RESUMO
Perivascular adipose tissue dysfunction induced by high-fat feeding leads to alterations in the modulation of inflammation, contractile activity of the vascular smooth muscle and endothelial function, all risk factors in the development of hypertension. Metformin, an activator of AMP-activated protein kinase (AMPK), is currently the first-line drug treatment for type 2 diabetes (T2DM) and metabolic syndrome. Besides its glucose-lowering effect, there is an interest in actions of this drug with potential relevance in cardiovascular diseases. The high-fat (HF) diet is an experimental model that resembles human metabolic syndrome. We have previously reported an altered pattern of prostanoid release in mesenteric vessels in this model. The aim of this study was to analyse the effects of metformin on mesenteric vascular bed prostanoid release, adiposity index and its relation to blood pressure in Sprague-Dawley rats fed a HF diet for 8 and 12 weeks. Eight groups were used: control (C8, C1), HF diet (HF8, HF12, 50% w/w bovine fat), metformin-treated (CMf8, CMf12, 500 mg/kg/day) and metformin-treated HF diet (HFMf8, HFMf12, both treatments). HF diet increased mesenteric vascular bed adiposity index (%, HF8: 1.7±0.1 vs C8: 0.9±0.04 and HF12: 1.8±0.1 vs C12: 0.8±0.1, P<.001); systolic blood pressure (SBP, mm Hg, HF8: 145±6 vs C8: 118±4, P<.01 and HF12: 151±1 vs C12: 121±3, P<.001). We found a positive correlation between these two parameters. Moreover HF diet increased the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 (ng PR/mg of tissue, HF8: 117±6 vs C8: 66±2 and HF12: 123±6 vs C12: 62±5, P<.001) and prostaglandin (PG) F2α (ng/mg, HF8: 153±9 vs C8: 88±3 and HF12: 160±11 vs C12: 83±5, P<.001). We also found that this increase in the release of vasoconstrictor prostanoids positively correlates with the elevation of SBP. In addition, HF diet increases the release of PGE2 and decreases the prostacyclin (PGI2 )/TXA2 release ratio at 8 and 12 weeks of treatment compared to control groups. In the HFMf group, metformin treatment prevented all these increases in mesenteric vascular bed adiposity index (%, HFMf8: 1.3±0.2 vs HF8 and HFMf12: 1.3±0.1 vs HF12, P<.05); SBP (mm Hg, HFMf8: 127±2 vs HF8 and HFMf12: 132±1 vs HF12, P<.001); TXB2 release (ng PR/mg of tissue, HFMf8: 65±12 vs HF8, P<.05 and HFMf12: 53±3 vs HF12, P<.001) and PGF2 α (ng PR/mg of tissue, HFMf8: 99±13 vs HF8, P<.01 and HFMf12: 77±8 vs HF12, P<.001). Meanwhile metformin prevented the increment in PGE2 release only at 12 weeks. On the other hand, metformin improved the PGI2 /TXA2 ratio in both periods studied. In conclusion, metformin could exert beneficial effects on adipose tissue and the vascular system by improving endothelial dysfunction induced by an imbalance of vasoactive substances in mesenteric perivascular adipose tissue in this model.
Assuntos
Artérias Mesentéricas/efeitos dos fármacos , Metformina/farmacologia , Prostaglandinas/metabolismo , Animais , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Dinoprostona/metabolismo , Epoprostenol/metabolismo , Hipertensão/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Ratos , Ratos Sprague-Dawley , Tromboxano B2/metabolismoRESUMO
In the rat, a high-fat (HF) plus fructose (F) diet produces cardiovascular and metabolic alterations that resemble human metabolic syndrome. Prostanoids (PR), cyclo-oxygenase-derived arachidonic acid metabolites, have vasoactive properties and mediate inflammation. The aim of this study was to analyse the effect of a HF+F diet on blood pressure (BP), metabolic parameters and mesenteric vascular bed PR production in male Sprague-Dawley rats. Four groups were studied over 9 weeks (n = 6 each): control (C), standard diet (SD) and tap water to drink; F+SD and 10% w/v F solution to drink; HF 50% (w/w) bovine fat added to SD and tap water; and HFF, both treatments. PR were determined by HPLC. Blood pressure was elevated in all experimental groups. Triglyceridaemia, insulinaemia and HOMA-IR were increased in the F and HF groups. HF+F animals showed elevated glycaemia, insulinaemia, HOMA-IR and triglyceridaemia. F decreased the vasodilator prostanoids PGI2 and PGE2 in the mesenteric vascular bed. Body weight was not significantly altered. In HFF, production of PGE2 , PGF2 alpha and TXB2 was elevated. The increased BP in HF and HFF could be partly attributed to the imbalance in vascular PR production towards vasoconstrictors. On the other hand, this dietary modification could induce inflammation, which would explain the elevation of PGE2 . In the F group, hypertension could be related to decreased vasodilator PRs. The simultaneous administration of HF and F in the rat produces deleterious effects greater than observed when treatments are applied separately.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Frutose/efeitos adversos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Síndrome Metabólica/sangue , Síndrome Metabólica/induzido quimicamente , Prostaglandinas/sangue , Animais , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Insulina/sangue , Resistência à Insulina , Masculino , Ratos , Tromboxano B2/sangue , Triglicerídeos/sangueRESUMO
(1) Fructose (F) overload produces elevated blood pressure (BP), hyperglycaemia, hypertriglyceridemia and insulin resistance, resembling human metabolic syndrome. Previously, we found altered vascular prostanoid (PR) production in this model. (2) Sodium molybdate (Mo), as well as sodium tungstate, causes insulin-like effects and normalizes plasma glucose levels in streptozotocin-treated diabetic rats. We studied the effects of Mo on BP, metabolic parameters and release of PR from the mesenteric vascular bed (MVB) in F-overloaded rats. (3) Four groups of male Sprague-Dawley rats were analysed: Control, tap water to drink; F, F solution 10% W/V to drink; CMo, Mo 100 mg kg day(-1) and FMo, both treatments. After 9 weeks, the animals were killed and MVBs removed and the released PRs measured. (4) F increased BP, glycemia, triglyceridemia and insulinemia. Mo treatment prevented the increases in BP and glycemia, but did not modify triglyceridemia or insulinemia. In addition, Mo decreased BP in controls. (5) Prostaglandins (PG) F2 alpha and E2, PG 6-ketoF1 alpha and thromboxane (TX) B2 , as well as inactive metabolites of prostacyclin (PGI2 ) and TXA2 were detected. F decreased the production of vasodilator PRs PGI2 and PGE2 in MVB. Mo prevented these alterations and increased PGE2 in controls. Vasoconstrict or PRs PGF2 alpha and TXA2 release was not modified. (6) Mo treatment, beyond its known lowering effect on glycemia, prevents the reduction in the vascular release of vasodilator PR observed in this model. This could be one of the mechanisms by which Mo avoids the increase in BP caused by F overload in the rat.
Assuntos
Frutose/antagonistas & inibidores , Hipertensão/prevenção & controle , Síndrome Metabólica/prevenção & controle , Molibdênio/farmacologia , Prostaglandinas/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Frutose/efeitos adversos , Hipertensão/metabolismo , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/metabolismo , RatosRESUMO
Metformin is a hypoglycaemic drug currently used to increase insulin sensitivity in the treatment of type 2 diabetes and metabolic syndrome. Its main mechanism of action is through activation of AMP-activated protein kinase, an enzyme that regulates cellular and whole organ metabolism. The fructose-overloaded rat is an experimental model with features that resemble human metabolic syndrome. We have previously reported alterations in vascular prostanoids (PR) in this model. The aim of this study was to analyse the effects of metformin treatment on blood pressure, metabolic parameters and PR production in aorta and mesenteric vascular bed (MVB) from fructose-overloaded animals. Four groups of male Sprague-Dawley rats were used: control, fructose overloaded (10% w/v fructose), metformin treated (50 mg kg(-1) day(-1) ) and fructose-overloaded treated with metformin. Rats with fructose overload had significantly elevated systolic blood pressure, glycaemia, triglyceridaemia, cholesterolaemia and insulinaemia compared with controls. Except for insulinaemia, metformin limited all these increases in fructose-overloaded animals. Fructose overload reduced prostacyclin levels in aorta and MVB, but prostaglandin E(2) levels were only reduced in MVB. Metformin treatment reduced the levels of the vasoconstrictor prostaglandins, PGF(2) α and thromboxane, in both vascular preparations from fructose-overloaded rats. PGF(2) α levels were significantly reduced by metformin in controls. In conclusion, one of the mechanisms by which metformin reduced blood pressure in this model is by decreasing vasoconstrictor prostaglandin production.
Assuntos
Aorta Torácica/metabolismo , Frutose/toxicidade , Artérias Mesentéricas/metabolismo , Metformina/farmacologia , Prostaglandinas/biossíntese , Vasoconstrição/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Metformina/uso terapêutico , Oxirredução , Prostaglandinas/metabolismo , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacosRESUMO
AIMS: Fructose (F) overload in rats induces metabolic dysfunctions that resemble the human metabolic syndrome. In this paper, we aimed to investigate the response of F overload rats to lipopolysaccharide (LPS) challenge in terms of nitric oxide (NO) production and prostanoids (PR) release. MAIN METHODS: NO blood steady-state concentration was monitored through the detection of nitrosyl-hemoglobin complexes (NO-Hb) by electronic spin resonance. Production of 6-keto PGF(1)α, PGE(2), PGF(2)α and TXB(2) was measured in aorta and mesenteric beds by HPLC. Western blot analysis was used to examine the changes in the expression levels of NOS-2 and COX-2 in aorta. KEY FINDINGS: Our results showed that increases in NO circulating steady-state concentration and PR production by aorta and mesenteric beds 6h after LPS administration were significantly attenuated in F overload rats with respect to control animals. Oxidative stress parameters were equally affected in the presence or absence of the F treatment. Aorta protein levels of NOS-2 and COX-2, two enzymes inducible by LPS, were significantly lower in F overload rats with respect to control rats at the end of the treatment (-39% and -61% for NOS-2 and COX-2 respectively). SIGNIFICANCE: These results suggest that the metabolic alterations established by 15 weeks of F overload should affect the response to LPS challenge due to an attenuation in the induction of NOS-2 and COX-2. This effect would be one of the components contributing to abnormalities in the course of the inflammatory response in other conditions associated to insulin resistance, such as diabetes.
Assuntos
Ciclo-Oxigenase 2/biossíntese , Frutose/farmacologia , Lipopolissacarídeos/farmacologia , Óxido Nítrico Sintase Tipo II/biossíntese , Animais , Glicemia/análise , Western Blotting , Ciclo-Oxigenase 2/efeitos dos fármacos , Indução Enzimática/efeitos dos fármacos , Insulina/sangue , Masculino , Nitratos/sangue , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Nitritos/sangue , Estresse Oxidativo/efeitos dos fármacos , Prostaglandinas/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangueRESUMO
1 There is a relationship between hypertension, insulin resistance and an altered plasmatic lipid profile known as 'metabolic syndrome'. Fructose (F) overload induces in the rat a mild hypertension associated with metabolic alterations such as hyperglycemia, hypertriglyceridemia and insulin resistance, resembling such syndrome. 2 Prostanoids (PR), metabolites of arachidonic acid, include vasoactive substances synthesized and released by the vessel wall. An altered pattern of PR release has been previously found in mesenteric vessels of experimental diabetic rats. 3 This study analyzed the effects of F-overload during different periods (4, 9, 15 and 22 weeks) on PR release in aorta (A) and mesenteric vascular beds (MVB). Animals received tap water (control) or F solution (10% w/v) to drink. 4 Rats with F overload showed significantly higher systolic blood pressure, glycemia and triglyceridemia than controls; but no differences in this parameters were found among periods of treatment either in controls or experimental animals. 5 In A, prostacyclin was decreased at 9, 15 and 22 weeks of treatment when compared to 4 weeks and controls. In MVB, prostacyclin showed different patterns of release in the studied periods of F overload. Prostaglandin (PG) E(2) diminish in MVB at the same extent in all periods. No changes were observed in A. The vasoconstrictor thromboxane was elevated in the MVB at 9 weeks. PGF(2)alpha, also a vasoconstrictor, remains unchanged. 6 In conclusion, F overload provokes in the rat a decrease in the vascular production of vasodilator PR and, in one of the studied periods, an increase in the release of the vasoconstrictor thromboxane, leading to a negative imbalance in the prostacylin/thromboxane ratio. This could be involved in the blood pressure alterations found in this experimental model of metabolic syndrome.
Assuntos
Vasos Sanguíneos/metabolismo , Frutose , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Prostaglandinas/biossíntese , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Circulação Esplâncnica/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
This study analyzes the effects of losartan (AT1 blocker) and pioglitazone (insulin sensitizer), alone and in combination, in the fructose-overloaded rat, a model of metabolic syndrome. All treatments (nine weeks) reduced blood pressure and triglyceridemia and also restored the diminished release of vasodilator prostaglandins (prostacyclin in aorta and mesenteric vascular bed and prostaglandin E(2) in the latter). Pioglitazone, alone and in combination with losartan, reduced the release of the vasoconstrictor thromboxane in controls and fructose rats in both vascular preparations. In conclusion, although combination therapy and single treatments exerted similar effects, there may still be some advantage to the combined treatment.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Vasos Sanguíneos/metabolismo , Frutose/farmacologia , Hemodinâmica/efeitos dos fármacos , Losartan/farmacologia , Prostaglandinas/metabolismo , Tiazolidinedionas/farmacologia , Animais , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Dinoprostona/metabolismo , Sinergismo Farmacológico , Epoprostenol/metabolismo , Técnicas In Vitro , Masculino , Mesentério/irrigação sanguínea , PPAR gama/agonistas , Pioglitazona , Ratos , Ratos Sprague-Dawley , Tromboxanos/antagonistas & inibidores , Triglicerídeos/sangueRESUMO
1 A fructose-enriched diet induces hypertension, metabolic alterations and insulin resistance in rats, resembling human metabolic syndrome. Previously, we found that prostanoid production was altered in fructose-fed rats. 2 This study analysed the effects of incubation with noradrenaline (NA) and angiotensin II (Ang II) on prostanoid release in mesenteric vascular beds from control and fructose-fed rats. Animals which received fructose solution (10% w/v) for 22 weeks showed higher systolic blood pressure and triglyceridaemia. 3 In controls, NA increased 6-keto-prostaglandin (PG) F(1)alpha (prostacyclin metabolite) and thromboxane (TX) production. Ang II increased only TX release. In fructose-fed animals, NA increased 6-keto-PG F(1)alpha and TX. PGF(2)alpha (vasoconstrictor) was also elevated. Ang II also increased PGF(2)alpha and PGE(2) levels. 4 In conclusion, in fructose rats Ang II in vitro stimulates a vasoconstrictor prostanoid not stimulated in controls. This could be related to the observed in vivo blood pressure increase. In fructose-fed animals, NA and Ang II also augment vasodilator prostanoids, suggesting a compensatory mechanism because of long-term hypertension.
Assuntos
Angiotensina II/fisiologia , Endotélio Vascular/metabolismo , Frutose/administração & dosagem , Hipertensão/metabolismo , Norepinefrina/fisiologia , Prostaglandinas/metabolismo , Animais , Endotélio Vascular/efeitos dos fármacos , Frutose/toxicidade , Hipertensão/induzido quimicamente , Masculino , Mesentério/irrigação sanguínea , Mesentério/efeitos dos fármacos , Mesentério/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
1. A fructose (Fru)-enriched diet induces a mild increase in blood pressure associated with hyperglycaemia, hypertriglyceridaemia, and insulin resistance, resembling the human 'syndrome X', being an useful model to study hypertension and type 2 diabetes. 2. A sustained elevation of blood pressure is associated with cardiovascular structural modifications such as left ventricular hypertrophy and increased wall thickness:lumen diameter ratio in blood vessels. 3. Prostanoids (PR), metabolites of arachidonic acid through the cyclooxygenase pathway, include vasoactive substances synthesized and released by the vessel walls. 4. The aim of the present study was to analyse, in Fru-treated rats: (i) the morphology of mesenteric vessels and; (ii) the PR production in aorta and mesenteric vessels, in order to assess whether these parameters are related with the haemodynamic alterations observed in this experimental model. 5. Blood pressure, glycaemia and triglyceridaemia, were significantly elevated in both (4 and 22 weeks) Fru-treated groups. Meanwhile body and heart weight as well as insulinaemia were similar between experimental animals and controls. 6. The mesenteric vessels of Fru-treated rats (22 weeks) showed an increased thickness and area of the media when compared with the controls; meanwhile, the lumen diameter was similar in both groups. 7. The Fru treatment for 4 weeks did not modify PR production in aorta, whereas in the mesenteric bed it diminished prostaglandin (PG) E(2) release significantly compared with the controls. However, in the group treated for 22 weeks, Fru reduced PGI(2) production in the aorta, as assessed by 6-keto-PGF(1)alpha measurements. Meanwhile, in the mesenteric bed, the chronic Fru treatment decreased PGE(2) release but, rather surprisingly, increased the output of PGI(2) when compared with its corresponding controls. 8. In conclusion, the present study shows the existence of an alteration in the morphology of mesenteric vessels in Fru-treated rats, which could be related to an increase in peripheral resistance and the consequent mild hypertension observed in this model. However, a diminished release of vasodilator PRs, such as PGE(2) in mesenteric vessels at 4 and 22 weeks and PGI(2) in aorta at 22 weeks could further impair the vessel response. The increase in PGI(2) observed in the chronic group in mesenteric vessels could be attributed to a compensatory mechanism.
Assuntos
Aorta Torácica/efeitos dos fármacos , Frutose/administração & dosagem , Artérias Mesentéricas/efeitos dos fármacos , Prostaglandinas/biossíntese , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Ratos , Ratos Sprague-DawleyRESUMO
1 There is good evidence that beta-blockers improve ventricular function, disease progression and survival in patients with left ventricular systolic dysfunction. The aim of this study was to determine the effects of atenolol therapy on the sympathetic nervous system at rest and after ergometric exercise, on left ventricular function and on baseline plasma atrial natriuretic factor (ANF) in ambulatory patients with chronic heart failure (CHF). 2 Twenty-two patients [left ventricular ejection fraction (LVEF) <36%; New York Heart Association II-III] were studied before atenolol treatment. Because of cardiac events (new Hospital admission or death) only 13 patients completed 1 year of treatment. Baseline noradrenaline (NE) concentrations were similar in patients and controls while ANF was higher in patients than in controls (328 +/- 35 pg ml(-1) vs. 37 +/- 3 pg ml(-1); P<0.01). 3 Patients with events showed higher NE (540 +/- 87 pg ml(-1) vs. 303 +/- 44 pg ml(-1); P<0.01) and ANF (460 +/- 70 pg ml(-1) vs. 291 +/- 44 pg ml(-1); P<0.03) at rest; and greater NE response to exercise (2.003 +/- 525 pg ml(-1) vs. 694 +/- 121 pg ml(-1); P<0.005). Atenolol treatment improved LVEF (19.5 +/- 1.9% vs. 33 +/- 3.9%; P<0.001), increased exercise tolerance (9 +/- 3.2 min vs. 17 +/- 4.8 min; P<0.001) and decreased plasma ANF (292 +/- 42 pg ml(-1) vs. 133 +/- 35 pg ml(-1); P<0.01). 4 Reduced basal dihydroxyphenylglycol (DHPG)/NE ratio (3.4 +/- 0.46 vs. 4.3 +/- 0.35; P<0.01) was observed in patients compared with healthy volunteers. Atenolol increased DHPG plasma levels (1.398 +/- 129 pg ml(-1) vs. 913 +/- 86 pg ml(-1); P<0.005) but the DHPG/NE ratio during exercise was not modified after treatment, suggesting that re-uptake of released NE is not changed by beta-blocker treatment. 5 In conclusion, the fact that atenolol treatment improves ventricular dysfunction and clinical status without changing plasma NE levels in CHF patients, suggests that plasma NE is a poor surrogate measurement for cardiac sympathetic activity in this pathology. In addition, decrease in plasma ANF produced by atenolol treatment may reflect the improvement of ventricular function.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Atenolol/uso terapêutico , Fator Natriurético Atrial/sangue , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Norepinefrina/sangue , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Cardiomiopatia Dilatada/complicações , Catecolaminas/sangue , Doença Crônica , Eletrocardiografia Ambulatorial , Ergometria , Exercício Físico/fisiologia , Feminino , Insuficiência Cardíaca/sangue , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
A fructose-enriched diet induces an increase in blood pressure associated with metabolic alterations in rats. Our hypothesis was that an increase in protein kinase C (PKC) activation, reported in the acute period of fructose overload, and an impaired vessel's response to vasoactive substances contribute to maintain elevated blood pressure levels in the chronic period. The aims of this study were to investigate in this animal model of hypertension: (1) if the increase in PKC activation was also found in the chronic stage; (2) the involvement of nitric oxide and insulin in the vessel's response; and plasma atrial natriuretic factor and nitrites/nitrates (nitric oxide metabolites) behavior. We evaluated the effects of: PKC-stimulator 12,13-phorbol dibutyrate, phenylephrine, insulin, nitric oxide synthase-inhibitor NG-nitro-L-arginine methyl esther (L-NAME) and PKC-inhibitor Calphostin C on aortic rings responses of Sprague-Dawley rats: fructose-fed and control. The fructose-fed group showed higher contractility to 12,13-phorbol dibutyrate than the control group in aortic rings pre-incubated with insulin, and this difference disappeared with L-NAME. The response to phenylephrine in rings pre-incubated with Calphostin C was decreased in the fructose-fed group and increased with Calphostin C plus L-NAME. Fructose-fed rats showed higher levels of plasma atrial natriuretic factor and nitrites/nitrates than controls. In conclusion, chronic fructose feeding seems to develop an impaired response to insulin, dependent on nitric oxide, suggesting a PKC alteration. Vasorelaxant agents, such as atrial natriuretic factor and nitric oxide, would behave as compensatory mechanisms in response to high blood pressure.
Assuntos
Frutose , Hipertensão/fisiopatologia , Resistência à Insulina/fisiologia , Proteína Quinase C/metabolismo , Animais , Fator Natriurético Atrial/sangue , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/enzimologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Naftalenos/farmacologia , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Dibutirato de 12,13-Forbol/farmacologia , Proteína Quinase C/antagonistas & inibidores , Ratos , Ratos Sprague-DawleyRESUMO
Enhanced atrial natriuretic factor (ANF) production by the heart is related to hemodynamic overload, cardiac growth, and hypertrophy. The heart is one of the most affected organs during Trypanosoma cruzi infection. We tested the hypothesis that myocarditis produced by parasite infection alters the natriuretic peptide system by investigating the behavior of plasma ANF during the acute and chronic stages of T. cruzi infection in rats. Sprague-Dawley rats were infected with T. cruzi clone Sylvio-X10/7. Cardiac morphology showed damage to myocardial cells and lymphocyte infiltration in the acute phase; and fibrosis and cell atrophy in the chronic period. Plasma ANF levels (radioimmunoassay) were significantly higher in acute (348 +/- 40 vs. 195 +/- 36 pg/ml, P < 0.05, n = 17) and chronic T. cruzi myocarditis (545 +/- 81 vs. 229 +/- 38 pg/ml, P < 0.001, n = 11) than in their respective controls (n = 10 and 14). Rats in the chronic phase also showed higher levels than rats in the acute phase (P < 0.01). The damage of myocardial cells produced by the parasite and the subsequent inflammatory response could be responsible for the elevation of plasma ANF during the acute period of T. cruzi infection. The highest plasma ANF levels found in chronically infected rats could be derived from the progressive failure of cardiac function.
Assuntos
Fator Natriurético Atrial/sangue , Cardiomiopatia Chagásica/sangue , Modelos Animais de Doenças , Doença Aguda , Animais , Peso Corporal , Cardiomiopatia Chagásica/mortalidade , Doença Crônica , Coração/parasitologia , Masculino , Miocárdio/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Previous studies from our own laboratory have shown that abdominal aorta rings from two kidney - two clip hypertensive rats (HT) develop hypersensitivity to serotonin (SER) which is related to a decreased nitric oxide (NO) availability and enhanced thromboxane A2 production. In the present study we investigated whether calcium and prostanoid-NO interactions are involved in these findings. To this purpose, the aortic responses to SER were analyzed in calcium-free medium and in calcium-depleted aorta placed in normal medium. Moreover, effects of ridogrel (RID, an antagonist of TxA 2/PGH2 receptors and inhibitor of thromboxane synthetase) were analysed by cumulative dose-response curves to SER in the presence and in the absence of the NO synthase inhibitor N(omega)-nitro-L-arginine (NOLA). Vascular responses to SER in vessels from HT rats were associated with increased intracellular calcium mobilization. In addition, hypersensitivity to SER in HT group respect to sham group (SH) disappeared in the presence of RID, NOLA and RID plus NOLA. RID decreases the maximum tension to SER and this effect was prevented by NOLA. This inhibition was of a greater magnitude in rings from sham rats (SH): 34 +/- 6% than in HT rats: 15 +/- 6% (p < 0.05). Besides, RID decreased the sensibility to SER in the presence of NOLA only in the HT group. In conclusion, the present study suggests that SER hypersensitivity observed in HT rats is related to a facilitated intracellular calcium mobilization and enhanced TxA2-endoperoxide response. Changes in membrane SER-gated calcium channels opening are observed only during the early hypertensive period. Besides, the lower depressor effect of RID on the maximal tension to SER in aorta rings from HT rats are related with a decreased NO availability in this model of renovascular hypertension.
Assuntos
Aorta/efeitos dos fármacos , Cálcio/farmacologia , Rim/metabolismo , Serotonina/farmacologia , 6-Cetoprostaglandina F1 alfa/biossíntese , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Sequestradores de Radicais Livres/farmacologia , Hipertensão/tratamento farmacológico , Masculino , Contração Muscular/efeitos dos fármacos , Nitroarginina/farmacologia , Ácidos Pentanoicos/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/farmacologia , Piridinas/farmacologia , Ratos , Ratos Wistar , Tromboxano B2/biossíntese , Fatores de TempoRESUMO
Atrial natriuretic factor (ANF) and C-type natriuretic peptide (CNP) receptors have been described in encephalic areas and nuclei related to the regulation of cardiovascular as well as sodium and water homeostasis. Stimulation of the anterior ventral third ventricular region of the brain modifies plasma ANF concentration, suggesting the participation of the central nervous system in the regulation of circulating ANF. The aim of this work was to study the effect of centrally applied ANF or CNP on plasma ANF. Normal and blood volume expanded rats (0.8 ml isotonic saline/100 g body weight) were intra cerebralventricularly injected with 1, 10 or 100 ng/microl/min ANF. Blood volume expanded animals were also centrally injected with the same doses of CNP. Blood samples were collected at 5 and 15 min. after intracerebralventricular administration of either ANF or CNP. Centrally applied ANF did not affect circulating ANF in normal blood volume rats. In blood volume expanded animals both ANF (1, 10 or 100 ng/microl/min) and CNP (1 ng/microl/min) decreased plasma ANF concentration after 15 min. Moreover, CNP (10 and 100 ng/microl/min) lowered circulating ANF levels not only at 15 min but also at 5 min. Neither ANF nor CNP elicited any change in mean arterial pressure and heart rate in normal and blood volume expanded rats. These results suggest the existence of a central regulation exerted by natriuretic peptides on circulating ANF levels. Furthermore, this is the first study reporting an effect on plasma ANF induced by centrally applied CNP.
Assuntos
Fator Natriurético Atrial/metabolismo , Encéfalo/metabolismo , Átrios do Coração/metabolismo , Peptídeo Natriurético Tipo C/metabolismo , Animais , Artérias/efeitos dos fármacos , Fator Natriurético Atrial/administração & dosagem , Fator Natriurético Atrial/sangue , Pressão Sanguínea/efeitos dos fármacos , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Masculino , Peptídeo Natriurético Tipo C/administração & dosagem , Ratos , Ratos WistarRESUMO
The aim of this study was to evaluate plasma levels of ANF in patients with catecholamine-secreting tumors with and without hypertension and to relate ANF secretion to levels of plasma and urinary catecholamines and blood pressure. Twenty-one pheochromocytoma (15 with sustained, 6 with paroxysmal hypertension), 6 neuroblastoma (1 hypertensive) patients and 28 aged-matched controls were studied in basal conditions. Plasma and urinary norepinephrine (NE),epinephrine (E), dopamine (DA) and DOPA were determined by HPLC-ED and plasma ANF by RIA. Both neuroblastoma and pheochromocytoma patients had significantly higher plasma ANF levels than controls. Neuroblastomas showed higher ANF concentration than pheochromocytomas. No differences were found in plasma ANF between hypertensive and normotensive patients. Pheochromocytomas with ANF levels within the normal range had plasma and urinary NE and urinary DA and DOPA levels significantly higher than patients with high ANF. Plasma ANF levels were unrelated to systolic or diastolic blood pressure or heart rate. A negative correlation between plasma ANF and urinary DA was found only in the patients groups. In conclusion, plasma ANF was increased in pheochromocytoma and neuroblastoma patients. Our data suggest that the excessive catecholamine secretion is not responsible for the increased ANF secretion in these patients. The significance of the relationships among plasma ANF and urinary and plasma catecholamines requires further investigation.
Assuntos
Neoplasias das Glândulas Suprarrenais/sangue , Fator Natriurético Atrial/sangue , Catecolaminas/sangue , Neuroblastoma/sangue , Feocromocitoma/sangue , Neoplasias Abdominais/sangue , Neoplasias Abdominais/secundário , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/urina , Pressão Sanguínea , Catecolaminas/urina , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/sangue , Hipertensão/urina , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla/sangue , Neoplasia Endócrina Múltipla/secundário , Estadiamento de Neoplasias , Neuroblastoma/patologia , Feocromocitoma/patologia , Neoplasias da Bexiga Urinária/sangue , Neoplasias da Bexiga Urinária/secundárioRESUMO
Hig levels of circulating atrial natriuretic factor (ANF) have been reported in several physiopathologic conditions like hypertension, heart and renal failure, pregnancy and high sodium intake. Nevertheless, neither relationships with water-sodium space regulation nor the role of an ANF vascular relaxant effect have been yet defined. The aim of present experiments was to characterize the contribution of circulating ANF and its vascular relaxing effects in the two kidney-two clip (2K2C) experimental model of renovascular hypertension. Complementary, plasma metabolites nitrite/nitrate of nitric oxide (NO) was examined because of mediation for both (NO an ANF) through cGMP. Three results showed (two-four weeks after surgery): indirect systolic blood pressure (mmHg), 186 +/- 4 in HT and 122 +/- 1 in SH (p < 0.001); a significant increase of plasma ANF (fmol/ml) in HT (n = 7, 1221 +/- 253) vs. SH (n = 9, 476 +/- 82; p < 0.02). Nitrate/nitrite plasma concentrations (mumol/l) were mpt different between SH and. The relaxant effect of ANF (10(-9), 10(-8) and 10(-7) M) on phenylephrine (3,5 x 10(-6) M) contracted rings from HT rats was smaller than SH rats (10(-8) M, p < 0.05). Contractions to phorbol 12, 13-dibutyrate (seven weeks after surgery) were significantly higher in rings from HT rats (p < 0.001). We conclude: 1) in addition to decreased granularity in atrial myocardiocytes, high circulating values of ANF here described suggest an increased turnover of the peptide in 2K2C hypertensive rats; 2) lower significant vascular relaxant effects in HT rats would indicate down regulation of ANF receptors in this model; the latter would derive from high plasma ANF concentration and, tentatively, because of greater activity of protein kinase C in the vascular wall; 39 similar values of plasma nitrite/nitrate in SH and HT rats would indicate a comparable NO circulating availability in both groups.
Assuntos
Fator Natriurético Atrial/sangue , Hipertensão Renovascular/metabolismo , Rim/metabolismo , Óxido Nítrico/sangue , Animais , Aorta Abdominal/metabolismo , Fator Natriurético Atrial/metabolismo , Pressão Sanguínea , Hipertensão Renovascular/sangue , Masculino , Músculo Liso Vascular/metabolismo , Nitratos/sangue , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Nitritos/sangue , Nitritos/metabolismo , Ratos , Ratos WistarRESUMO
The effect of atrial natriuretic factor (ANF) on peritoneal dialysis was studied in bilaterally nephrectomized rats. ANF was injected prior to every dialysis exchange and blood samples were obtained before the instillation of the dialysis solution and during the collection of dialysates. Urea, creatinine, potassium, and sodium were determined in both plasma and dialysates. Results showed that ANF increased the plasma clearance of all studied solutes, probably through vasodilation. Solute clearances showed a gradual increase with each dialysis exchange in both control and experimental animals. Therefore, ANF plasma levels were assayed before, during, and after peritoneal dialysis in a control group of nephrectomized rats to determine whether ANF plasma levels were modified during dialysis. Plasma ANF values were higher during and after peritoneal dialysis, though basal levels were similar to those of non-nephrectomized rats. These results suggest the release of endogenous ANF from the cardiac atria during peritoneal dialysis. The present results suggest that ANF may be of potential interest in the clinical field to increase the efficiency of peritoneal dialysis in man.
Assuntos
Fator Natriurético Atrial/farmacologia , Diálise Peritoneal , Animais , Fator Natriurético Atrial/administração & dosagem , Fator Natriurético Atrial/sangue , Creatinina/metabolismo , Soluções para Diálise , Masculino , Nefrectomia , Potássio/metabolismo , Ratos , Ratos Wistar , Sódio/metabolismo , Ureia/metabolismoRESUMO
The importance of the interaction of alpha- and beta-adrenoceptors in maintaining vascular tone in rats was studied. This interaction after clenbuterol (CLEN) treatment indicates an important contribution of the circulating epinephrine (EPI) levels. In urethane-anesthetized rats, the beta 2-adrenoceptor antagonist ICI 118.551 was more effective in antagonizing isoproterenol-induced hypotension (mainly beta 2-mediated) than tachycardia (mainly beta 1-mediated). Intravenous (i.v.) administration of the alpha 2-adrenoceptor agonist clonidine (CLO) induced an initial pressor response followed by a more prolonged hypotension and bradycardia. The initial hypertensive effect was potentiated by previous acute administration of ICI 118.551 as well as by the nonselective beta-adrenoceptor antagonist propranolol, but not by metoprolol, a more selective beta 1-blocker. Fourteen days of administration of the beta 2-adrenoceptor agonist CLEN [0.3 mg/kg, subcutaneously (s.c.) twice daily], a treatment that induces desensitization of beta 2-mediated vasodilation, increased the pressor response induced by CLO, an effect that was not observed in pentobarbital-anesthetized rats. In any case, neither beta-blockers nor CLEN treatment affects the hypotension and bradycardia induced by CLO. Mean blood pressure (BP) of CLEN-treated rats was increased under urethane anesthesia but not under pentobarbital anesthesia. Catecholamine levels (principally EPI) were higher in urethane-anesthetized rats. These results provide further evidence of a functional interaction between alpha 2- and beta 2-adrenoceptor-mediated responses in rat vasculature and suggest that vasodilator beta 2-adrenoceptors might contribute to the determination of peripheral vascular tone when circulating EPI is substantially elevated.
Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Anestesia , Animais , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/sangue , Clembuterol/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol/farmacologia , Masculino , Tono Muscular/efeitos dos fármacos , Propanolaminas/farmacologia , RatosRESUMO
Short-term treatment with clenbuterol [0.6 mg/kg-1 subcutaneously (s.c.) daily] produces a pressor effect in stressed rats after a period of immobilization (40 min). The stress applied markedly increases the plasma concentrations of norepinephrine (NE) and epinephrine. After bilateral adrenal demedullation, the increased levels of catecholamines and the hypertensive response obtained after clenbuterol treatment in the stressed animals were reduced to the values of the control rats. Clenbuterol treatment produced desensitization of the beta 2-adrenoceptor-mediated effect and thus reduced the vasodilator response induced by isoproterenol and increased the vasoconstriction produced by epinephrine but not that caused by NE. This desensitization may be responsible for the hypertensive response after clenbuterol treatment in stressed animals which is attenuated after adrenal demedullation. In conclusion, our results provide evidence that clenbuterol treatment induces pressor effect in normotensive animals under stress.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Clembuterol/farmacologia , Etanolaminas/farmacologia , Medula Suprarrenal/fisiologia , Animais , Catecolaminas/sangue , Epinefrina/sangue , Feminino , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Isoproterenol/farmacologia , Norepinefrina/sangue , Ratos , Ratos Endogâmicos , Restrição FísicaRESUMO
We used a radioenzymatic method to determine plasma levels of free and total (free plus sulfoconjugated) norepinephrine and dopamine in 20 children with neuroblastoma (two were hypertensive), seven patients with pheochromocytoma, and 39 normotensive controls (24 children and 15 adults). No significant differences were noted between the two control groups. Patients with neuroblastoma and pheochromocytoma showed significantly higher levels of free and total norepinephrine than controls (p less than 0.01), and those with pheochromocytoma had higher levels than those with neuroblastoma (p less than 0.01). Although the differences were not statistically significant, free dopamine was higher in both groups of patients than in controls. Total dopamine was significantly higher in patients than in controls (p less than 0.01). A positive correlation was noted between levels of total norepinephrine and total dopamine in controls (r = 0.41, p less than 0.05) and in patients with neuroblastoma (r = 0.72, p less than 0.001). Such a correlation was not found in patients with pheochromocytoma. The total dopamine/total norepinephrine ratio was higher (p less than 0.005) in patients with neuroblastoma than in controls and patients with pheochromocytoma. Patients with pheochromocytoma had significantly lower ratios than the other groups (p less than 0.001). A negative correlation was found between the ratios in the different groups and either systolic (p less than 0.001) or diastolic (p less than 0.001) blood pressure. Our results not only support a role for plasma dopamine in the regulation of blood pressure but also suggest that, regardless of the actual levels of both catecholamines, a balance has to be achieved in order to maintain normal blood pressure levels.