vascular/fisiologia , Norepinefrina/farmacologia , Toxina Pertussis , Vasoconstrição/fisiologia , Fatores de Virulência de Bordetella/farmacologia , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Relação Dose-Resposta a Droga , Ativação Enzimática , GTP Fosfo-Hidrolases/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/isolamento & purificação , Proteínas Heterotriméricas de Ligação ao GTP/isolamento & purificação , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Prazosina/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Adrenérgicos/fisiologia , Receptores Adrenérgicos alfa 1/análise , Trítio
5.
Am J Physiol Heart Circ Physiol ; 280(1): H420-5, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11123259

RESUMO

Because little is known of the intracellular mechanisms involved in the vasoconstrictor effect of melatonin (Mel), we examined the in vitro effects of Mel by using perfused cylindrical segments of the rat tail artery loaded with the intracellular Ca(2+) concentration ([Ca(2+)](i))-sensitive fluorescent dye, fura 2. Mel (10(-14) to 10(-4) M) had no effect on baseline perfusion pressure or [Ca(2+)](i) but increased, at submicromolar concentrations, the vasoconstrictor effect of norepinephrine (NE) (P = 0.0029). Mel did not modify NE-induced [Ca(2+)](i) mobilization, and thus the [Ca(2+)](i) sensitivity of NE-induced contraction increased in the presence of Mel. Mel consistently increased KCl-induced vasoconstriction and [Ca(2+)](i) sensitivity of contraction, but differences were not statistically significant. In conclusion, Mel increases the [Ca(2+)](i) sensitivity of vasoconstriction evoked by NE suggesting that Mel may amplify endogenous vasoconstrictor responses to sympathetic outflow.


Assuntos
Antioxidantes/farmacologia , Cálcio/metabolismo , Citosol/metabolismo , Melatonina/farmacologia , Norepinefrina/farmacologia , Vasoconstritores/farmacologia , Animais , Artérias/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Sinergismo Farmacológico , Técnicas In Vitro , Masculino , Perfusão , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Cauda/irrigação sanguínea
6.
Br J Pharmacol ; 131(7): 1337-44, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11090105

RESUMO

1. We studied the involvement of pertussis toxin (PTX)-sensitive G-proteins in the sensitivity of arterial constriction to intracellular calcium ([Ca(2+)](i)) mobilization. 2. Vasoconstriction was measured in vitro in perfused, de-endothelialized rat tail arteries loaded with the calcium-sensitive dye, fura-2 and treated or not with PTX (30 - 1000 ng ml(-1)). Arteries were stimulated with noradrenaline (NA, 0.1 - 100 microM) or KCl (15 - 120 mM). 3. KCl elicited a smaller vasoconstrictor response (E(max)=94+/-8 mmHg) than NA (E(max)=198+/-9 mmHg) although [Ca(2+)](i) mobilization was similar (E(max)=123+/-8 and 135+/-7 nM for KCl and NA, respectively). PTX (1000 ng ml(-1)) had no effect on [Ca(2+)](i) mobilization but lowered NA- (but not KCl-) induced vasoconstriction (E(max)=118+/-7 mmHg). 4. G(i/o)-proteins were revealed by immunoblotting with anti-G(i alpha) and anti-G(o alpha) antibodies in membranes prepared from de-endothelialized tail arteries. [alpha(32)P]-ADP-ribosylation of G-proteins by PTX (1000 ng ml(-1)) was demonstrated in the intact rat tail artery (pixels in the absence of PTX: 3150, presence: 25053). 5. In conclusion, we suggest that smooth muscle cells possess a PTX-sensitive G(i)-protein-mediated intracellular pathway which amplifies [Ca(2+)](i) sensitivity of contraction in the presence of agonists such as NA.


Assuntos
Artérias/efeitos dos fármacos , Cálcio/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Toxina Pertussis , Vasoconstrição/efeitos dos fármacos , Fatores de Virulência de Bordetella/farmacologia , Animais , Artérias/química , Artérias/fisiologia , Relação Dose-Resposta a Droga , Immunoblotting , Técnicas In Vitro , Masculino , Membranas/química , Membranas/efeitos dos fármacos , Norepinefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Cauda/irrigação sanguínea
7.
Br J Pharmacol ; 131(6): 1227-35, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11082132

RESUMO

1. This study was designed to evaluate the effects of aminoguanidine, a selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), on the reactivity and intracellular calcium ([Ca(2+)](i)) mobilization induced by noradrenaline in the perfused tail artery from aged WAG/Rij rats. Global mean internal diameter was 350+/-15 microns and wall thickness 161+/-3 microns. The influence of the endothelium on these responses was also analysed. The intracellular dye fura-2 for [Ca(2+)](i) measurements was used. 2. Noradrenaline-induced vasoconstriction decreased progressively from 3 to 20 and 30 months. Removal of the endothelium attenuated vasoconstriction in 20 and 30 month-old rats (P<0.05) but not in young rats. 3. Chronic administration of aminoguanidine (50 mg kg(-1) day(-1), p.o.) to WAG/Rij rats from 20 to 30 months enhanced (P<0. 01) the [Ca(2+)](i)-sensitivity of noradrenaline-induced vasoconstriction. 4. Aminoguanidine (300 microM) in vitro significantly shifted the concentration-vasoconstriction curve to noradrenaline to the left (P<0.01) in denuded vessels from both 20 and 30 month-old rats. The acute inhibitory effect of aminoguanidine was also observed after chronic aminoguanidine treatment. Aminoguanidine failed to modify vasoconstriction in the presence of the endothelium. 5. Acute aminoguanidine (300 microM) treatment did not modify vasoconstriction induced by noradrenaline in young rats. 6. Quantification of iNOS mRNA expression in tail arteries from 3 and 20 month-old WAG/Rij rats showed that expression was enhanced (x2.1, P<0.01) with age. 7. These results suggest that an inflammatory process develops in the media of the rat tail artery with age and that the subsequent increase in non-endothelial iNOS activity attenuates noradrenaline-induced vasoconstriction.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Guanidinas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Cauda/irrigação sanguínea , Vasoconstrição/efeitos dos fármacos , Fatores Etários , Animais , Artérias/efeitos dos fármacos , Artérias/fisiologia , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Inibidores Enzimáticos/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Norepinefrina/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Cauda/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasoconstritores/farmacologia
8.
Life Sci ; 66(24): 2371-81, 2000 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-10864099

RESUMO

In man, i) arteries calcify with age and ii) age-linked arterial calcification is amplified by vascular pathology such as hypertension or arteriosclerosis. Age-linked arterial calcification has a bad prognosis but drugs to prevent it are lacking. This is partially due to the lack of appropriate animal models. This paper looks at the extent to which arteries calcify with age in the rat and whether hypertension or arteriosclerosis amplifies such calcification. Total calcium levels were determined by acid digestion and flame spectrophotometry and intracellular calcium levels ([Ca2+]i) by the intracellular calcium-sensitive dye, fura-2. Arteries contained up to 5 times more calcium than other soft tissues. Arteries progressively calcified with age whereas other soft tissues did not. Accumulation of calcium with age was essentially extracellular. Hypertension had no effect on age-related arterial calcification. Calcification of the same order as in man was produced in a rat model of arteriosclerosis (vitamin D plus nicotine treatment). In conclusion, as in man, age-linked, organ-specific arterial calcification does occur in rats but its intensity is far less. Arterial calcification of a similar degree to that observed in man can be obtained in rats by hypervitaminosis D plus nicotine.


Assuntos
Envelhecimento/fisiologia , Calcificação Fisiológica/fisiologia , Cálcio/metabolismo , Animais , Aorta Torácica/metabolismo , Arteriosclerose/induzido quimicamente , Arteriosclerose/metabolismo , Colecalciferol , Hipertensão/genética , Hipertensão/metabolismo , Masculino , Nicotina , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar
9.
Hypertension ; 35(5): 1105-10, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10818072

RESUMO

Statins, which are often given to hypertensive patients, reduce the incidence of stroke. However, their effects on the cerebral circulation have been scarcely studied, although lovastatin has been reported to reduce hypertension-induced renal arteriolar hypertrophy. We examined the structure and mechanics of cerebral arterioles and the lower limit of cerebral blood flow (CBF) autoregulation in spontaneously hypertensive rats (SHR) that were untreated (n=9) or treated for 1 month with lovastatin (n=12; 20 mg x kg(-1) x d(-1)) and in untreated Wistar-Kyoto rats (WKY; n=8). We studied the lower limit of CBF autoregulation by repeated measurement of CBF (arbitrary units; laser Doppler) and internal arteriolar diameter (microm; cranial window) at baseline and during stepwise hypotension. Stress-strain relationships were calculated from repeated measurement of internal arteriolar diameter during stepwise hypotension and cross-sectional area (CSA) of the vessel wall in maximally dilated cerebral arterioles (EDTA, 67 mmol/L). Lovastatin slightly reduced mean arterial pressure (treated, 153+/-3 versus untreated, 171+/-5 mm Hg, P<0.05; WKY, 106+/-3 mm Hg) and normalized CSA (treated, 826+/-52 versus untreated, 1099+/-16 microm(2), P<0. 05; WKY, 774+/-28 microm(2)). Stress-strain curves show that lovastatin also attenuated the increase in passive distensibility. Lovastatin had no effect on the external diameter of cerebral arterioles or the lower limit of CBF autoregulation. Our results show that although lovastatin has substantial effects on arteriolar mechanics and wall CSA, it has little effect on internal diameter. This phenomenon may explain its lack of effect on CBF autoregulation.


Assuntos
Anticolesterolemiantes/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Hipertensão/fisiopatologia , Lovastatina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
10.
Hypertension ; 34(2): 207-11, 1999 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10454442

RESUMO

The effect of antihypertensive treatment on the development of large-artery remodeling in young animals has been widely studied, but reversal of established changes in older hypertensive animals has been largely ignored, although the latter represents a better paradigm for the human condition. We studied the effect of treatment with captopril plus hydrochlorothiazide, from 3 months onward, on geometry and wall stress of the thoracic aorta of adult (9 months, maturation) and old (15 months, senescence) spontaneously hypertensive rats; normotensive Wistar-Kyoto rats were used as controls. At 3 months of age, blood pressure, medial cross-sectional area, and internal diameter were higher in spontaneously hypertensive rats than in Wistar-Kyoto rats. In both strains, medial cross-sectional area and lumen diameter increased during maturation; there was little change with senescence. Changes in blood pressure were minor. Because medial hypertrophy failed to compensate for the wider lumen and higher intraluminal pressure in spontaneously hypertensive rats, medial stress was higher in these rats than in Wistar-Kyoto rats. Captopril plus hydrochlorothiazide rapidly lowered blood pressure and medial cross-sectional area. Despite a marked fall in blood pressure, the internal diameter of the thoracic aorta of treated animals was similar to that of untreated animals after 6 months of treatment and started to fall only after the animals had been treated for 1 year. Thus, under treatment with captopril plus hydrochlorothiazide, medial stress remained elevated, even after very-long-term treatment, because medial cross-sectional area was not adapted to internal diameter. We suggest that some changes in large-artery structure associated with hypertension and aging, such as the increase in diameter, take considerable time to regress after blood pressure is lowered, and this may explain why, despite treatment, wall stress remains elevated.


Assuntos
Envelhecimento , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Aorta Torácica/patologia , Captopril/uso terapêutico , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Fatores Etários , Análise de Variância , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Pressão Sanguínea , Captopril/administração & dosagem , Diuréticos , Hidroclorotiazida/administração & dosagem , Hipertrofia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Inibidores de Simportadores de Cloreto de Sódio/administração & dosagem , Fatores de Tempo
11.
Am J Physiol ; 274(6): R1604-12, 1998 06.
Artigo em Inglês | MEDLINE | ID: mdl-9608014

RESUMO

In male Wistar rats, the in vitro vasoconstrictor response of the perfused tail artery elicited by norepinephrine or serotonin decreased with age (24 mo old vs. 3 mo old), whereas the fluorescent signal (fura 2) produced by intracellular calcium (Ca2+i) mobilization increased. Both vasoconstriction and the increase in intracellular calcium concentration elicited by a high-K+, depolarizing solution were unaffected by aging. Pertussis toxin, a G protein inhibitor, had no effect on vasoconstriction induced by high K+ but diminished vasoconstrictor responses to norepinephrine in 3- and 12-mo-old animals but not in 24-mo-old animals. Pertussis toxin had no effect on Ca2+i mobilization. The sensitivity of receptor activation to pertussis toxin in tail arteries from 24-mo-old animals was restored by pretreatment with the alpha-adrenoceptor antagonist nicergoline. Nicergoline had no effect on vasoconstriction induced by high K+. Plasma norepinephrine concentration rose with age; nicergoline had no effect on this rise. We suggest that aging leads to a decrease in the intracellular G protein-modulated amplification of vasoconstriction produced by receptor activation and that this could be linked to the hyperadrenergic state. Ca2+ sensitivity can be restored by chronic treatment with an alpha-adrenoceptor antagonist.


Assuntos
Envelhecimento/fisiologia , Norepinefrina/farmacologia , Toxina Pertussis , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Fatores de Virulência de Bordetella/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Cálcio/metabolismo , Cálcio/farmacologia , Proteínas de Ligação ao GTP/antagonistas & inibidores , Membranas Intracelulares/metabolismo , Masculino , Nicergolina/farmacologia , Concentração Osmolar , Ratos , Ratos Wistar , Serotonina/farmacologia , Vasodilatadores/farmacologia
12.
J Physiol ; 507 ( Pt 1): 163-74, 1998 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-9490833

RESUMO

1. Controversy exists as to whether a fall in the intracellular Ca2+ concentration ([Ca2+]i) is a requisite element of the vasodilatory response to nitric oxide (NO). 2. We studied the effect of NO on the coupling between [Ca2+]i and vasoconstriction in arterial segments loaded with the [Ca2+]i-sensitive, intracellular dye fura-2. As data interpretation is equivocal when fura-2 is loaded into both endothelial and smooth muscle cells, we compared results from in vitro experiments on segments of the rat tail artery in which fura-2 and noradrenaline were applied on the luminal or adventitial side, and endothelium was removed 'physically' (rubbing or air) or 'functionally' (Nomega-nitro-L-arginine methyl ester). The use of air perfusion to remove endothelium is of considerable benefit since it allows paired observations in a single tissue. 3. Fura-2 loaded into endothelial cells but endothelial 'contamination' of the smooth muscle cell [Ca2+]i signal was minimal. 4. Endogenous NO decreased vasoconstrictor responses to noradrenaline but had no effect on [Ca2+]i. 5. Nitroglycerine decreased vasoconstrictor responses in a concentration-dependent fashion but had no effect on [Ca2+]i. 6. In conclusion, NO causes vasodilatation via a mechanism which is downstream of [Ca2+]i mobilization.


Assuntos
Cálcio/fisiologia , Óxido Nítrico/farmacologia , Cauda/irrigação sanguínea , Sistema Vasomotor/fisiologia , Ar , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Artérias/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes , Fura-2 , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Vasoconstritores/farmacologia , Sistema Vasomotor/efeitos dos fármacos
13.
IDrugs ; 1(6): 650-1, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18465614

RESUMO

In developed countries, premature death and morbidity caused by cardiovascular diseases of the aged are an important issue. This is also an increasing problem in the developing world. This symposium discussed the structural and functional changes, which underlie the way in which the susceptibility of the cardiovascular system to disease increases with age, and how such changes are influenced by external factors.

14.
Am J Physiol ; 273(3 Pt 1): C834-42, 1997 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9316403

RESUMO

We investigated the possibility that the inhibition of oxidative phosphorylation in vascular smooth muscle attenuates norepinephrine- or KCl-evoked vasoconstriction with no change in mobilization of intracellular calcium concentration ([Ca2+]i). Experiments were performed in perfused segments of the rat tail artery loaded with the intracellular calcium dye fura 2, in the absence and presence of dinitrophenol or sodium cyanide; inhibition of oxidative phosphorylation was evaluated from the fall in intracellular ATP levels. The metabolic inhibitors reduced vasoconstriction with no change in [Ca2+]i handling, suggesting that 1) inhibition of oxidative phosphorylation attenuates vasoconstriction via a mechanism downstream of [Ca2+]i, and 2) [Ca2+]i homeostasis (both increases and decreases in [Ca2+]i) can be maintained in the presence of inhibitors of oxidative phosphorylation.


Assuntos
Artérias/fisiologia , Cálcio/metabolismo , Tono Muscular/fisiologia , Músculo Liso Vascular/fisiologia , Norepinefrina/farmacologia , Fosforilação Oxidativa , Vasoconstrição/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Artérias/efeitos dos fármacos , Dinitrofenóis/farmacologia , Técnicas In Vitro , Cinética , Masculino , Tono Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Cianeto de Sódio/farmacologia , Vasoconstrição/efeitos dos fármacos
15.
Cell Calcium ; 18(5): 420-8, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8581970

RESUMO

A new method for the determination of tissue concentrations of Fura-2 and Fura-2/AM was developed based upon acetonitrile extraction followed by RP-HPLC separation (using tetrahexylammonium as counter-ion), post-column alkaline hydrolysis of Fura-2/AM, and fluorimetric detection. The detection limit was 1.2 nM and 1 nM for Fura-2 and Fura-2/AM, respectively. When this technique was applied to perfusion-loaded segments of the rat tail artery, intracellular concentrations of Fura-2 determined by tissue disruption were 10 times those obtained by comparing the increase in fluorescence at the isoemissive point (following loading), with a calibration curve for Fura-2. Loading conditions of 90 min at [Fura-2/AM]e = 5 microM were optimal in terms of [Fura-2]i which attained a concentration not significantly different from [Fura-2/AM]e. Under such conditions, however, Fura-2/AM also accumulated in the arterial wall. Although incompletely de-esterified, Fura-2/AM metabolites produced by in vitro incubation of Fura-2/AM with pig liver esterases could be easily detected, fluorescent forms of Fura-2 with a different sensitivity for calcium were not detected in arterial extracts.


Assuntos
Corantes Fluorescentes/análise , Fura-2/análise , Músculo Liso Vascular/metabolismo , Animais , Artérias/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Fura-2/análogos & derivados , Fura-2/isolamento & purificação , Técnicas In Vitro , Masculino , Perfusão , Ratos , Ratos Wistar , Espectrometria de Fluorescência
16.
Am J Physiol ; 268(6 Pt 2): R1394-400, 1995 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-7611514

RESUMO

Age-related changes in intracellular calcium ([Ca2+]i)-vasoreactivity coupling efficiency (i.e., perfusion pressure divided by [Ca2+]i) were studied in vitro in tail arteries of male, normotensive, WAG/Rij rats aged 6, 12, 24, or 30 mo; one-half of these were chronically treated with the angiotensin I-converting enzyme inhibitor (ACEI) perindopril (1 mg.kg-1.day-1 orally) from 6 mo onward. Arterial segments were perfused at a constant flow rate (perfusion pressure taken as an index of arterial tone) and loaded with the acetoxymethyl ester of fluorescent dye fura 2 (fura 2-AM). Increases in [Ca2+]i were measured simultaneously with vasoconstriction after stimulation with a depolarizing hyperkalemic solution or the agonists norepinephrine or serotonin. Age had no effect on increases in [Ca2+]i vasoconstrictor responses, or electromechanical coupling efficiency (hyperkalemic solution). Increases in [Ca2+]i after agonists were similar in all groups, but vasoconstrictor responses and pharmacomechanical coupling efficiency decreased with age. ACEI had no effect on vasoconstriction or [Ca2+]i signals. In conclusion, coupling efficiency after agonist stimulation decreased with age; ACEI had no effect on coupling efficiency.


Assuntos
Envelhecimento/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Artérias/fisiologia , Cálcio/metabolismo , Indóis/farmacologia , Envelhecimento/efeitos dos fármacos , Análise de Variância , Animais , Artérias/crescimento & desenvolvimento , Pressão Sanguínea/efeitos dos fármacos , Cinética , Masculino , Desenvolvimento Muscular , Músculo Liso Vascular/crescimento & desenvolvimento , Músculo Liso Vascular/fisiologia , Perindopril , Ratos , Ratos Endogâmicos , Serotonina/farmacologia , Cauda/irrigação sanguínea
17.
Br J Pharmacol ; 113(2): 363-8, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7834184

RESUMO

1. Age-related changes in noradrenergic neurotransmission in the tail arteries of three rat strains: outbred Wistar (WI/Ico), inbred Wistar (WAG/Rij) and inbred Fischer (F344) have been compared in the present study. 2. The arterial noradrenaline content varied from 5 to 10 ng mg-1 wet weight amongst young (3 to 6-month old) representatives of each strain, but did not change with age. As protein content increased in senescent rats (24-month old) by 30-40%, arterial tissue growth would not appear to receive a concomitant increase in sympathetic growth leading to relative, age-related, structural sympathectomy in all strains. 3. The vasoconstrictor response to transmural electrical stimulation was diminished in adult and senescent rats of all strains. 4. As far as could be judged from the increase in noradrenaline release following perfusion with the alpha-adrenoceptor antagonist, phentolamine (1 microM), the presynaptic alpha 2-adrenoceptor-mediated inhibition of noradrenaline release was intact in old representatives of all strains. 5. With blockade of the two main systems which control noradrenaline release in the rat tail artery, viz, neuronal reuptake with cocaine (4 microM) and presynaptic alpha 2-adrenoceptors with phentolamine (1 microM), stimulation-evoked release of noradrenaline was similar at all ages and in all strains. This suggests that in the rat tail artery the basic mechanism of neuronal release of noradrenaline is not functionally modified by aging. 6 We conclude that as sympathetic nerve terminals are apparently intact in all three strains of senescent rats used, the age-associated deficit of alpha-adrenergic control of vascular function is postsynaptic in nature.


Assuntos
Envelhecimento/fisiologia , Músculo Liso Vascular/inervação , Sistema Nervoso Simpático/fisiologia , Transmissão Sináptica/fisiologia , Anestesia , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Peso Corporal/fisiologia , Cocaína/farmacologia , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Fentolamina/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Cauda/irrigação sanguínea , Vasoconstrição/fisiologia
18.
Am J Physiol ; 267(3 Pt 2): R687-94, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8092312

RESUMO

Age-related changes in systemic arterial blood pressure, basal cerebral blood flow (CBF), and CBF regulatory capacity were investigated in awake 6-, 12-, 24-, and 30-mo-old male Wistar (WAG/Rij) rats, one-half of which received the angiotensin I-converting enzyme inhibitor (ACEI) perindopril from 6 mo onward. There was no age-dependent change in mean arterial blood pressure, basal CBF, or cerebrovascular reactivity to hypercapnia, but the lower limit of CBF autoregulation rose from 70 mmHg at 6 and 12 mo to 90 mmHg in 24- and 30-mo-old animals. ACEI lowered mean arterial blood pressure but had no effect on basal CBF or on cerebrovascular reactivity to hypercapnia. ACEI shifted the lower limit of CBF autoregulation to a 20-mmHg-lower level in 12- and 24-mo animals but not in rats treated for 2 yr, i.e., from the ages of 6 to 30 mo. In conclusion, the main age-related change in CBF regulation was an increase in the lower limit of CBF autoregulation to a higher blood pressure level. Treatment with ACEI partially restored the lower limit of CBF autoregulation.


Assuntos
Envelhecimento/fisiologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Hipercapnia/fisiopatologia , Masculino , Ratos , Ratos Wistar , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos
19.
Br J Pharmacol ; 111(4): 1184-8, 1994 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8032604

RESUMO

1. Age-related changes in endothelial vasodilator function were studied in an in vitro preparation of the mesenteric arterial bed removed from male, normotensive, Wistar rats. 2. Animals were killed at 2, 12 or 22 months of age, the superior mesenteric artery was cannulated and the gut removed. The mesenteric arterial bed was perfused at a constant flow rate of 4 ml min-1 and perfusion pressure was taken as an index of arteriolar tone. 3. The muscarinic agonist, carbachol, antagonized noradrenaline-induced vasoconstriction in the presence, but not in the absence, of endothelium. This cholinoceptor agonist-induced release of endothelial-derived relaxing factor (EDRF) was impaired in 22 month old rats. 4. Noradrenaline-induced vasoconstriction increased following removal of endothelium suggesting that agonist-induced release of EDRF attenuates vasoconstrictor responses to noradrenaline measured in the presence of endothelium. 5. Removal of endothelium had less effect on noradrenaline-induced vasoconstriction in old rats suggesting once again that agonist-induced release of EDRF is impaired in old rats. 6. The noradrenaline dose-response curve established in the presence of endothelium was shifted to the left in 22 month old rats. 7. In conclusion, aging in the rat appears to lead to a reduction in endothelial vasodilator function in a resistance vessel.


Assuntos
Envelhecimento/fisiologia , Endotélio Vascular/fisiologia , Artérias Mesentéricas/fisiologia , Animais , Masculino , Nitroprussiato/farmacologia , Norepinefrina/farmacologia , Ratos , Ratos Wistar , Vasodilatação
20.
Am J Physiol ; 265(6 Pt 1): C1689-702, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8279530

RESUMO

To measure, simultaneously, intracellular free Ca2+ ([Ca2+]i) and vasoconstriction in a perfused vessel, we used the fluorescent Ca2+ indicator fura 2 with a dual-wavelength excitation method. One-centimeter-long segments of the caudal artery were dissected from 12-mo-old male Wistar rats. The endothelium was removed by gentle rubbing. The artery was mounted in a specially constructed spectrofluorometer cuvette, perfused with oxygenated physiological saline solution at 37 degrees C, and loaded by perfusion with fura 2 acetoxymethyl ester (5 microM) over a 90-min period. This paper is a description of the technique and the experiments that validate it as a useful method for examining Ca(2+)-related vascular reactivity in an intact perfused vessel.


Assuntos
Artérias/fisiologia , Cálcio/metabolismo , Músculo Liso Vascular/fisiologia , Vasoconstrição/fisiologia , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Corantes Fluorescentes , Fura-2/análogos & derivados , Técnicas In Vitro , Cinética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Perfusão/instrumentação , Perfusão/métodos , Cianeto de Potássio/farmacologia , Ratos , Ratos Wistar , Espectrometria de Fluorescência/instrumentação , Espectrometria de Fluorescência/métodos , Cauda/irrigação sanguínea , Fatores de Tempo
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