Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Melanoma/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Humanos , Imidazóis/administração & dosagem , Neoplasias Pulmonares/secundário , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Oximas/administração & dosagem , Prognóstico , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagemRESUMO
We investigated the effect of the lipid-lowering agent, bezafibrate, on insulin sensitivity in a dietary model of insulin resistance. Male Sprague-Dawley rats were divided into four groups: control group, administered a standard diet; high-fructose group, given a 40% fructose diet; high-fructose plus lard group, given a 40% fructose diet with 7% lard; and bezafibrate group, given a 40% fructose plus 7% lard diet with 10 mg x kg-1 x day-1 of oral bezafibrate. Insulin action was assessed after 2 weeks with a steady-state plasma glucose (SSPG) level. The fatty acid (FA) composition of skeletal-muscle triglycerides was also determined. A higher SSPG level (20.9 +/- 0.9 vs. 16.5 +/- 1.1 mmol/l in the control group, P < 0.05) as well as a higher systolic blood pressure (120 +/- 2 vs. 101 +/- 2 mmHg, P < 0.01) was observed in the high-fructose plus lard group, but not in the high-fructose group. These changes were prevented by bezafibrate administration. The FA composition of skeletal-muscle triglycerides demonstrated a higher percentage of saturated and monounsaturated FAs (P < 0.01) and a lower percentage of polyunsaturated FAs (P <0.01) in the high-fructose plus lard group versus the control group. These changes were consistent with differences in the dietary intake of FAs. Bezafibrate virtually normalized the FA composition in the high-fructose plus lard group. The ratio of C20:4 to C20:3, an index of delta5 desaturase activity, was significantly higher in the bezafibrate group versus the high-fructose plus lard group (8.60 +/- 0.76 vs. 2.04 +/- 0.27, P < 0.01). In conclusion, the dietary FA composition was closely related to insulin resistance in rats fed 40% fructose. Bezafibrate increased delta5 desaturase activity. Such action may contribute to the improvement of insulin sensitivity.
Assuntos
Bezafibrato/farmacologia , Ácidos Graxos/análise , Resistência à Insulina , Músculo Esquelético/metabolismo , Triglicerídeos/metabolismo , Animais , Glicemia/metabolismo , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Dessaturase de Ácido Graxo Delta-5 , Carboidratos da Dieta , Gorduras na Dieta , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos não Esterificados/sangue , Frutose/farmacologia , Insulina/sangue , Masculino , Músculo Esquelético/efeitos dos fármacos , Fosfolipídeos/sangue , Ratos , Ratos Sprague-Dawley , Triglicerídeos/químicaRESUMO
This study investigated the possible involvement of prostaglandin H2, an acetylcholine-induced endothelium-derived contracting factor in rat aorta, in the development of abnormality of the vasculature in diabetes. Rings of thoracic aorta were prepared from control Wistar-Kyoto and STZ-induced diabetic rats to examine the changes in isometric tension. In 10(-7) M norepinephrine-precontracted rings, acetylcholine induced relaxations, which were significantly impaired in diabetic rats. Inhibition of thromboxane A2-prostaglandin H2 receptors with ONO-3708 (10(-6) M) prevented the development of the impairment of relaxation in diabetic rats. Thromboxane A2 synthesis inhibition with OKY-046 (10(-5) M) did not affect the acetylcholine-induced relaxation in both control and diabetic rats. In aortic rings under resting tension, acetylcholine induced a contraction that was greater in diabetic than control rats, when the nitric oxide production was inhibited by NG-nitro-L-arginine methylester (10(-4) M). This acetylcholine-induced contraction was observed only in the rings with intact endothelium and was completely abolished by ONO-3708 (10(-6) M). The concentration of 6-keto-prostaglandin F1 alpha in the solution bathing diabetic rat aortic rings increased significantly after acetylcholine (10(-5) M) administration. Prostacyclin (10(-9)-10(-6) M) did not induce contractions at all. Prostacyclin is unlikely to mediate contractions because of its low contractile potency.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Endotelinas/fisiologia , Óxido Nítrico/fisiologia , Prostaglandinas H/fisiologia , Acetilcolina/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/fisiologia , Masculino , Óxido Nítrico/antagonistas & inibidores , Norepinefrina/farmacologia , Prostaglandina H2 , Prostaglandinas/farmacologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos WKY , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Tromboxanos/antagonistas & inibidores , Receptores de Tromboxano A2 e Prostaglandina H2 , Vasodilatação/fisiologiaRESUMO
OBJECTIVES: We investigated the relation between insulin and coronary atherosclerosis and restenosis of the coronary arteries, by performing elective percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Insulin is known to promote atherosclerosis of the arteries and has been implicated in the development of restenosis after PTCA. METHODS: Of 210 angina patients who underwent PTCA, newly detected lesions in 35 consecutive nondiabetic subjects without previous intervention on the same main coronary arteries were analyzed after a 75-g oral glucose tolerance test (OGTT) and follow-up coronary angiography. Atherosclerotic lesions were evaluated by pattern, severity and extent. Restenosis was defined as loss of gain, the percentage of loss of the initial gain in the coronary diameter achieved by PTCA > or = 50%. RESULTS: Patients with restenosis had a significantly higher extent index (a marker of atherosclerosis), insulin area, ratio of insulin area to glucose area, insulinogenic index and minimal lumen diameter after PTCA than those without restenosis (p=0.001, 0.011, 0.002, 0.016 and 0.041, respectively). Simple regression analysis revealed that only the ratio of insulin area to glucose area (a relative marker of enhanced insulin secretion) significantly correlated with the extent index (p=0.035). Extent index, insulin area, the ratio of insulin area to glucose area and insulinogenic index significantly correlated with loss of gain (p=0.001, 0.010, 0.002 and 0.032, respectively). Stepwise multiple regression analyses revealed that extent index and the ratio of insulin area to glucose area significantly correlated with loss of gain. CONCLUSIONS: Enhanced secretion of insulin during the OGTT might be useful as a predictor of coronary atherosclerosis and of restenosis after elective PTCA in nondiabetic patients with effort angina.
Assuntos
Angina Pectoris/terapia , Angioplastia Coronária com Balão , Arteriosclerose/etiologia , Doença das Coronárias/terapia , Insulina/metabolismo , Idoso , Angina Pectoris/etiologia , Arteriosclerose/diagnóstico por imagem , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Feminino , Teste de Tolerância a Glucose , Humanos , Secreção de Insulina , Masculino , Pessoa de Meia-Idade , Esforço Físico , Recidiva , Análise de RegressãoRESUMO
OBJECTIVES: We sought to elucidate the long-term prognostic importance of angiographic no-reflow phenomenon after percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction (AMI). BACKGROUND: Angiographic no-reflow phenomenon, a reduced coronary antegrade flow (Thrombolysis in Myocardial Infarction [TIMI] flow grade < or =2) without mechanical obstruction after recanalization, predicts poor left ventricular (LV) functional recovery and survival in the early phase of AMI. We hypothesized that angiographic no-reflow phenomenon also predicts long-term clinical outcome. METHODS: We studied 120 consecutive patients with their first AMI treated by PTCA without flow-restricting lesions. The patients were classified as either no-reflow (n = 30) or reflow (TIMI-3) (n = 90) based on post-PTCA cineangiograms to follow up (5.8 +/- 1.2 years) for cardiac death and nonfatal events. RESULTS: Patients with no-reflow had congestive heart failure (p < 0.0001), malignant arrhythmia (p = 0.038), and cardiac death (p = 0.002) more often than did those with reflow. Kaplan-Meier curves showed lower cardiac survival and cardiac event-free survival (p < 0.0001) in patients with no-reflow than in those with reflow. Multivariate analyses disclosed that no-reflow phenomenon was an independent predictor of long-term cardiac death (relative risk [RR] 5.25, 95% confidence interval [CI] 1.85 to 14.9, p = 0.002) and cardiac events (RR 3.71, 95% CI 1.79 to 7.69, p = 0.0004). At follow-up, survivors with no-reflow had higher end-diastolic and end-systolic LV volume indices and plasma brain natriuretic peptide levels, and lower LV ejection fractions (p = 0.0002, p < 0.0001, p = 0.002, p < 0.0001, respectively) than did those with reflow, indicating that no-reflow may be involved in LV remodeling. CONCLUSIONS: Angiographic no-reflow phenomenon strongly predicts long-term cardiac complications after AMI; these complications are possibly associated with LV remodeling.
Assuntos
Angioplastia Coronária com Balão/efeitos adversos , Angiografia Coronária , Circulação Coronária/fisiologia , Infarto do Miocárdio/terapia , Função Ventricular Esquerda/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioplastia Coronária com Balão/mortalidade , Causas de Morte , Cineangiografia , Angiografia Coronária/métodos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Volume Sistólico , Taxa de SobrevidaRESUMO
OBJECTIVE: 1,2-Diacylglycerol may initiate cardiac hypertrophy, probably by activating protein kinase C. To test this hypothesis we determined the 1,2-diacylglycerol content of hypertrophied tissue. METHODS: Rats were treated with monocrotaline and developed severe right ventricular hypertrophy followed by congestive heart failure. 1,2-Diacylglycerol content and fatty acid composition, DNA concentrations, and RNA concentrations in the right ventricle from monocrotaline treated rats were compared with values obtained from the left side or from control rats. RESULTS: During the first week, the right ventricle showed no significant change in 1,2-diacylglycerol content and a small increase in RNA concentration. However, the 1,2-diacylglycerol content was significantly increased by 55% at two weeks after monocrotaline injection, when DNA and RNA synthesis was also enhanced to its highest level when compared with control rats (37% and 18%, respectively). At four weeks after monocrotaline injection, conversely, the 1,2-diacylglycerol content was decreased by 25% in the right ventricle from monocrotaline treated rats, most of which had pleural and peritoneal effusions indicating congestive heart failure, although RNA synthesis was sustained at a high level. The fatty acid composition of 1,2-diacylglycerol did not differ significantly between the right and left ventricles or control rat ventricles. CONCLUSIONS: These results suggest that 1,2-diacylglycerol accumulation is associated with development of hypertrophy in monocrotaline treated rats. In contrast, at a stage of congestive heart failure 1,2-diacylglycerol production decreased, suggesting that intracellular transduction mechanisms may be attenuated.
Assuntos
Diglicerídeos/metabolismo , Monocrotalina/farmacologia , Miocárdio/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , DNA/metabolismo , Ácidos Graxos/metabolismo , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/metabolismo , Ventrículos do Coração , Hipertensão Pulmonar/induzido quimicamente , Metabolismo dos Lipídeos , Masculino , Concentração Osmolar , RNA/metabolismo , Ratos , Ratos WistarRESUMO
Leakage of lysosomal enzymes is associated with irreversible cellular damage. To determine the effect of prostaglandin I2 analogue and propranolol on the ischaemic myocardium in relation to changes in lysosomal integrity 26 anaesthetised mongrel dogs were divided into three treatment groups and subjected to 2 h coronary occlusion. In the control group (n = 12) physiological saline was infused throughout the experiment. In the prostaglandin I2 analogue group (n = 7) the prostaglandin I2 analogue, OP-41483-alpha-CD;5(E)-6-Deoxa-6,9 alpha-methylene-15-cyclopentyl-16,17,18,19,20-pentanor-PGI2. alpha-cyclodextrin clathrate (5 ng.kg-1.min-1) was infused from 25 min before occlusion until the end of the experiment. In the propranolol group (n = 7) propranolol (0.3 mg.kg-1) was injected for 10 min 25 min before occlusion. Two hours after occlusion mitochondria were prepared from both ischaemic and non-ischaemic areas in each group and their function measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both non-ischaemic and ischaemic areas was performed and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase; beta-glucuronidase) were measured. In the control group, mitochondrial function in the ischaemic area was reduced compared with that from the non-ischaemic area. The activities of both lysosomal enzymes were increased significantly in the supernatant fraction obtained from the ischaemic area compared with those for the supernatant from the non-ischaemic area. The administration of prostaglandin I2 analogue or propranolol not only prevented the leakage of lysosomal enzymes but also maintained mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doença das Coronárias/prevenção & controle , Ciclodextrinas/uso terapêutico , Dextrinas/uso terapêutico , Epoprostenol/uso terapêutico , Lisossomos/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Propranolol/uso terapêutico , Amido/uso terapêutico , alfa-Ciclodextrinas , Animais , Pressão Sanguínea/efeitos dos fármacos , Doença das Coronárias/fisiopatologia , Cães , Frequência Cardíaca/efeitos dos fármacos , Lisossomos/enzimologia , Mitocôndrias Cardíacas/fisiologiaRESUMO
OBJECTIVE: The aim of this study was to evaluate the possible role of prostacyclin (PGI2) in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR). METHODS: Measurement of mRNA and protein levels of PGH synthase (PGHS)-1, PGI2 synthase and the PGI2 receptor, in the thoracic aorta was performed in SHR aged 5, 10, 20, and 40 weeks old and in age-matched normotensive Wistar-Kyoto (WKY) rats with a competitive polymerase chain reaction method and immunoblotting. Aortic production of 6-keto-PGF1 alpha, the main metabolite of PGI2, was also measured. RESULTS: Compared with age-matched WKY rats, PGHS-1 mRNA and protein levels in the thoracic aorta of SHR increased with age, reaching three- and twofold higher than WKY rats at 40 weeks old, respectively. PGI2 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old. In contrast, PGI2 receptor mRNA levels in SHR were consistently lower than in WKY rats at all ages. CONCLUSIONS: These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites, including PGH2 and PGI2. They also suggest that the decreased expression of PGI2 receptor mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR.
Assuntos
Aorta Torácica/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Hipertensão/metabolismo , Oxirredutases Intramoleculares/genética , Receptores de Prostaglandina/genética , Envelhecimento/metabolismo , Animais , Sistema Enzimático do Citocromo P-450/análise , Expressão Gênica , Oxirredutases Intramoleculares/análise , Masculino , Reação em Cadeia da Polimerase , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/isolamento & purificação , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores de Epoprostenol , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: This study was designed to compare the effects of prostacyclin synthase (PCS) gene transfer with those of a systemic infusion of beraprost sodium (BPS), a prostacyclin analogue, on vascular smooth muscle cell (VSMC) proliferation and neointimal formation after arterial injury. METHODS: PCS gene (3 or 30 micrograms) was transfected into rat balloon-injured carotid arteries by a non-viral lipotransfection method. BPS (100 or 300 micrograms/kg/day) was subcutaneously infused with osmotic pumps after the injury. LacZ gene (30 micrograms) was used as a control. VSMC proliferation was estimated by the bromodeoxyuridine (BrdU) index (BrdU-positive nuclei/total nuclei) at day 7. Neointimal formation was evaluated at day 14. Each treatment group had six rats. RESULTS: PCS gene transfer prevented the increase in intimal/medial area ratio (3 micrograms: 46.6%, 30 micrograms: 61.1% reduction; P < 0.05, P < 0.01, respectively), as did BPS 300 micrograms/kg/day (49.8% reduction; P < 0.05). BPS 100 micrograms/kg/day, however, had no effects on the ratio. PCS gene transfer and BPS 300 micrograms/kg/day significantly suppressed the BrdU index. BPS 300 micrograms/kg/day group had more frequent hematoma and longer bleeding time. There were no significant differences in blood pressure, heart rate, or urinary volume among all groups. CONCLUSION: Both PCS gene transfer and BPS 300 micrograms/kg/day reduced neointimal formation after arterial injury by inhibiting VSMC proliferation. PCS gene transfer may be a safer therapeutic modality against neointimal formation than a systemic infusion of BPS because the former method resulted in fewer bleeding complications.
Assuntos
Sistema Enzimático do Citocromo P-450/genética , Epoprostenol/análogos & derivados , Técnicas de Transferência de Genes , Oxirredutases Intramoleculares/genética , Músculo Liso Vascular/patologia , Inibidores da Agregação Plaquetária/farmacologia , Análise de Variância , Animais , Western Blotting , Cateterismo , Divisão Celular/efeitos dos fármacos , Epoprostenol/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Ratos , Túnica Íntima/patologiaRESUMO
To examine a relation between the production of acetylcholine-induced endothelium-derived contracting factor and an increase in blood pressure, endothelium-dependent contraction and relaxation were evaluated by measuring the isometric tension of aortic rings from spontaneously hypertensive rats and Wistar-Kyoto rats at 5, 10, 20, and 30 weeks of age. In norepinephrine-precontracted rings, acetylcholine (10(-8) to 10(-5) M)-induced relaxations diminished at the doses of 10(-6) to 10(-5) M in both strains except at 5 weeks of age. Treatment with a thromboxane A2/prostaglandin H2 antagonist (ONO-3708) prevented this reduction in acetylcholine-induced relaxations in both strains and induced dose-dependent relaxations, which were completely inhibited by treatment with a nitric oxide inhibitor, NG-nitro-L-arginine methyl ester. In aorta treated with NG-nitro-L-arginine methyl ester without precontraction, acetylcholine induced dose-dependent contractions, which were greater in spontaneously hypertensive rats than in Wistar-Kyoto rats. These acetylcholine-induced contractions, which were observed only in rings with endothelium, were completely inhibited by treatment with ONO-3708 but not with a thromboxane A2 synthetase inhibitor (OKY-046). There was a statistically significant correlation between the acetylcholine-induced contractions and blood pressure. Release of 6-ketoprostaglandin F1 alpha by acetylcholine from the aorta was greater in spontaneously hypertensive rats. In vivo administration of another thromboxane A2/prostaglandin H2 antagonist (ONO-8809) (10 or 30 micrograms per body per day) for 3 weeks (5-8 weeks of age) did not affect blood pressure in either rat strain.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Acetilcolina/farmacologia , Pressão Sanguínea/fisiologia , Endotelinas/biossíntese , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , 6-Cetoprostaglandina F1 alfa/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Arginina/análogos & derivados , Arginina/farmacologia , Relação Dose-Resposta a Droga , Masculino , NG-Nitroarginina Metil Éster , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacologiaRESUMO
OBJECTIVE: To investigate the roles of the renin-angiotensin system and blood pressure in cardiac hypertrophy caused by a pressure overload. METHODS: Cardiac hypertrophy was induced by constricting the abdominal aorta above the renal arteries. After they had been banded, the rats were treated with the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of quinapril [an angiotensin converting enzyme (ACE) inhibitor], or the lower (1 mg/kg per day) or the higher (10 mg/kg per day) dose of TCV-116 [an angiotensin II (AngII) AT1 receptor antagonist], for 4 weeks. Then, we measured the mean blood pressure (MBP), body weight, left ventricular weight (LVW), and serum and cardiac ACE activities. RESULTS: The higher dose of quinapril and that of TCV-116 prevented left ventricular hypertrophy and MBP elevation. Both the higher and the lower doses of quinapril reduced the serum and cardiac ACE activities significantly, whereas the higher dose of TCV-116 reduced the cardiac ACE activity and increased the serum ACE activity. The lower dose of quinapril, however, exerted no significant effect on MBP and the LVW:body weight ratio, although it reduced the cardiac and serum ACE activities significantly. There was a significant positive correlation between the MBP and the LVW:body weight ratio regardless of the cardiac ACE activity in data from all groups (r = 0.676, P < 0.0001). CONCLUSIONS: Our data indicate the importance of the blood pressure as a determinant of cardiac hypertrophy because inhibition of cardiac ACE activity alone without lowering of the blood pressure is insufficient to prevent cardiac hypertrophy. Our results suggest the presence of other pathways for AngII production not mediated by ACE, or growth factors other than AngII in pressure-overload cardiac hypertrophy.
Assuntos
Cardiomegalia/etiologia , Peptidil Dipeptidase A/metabolismo , Tetra-Hidroisoquinolinas , Tetrazóis , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Benzimidazóis/administração & dosagem , Compostos de Bifenilo/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Isoquinolinas/administração & dosagem , Masculino , Peptidil Dipeptidase A/sangue , Quinapril , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de AngiotensinaRESUMO
OBJECTIVE: To investigate the possible involvement of prostaglandin H2, an endothelium-derived contracting factor in the rat aorta, in the development of the contraction induced by endothelin-1. METHODS: The aortic rings from spontaneously hypertensive rats (SHR) were prepared, and the changes of isometric tension of these rings developed by endothelin-1 were recorded with or without the treatment of several inhibitors or an antagonist. The concentrations of prostaglandins and thromboxane B2 in the bath solution with the rings contracted by endothelin-1 were measured by radioimmunoassay. The effects of a thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) on endothelin-1-induced contraction were compared in SHR and Wistar-Kyoto (WKY) rats. RESULTS: Indomethacin (10(-5) mol/l) and ONO-3708 (10(-6) mol/l) significantly diminished endothelin-1 (3 x 10(-8) mol/l)-induced contractions in the aortic rings from SHR with but not without endothelium. The thromboxane A2 synthetase inhibitors OKY-046 (10(-5) mol/l) and RS-5186 (10(-5) mol/l) did not attenuate the contractions either with or without endothelium. Endothelin-1 significantly increased the release of 6-keto-prostaglandin F1 alpha, which is the metabolite of prostaglandin I2 and its precursor prostaglandin H2, from rings with endothelium of SHR, but the concentration of thromboxane B2 from aortic rings was unchanged. In the rings without endothelium the endothelin-1-induced release of 6-keto-prostaglandin F1 alpha was also observed. The half-maximal effective concentration of endothelin-1 for rings from SHR was shifted to the right by ONO-3708, but that of WKY rats was not changed, and significantly greater amounts of 6-keto-prostaglandin F1 alpha were released in the rings from SHR than in those from WKY rats by endothelin-1. CONCLUSIONS: Endothelin-1 induced the release of prostaglandin H2 from endothelial cells in the rat aorta, the effect being greater in the hypertensive state. The released prostaglandin H2, an endothelium-derived contracting factor, modulated the vasoconstriction that is induced by endothelin-1, another endothelium-derived contracting factor, in addition to the direct vasoconstrictive action of endothelin-1 on vascular smooth muscle.
Assuntos
Endotelinas/farmacologia , Prostaglandinas H/farmacologia , Vasoconstritores/farmacologia , 6-Cetoprostaglandina F1 alfa/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Endotelinas/antagonistas & inibidores , Endotélio Vascular/metabolismo , Técnicas In Vitro , Contração Isométrica , Masculino , Norepinefrina/metabolismo , Prostaglandina H2 , Prostaglandinas/metabolismo , Prostaglandinas/farmacologia , Prostaglandinas H/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Tromboxano A2/análogos & derivados , Tromboxano A2/antagonistas & inibidores , Tromboxano A2/metabolismo , Tromboxano A2/farmacologia , VasoconstriçãoRESUMO
This study evaluated the role of adrenomedullin in patients with vasospastic angina pectoris. Adrenomedullin may be involved in regulating a basal tone of the coronary artery in these patients.
Assuntos
Angina Pectoris Variante/sangue , Peptídeos/sangue , Vasodilatadores/sangue , Acetilcolina , Adrenomedulina , Idoso , Angina Pectoris Variante/etiologia , Peptídeo Relacionado com Gene de Calcitonina/sangue , Estudos de Casos e Controles , Circulação Coronária , Feminino , Humanos , Masculino , Peptídeos/fisiologia , Projetos PilotoRESUMO
The mechanism by which hyperinsulinemia promotes atherogenesis is unknown. The effects of hyperinsulinemia on risk factors for atherosclerosis were investigated by subcutaneously injecting rats daily with an insulin-zinc suspension (20 U/kg) for 12 weeks. After this period, body mass and food consumption did not differ significantly between control and insulin-treated animals. Daily insulin injection significantly increased urinary excretion of epinephrine and decreased urinary excretion of norepinephrine and dopamine, but had no significant effect on blood pressure or heart rate. Although insulin decreased plasma triglyceride concentration by 44% (P < .01), the triglyceride to protein ratio in plasma low-density lipoprotein (LDL) was increased by 34% (P < .05) in insulin-treated rats; the cholesterol to protein and triglyceride to protein ratios remained unaffected, indicating a change in the quality of the LDL particle. Insulin also increased the percentage of arachidonic acid (20:4) in LDL triglycerides by 37% (P < .05). In contrast, cholesteryl esters and triglycerides in the thoracic aorta were significantly increased (49% and 91%, respectively) by insulin treatment. Insulin increased the percentage of monounsaturated fatty acids and decreased the percentage of n-6 fatty acids, including arachidonate, in aortic triglycerides. Insulin also increased the percentage of palmitoleic acid (16:1) and decreased the percentages of saturated fatty acids and n-6 fatty acids in aortic cholesteryl esters. These results indicate that insulin induced deposition of cholesteryl esters and triglycerides, especially those containing monounsaturated fatty acids, and abnormal arachidonate distribution in LDL and tissues. The data further suggest that the development of atherosclerosis in response to hyperinsulinemia may be associated with arachidonate-rich triglycerides in LDL.
Assuntos
Aorta Torácica/metabolismo , Ácido Araquidônico/metabolismo , Hiperinsulinismo/metabolismo , Lipoproteínas LDL/metabolismo , Animais , Colesterol/sangue , Ésteres do Colesterol/sangue , Insulina/farmacologia , Masculino , Fosfolipídeos/sangue , Ratos , Ratos Wistar , Distribuição Tecidual , Triglicerídeos/sangueRESUMO
Insulin and glucose increase the synthesis of 1,2-diacylglycerol (1,2-DAG), the physiological activator of protein kinase C (PKC) in a variety of tissues and cells. The effects of insulin and glucose on the abundance and fatty acid composition of 1,2-DAG were investigated in isolated perfused rat hearts with the use of capillary gas chromatography and 1,2-dipentadecanoin as an internal standard. A high concentration of insulin (25 mU/ mL) significantly increased cardiac contractility and reduced coronary flow. In addition, perfusion with 25 mU/mL insulin induced significant increases of 18.2% and 26.4% in 1,2-DAG mass after 5 and 30 minutes, respectively, in the presence of 8.6 mmol/L glucose, whereas there was no increase in 1,2-DAG with 2.5 mU/mL insulin. Analysis of the fatty acid composition of 1,2-DAG showed that only species containing specific fatty acids (16:0, 18:1, and 18:2) were increased in response to insulin. In contrast, an increase in glucose concentration in the perfusion medium from 3 to 17 mmol/L had no effect on the total mass or fatty acid composition of 1,2-DAG, cardiac contractility, or coronary flow. Addition of a high insulin concentration to the high-glucose medium increased the abundance of 1,2-DAG containing 16:0, 18:1, and 18:2 fatty acids, as well as cardiac contractility. It is concluded that the effect of insulin on cardiac contractility may be related to the associated increase in 1,2-DAG abundance.
Assuntos
Diglicerídeos/metabolismo , Glucose/farmacologia , Coração/efeitos dos fármacos , Insulina/farmacologia , Animais , Ácidos Graxos/metabolismo , Coração/fisiologia , Técnicas In Vitro , Masculino , Ratos , Ratos WistarRESUMO
In the current study, we investigated the NO-generation pathway in response to mechanical stimuli in SHR at the prehypertensive stage. To examine the role of NO in coronary autoregulation, we evaluated the effects of L-NAME on the coronary flow in SHR at both the prehypertensive and hypertensive stages. Isolated perfused hearts from 5- and 15-week-old SHR and from age-matched Wistar-Kyoto rats (WKY) were used. After stabilization at 60 mmHg, perfusion pressure was immediately raised to 90 mmHg to record the change in coronary flow for 10 min without (control) or with NO synthesis blockade by Nomega-nitro-L-arginine methyl ester (L-NAME). NOx- (nitrite/nitrate) was measured in coronary effluent. At 5 weeks of age, SHR did not have hypertension, while the coronary autoregulation was enhanced. L-NAME did not affect this enhanced autoregulation in 5-week-old SHR. At perfusion pressures of both 60 and 90 mmHg, 5-week-old SHR showed less coronary NOx- production than age-matched WKY. At 15 weeks, SHR showed a higher blood pressure than WKY. The coronary autoregulation in SHR remained higher than that in WKY, but was below that in 5-week-old SHR. NOx- production in 15-week-old SHR recovered to the level of age-matched WKY. These results indicate that NOx- production induced by mechanical stimulation was markedly reduced in 5-week-old SHR at the prehypertensive stage, which may have enhanced coronary autoregulation. An impaired nitric oxide production may precede the onset of hypertension in SHR.
Assuntos
Circulação Coronária , Homeostase , Óxido Nítrico/biossíntese , Ratos Endogâmicos SHR/fisiologia , Animais , Pressão Sanguínea/fisiologia , Circulação Coronária/efeitos dos fármacos , Circulação Coronária/fisiologia , Endotélio Vascular/fisiologia , Masculino , Nitratos/sangue , Doadores de Óxido Nítrico/farmacologia , Nitritos/sangue , Nitroprussiato/farmacologia , Ratos , Ratos Endogâmicos WKY , Vasodilatação/fisiologiaRESUMO
The aim of this study was to evaluate the possible role of prostacyclin (PGl2) in the onset and development of hypertension and chronic renal failure in 5/6-nephrectomized rats (5/6NX). We measured the systolic blood pressure, 24-h urinary excretion levels of 6-keto-PGF1alpha, which was a stable metabolite of PGI2, and levels of PGI2 synthase (PCS) mRNA in the kidneys. Immunostaining for PCS in the kidneys was also evaluated. Systolic blood pressure was higher in 5/6NX than in sham-operated rats. The 24-h urinary excretion levels of 6-keto-PGF1alpha in 5/6NX at 1 week postsurgery were lower than in sham-operated rats. In renal morphology, tubulointerstitial injury was observed at 2 weeks postsurgery, and glomerulosclerosis at 4 weeks. Levels of PCS mRNA in 5/6NX decreased significantly at 1 and 2 weeks postsurgery compared with those in sham-operated rats, but at 8 weeks these levels showed a tendency to increase. Immunostaining for PCS was positive in a subset of the cortical thick ascending limb of Henle's loop cells, including macula densa in both groups. Moreover, in 5/6NX at 8 weeks postsurgery, mesangial cells also stained positive for PCS. In conclusion, our findings suggest that PCS might play an important role in mitigating glomerular hemodynamic changes associated with reduction of renal mass.
Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Mesângio Glomerular/enzimologia , Oxirredutases Intramoleculares/metabolismo , Alça do Néfron/enzimologia , Nefrectomia/métodos , 6-Cetoprostaglandina F1 alfa/urina , Animais , Pressão Sanguínea , Ritmo Circadiano , Sistema Enzimático do Citocromo P-450/genética , Mesângio Glomerular/patologia , Coração/fisiopatologia , Frequência Cardíaca , Hormônios/sangue , Imuno-Histoquímica , Oxirredutases Intramoleculares/genética , Rim/metabolismo , Rim/patologia , Rim/fisiologia , Alça do Néfron/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Sístole , Tromboxano B2/urinaRESUMO
Our objective was 1) to assess postischemic vasodilatation using simultaneous intravascular two-dimensional and Doppler ultrasound, and 2) to clarify whether plasma nitrite and nitrate (NOx-) levels change during postischemic vasodilatation. The vascular cross-sectional area (CSA) was evaluated in 18 mongrel dogs, and the average instantaneous peak velocity (APV) in the iliac arteries after the 5-min occlusion of blood flow was determined. Plasma NOx- levels were measured at the baseline, during the occlusion of blood flow, and 1.5, 3, and 10 min after recanalization. The %CSA significantly increased from 30 s to 7 min after the recanalization, and maximal vasodilatation was observed at 1.5 min after the recanalization (14.1 +/- 0.9 to 15.8 +/- 1.0 mm2, p< 0.0001 vs. baseline). Plasma NOx- levels were significantly reduced during the occlusion of blood flow and remained reduced at 1.5, 3, and 10 min after recanalization compared with the baseline values. We concluded that simultaneous intravascular two-dimensional and Doppler ultrasound is useful for assessment during postischemic vasodilatation, and that plasma NOx- levels assayed with the Griess reagent do not significantly increase, even when maximal vasodilatation is observed.
Assuntos
Ecocardiografia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ultrassonografia de Intervenção , Vasodilatação , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiologia/métodos , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Cães , Inibidores Enzimáticos/farmacologia , Feminino , Injeções Intra-Arteriais , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Nitratos/sangue , Óxido Nítrico/fisiologia , Nitritos/sangue , Fatores de Tempo , ômega-N-Metilarginina/farmacologiaRESUMO
Individuals with a predominance of small low-density lipoprotein (LDL) particles appear to be at increased risk for coronary artery disease. The purpose of this study was to determine whether the LDL particle size was modulated in response to a 75-g oral glucose load. Overall, there were no significant changes in the LDL particle size after glucose load. However, the difference in LDL particle size (deltaLDL size) between the fasting and 2-h post-load states was inversely correlated with the fasting LDL particle size. Also, deltaLDL size was positively correlated with BMI and the post-load glucose levels. Forward stepwise regression analysis revealed three parameters as independent factors capable of modulating LDL particle size: BMI, fasting insulin, and post-load glucose levels. After adjustment for BMI and glucose levels, the levels of fasting and 2-h post-load insulin remain independent determinants of deltaLDL size. These results suggest that plasma insulin levels during glucose load modulate LDL particle size.
Assuntos
Glicoproteínas , Lipoproteínas LDL/sangue , Adulto , Idoso , Pressão Sanguínea , Proteínas de Transporte/metabolismo , Proteínas de Transferência de Ésteres de Colesterol , Feminino , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Lipase Lipoproteica/sangue , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Período Pós-PrandialRESUMO
We investigated whether the apolipoprotein E (apoE) and the angiotensin-converting enzyme (ACE) genotypes contribute to the variance in low-density lipoprotein (LDL) particle size in Japanese subjects (n = 136; M/F= 106/30). ACE polymorphism was associated with neither LDL size nor individual lipid levels. In contrast, the subjects with the epsilon2 allele of the apoE genotype had significantly lower levels of total cholesterol (P = 0.002) and LDL cholesterol (P = 0.004) compared with those without the epsilon2 allele. The subjects with the epsilon4 allele had a significantly smaller LDL particle size than those without the epsilon4 allele (P = 0.012). Separate analyses of the male subjects showed similar associations. A stepwise regression analysis revealed the epsilon4 allele to be an independent contributing variable that could affect LDL particle size. Our results suggest that the apoE genotype is associated with the development of atherosclerotic disease, since the epsilon2 and epsilon4 alleles relate to a decrease in LDL cholesterol levels and a decrease in LDL particle size, respectively.