RESUMO
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
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
1.-- In the rat, a fructose-enriched diet induces hyperglycaemia, hypertriglyceridaemia, insulin resistance and hypertension; a model which resembles the human metabolic syndrome. 2.-- Prostanoids, metabolites of arachidonic acid, include vasoactive substances synthesized and released from the vascular wall that have been implicated in the increase of peripheral resistance, one of the mechanisms involved in the fructose-induced hypertension. 3.-- The aim of the present study was to: (i) analyse the effects of the in vitro incubation with fructose on the production and release of prostanoids in rat thoracic aorta and in rat mesenteric bed and (ii) compare the effects of incubation with those of the in vivo acute and chronic treatment of rats with fructose and with the combination of both in vivo and in vitro procedures. 4.-- Blood pressure, glycaemia and triglyceridaemia were significantly elevated in both 4- and 22-week fructose-treated groups. Meanwhile, body and heart weight as well as insulinaemia were similar between experimental animals and controls. 5.-- In aortae, 4 weeks of Fructose treatment did not modify the prostanoid pattern release, but in vitro incubation decreased prostacyclin (PGI(2)) production. However, after 22 weeks, fructose treatment and incubation exerted the same effect. 6.-- In mesenteric bed, after 4 weeks, the incubation and the combination of both procedures reduced the release of the vasodilators PGI(2) and PGE(2), while fructose treatment only diminished the PGE(2) release. On the contrary, the production of the vasoconstrictor thromboxane A(2) (TXA(2)) was enhanced by incubation and both the procedures. After 22 weeks, fructose treatment increased PGI(2) release, while it was reduced by incubation. The combination of both did not modify this peripheral resistance when compared with controls. Finally, incubation of tissues from treated rats increased the release of the vasoconstrictors, PGF(2alpha) and TXA(2). 7.-- In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of fructose on prostanoid production. This difference could be related to a more relevant role of resistance vessels in the regulation of peripheral resistance and consequently of blood pressure. The observed effects should contribute to a shift in the balance of the release of prostanoid in favour of vasoconstrictor metabolites. This phenomenon could be related to an increase in the peripheral resistance and the mild hypertension observed in the fructose-treated rats.
Assuntos
Frutose/farmacologia , Síndrome Metabólica/metabolismo , Prostaglandinas/metabolismo , 6-Cetoprostaglandina F1 alfa/metabolismo , Administração Oral , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Pressão Sanguínea , Dinoprostona/metabolismo , Modelos Animais de Doenças , Frutose/administração & dosagem , Hipertensão/sangue , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/metabolismo , Síndrome Metabólica/sangue , Síndrome Metabólica/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Tromboxano A2/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
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
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
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
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
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
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
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
(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
The aim of the present study was to determine if insulin is able to modulate the pressor response to intracerebroventricularly administered angiotensin II in insulin resistant fructose overloaded rats. Male Sprague-Dawley rats were divided into two groups: 1) Control group (C) with tap water to drink for 6 weeks (n=36); and 2) fructose treated (F), with fructose solution (10% w/v) to drink for 6 weeks (n=36). On the day of the experiment, anesthetized male C and F rats were intracerebroventricularly infused with insulin (12 mU/h, n=15) or Ringer's solution as vehicle (n=15) for 2h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n=10) or vehicle (n=5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In a subset of C (n=10) and F (n=20) animals, PD98059 (p44/42 MAPK inhibitor) or vehicle was administered intracerebroventricularly at a flow rate of 5 µl/min for 1 min. Ten minutes later, insulin (12 mU/h, n=5 for each group) or vehicle (Ringer's solution, only in the F group, n=5) was perfused for 2h at a flow rate of 4 µl/h, and cardiovascular parameters were measured every 15 min. Immediately, changes in MAP and HR in response to a subpressor dose of Ang II (5 pmol/2 µl) were evaluated for 10 min (n=5 for each group). In other subset of animals (n=6 for each group), AT1 and AT2 hypothalamic receptor levels were measured by Western blotting. Intracerebroventricular insulin pre-treatment increased the pressor response to angiotensin II in C rats. In F rats (with or without insulin pretreatment), the pressor response to angiotensin II was higher than that in vehicle pre-treated C animals, but similar to that observed in C after insulin infusion. In C rats phospho-ERK 1/2 hypothalamic levels significantly increased after angiotensin II injection in insulin pretreated animals compared to vehicle pre-treated rats, suggesting that MAPK activation might be involved in insulin potentiation of blood pressure response to angiotensin II in the brain. Phospho-ERK 1/2 hypothalamic levels were significantly increased in vehicle treated F rats compared to C, suggesting that basal MAPK activation might play a role in the enhanced response to angiotensin II observed in these animals. Finally, in F rats, either after vehicle or insulin infusion, angiotensin II injection was associated with a similar increase in phospho-ERK 1/2 hypothalamic levels, comparable to that observed after angiotensin II injection in insulin pre-treated C animals. ERK 1/2 blockade significantly reduced MAP in F rats compared to C. Moreover, ERK 1/2 inhibition completely abolished the Ang II pressor response in F rats and in insulin pre-treated C animals. All these findings suggest that insulin-angiotensin II interaction at hypothalamic level might be involved in the increase in blood pressure observed in the insulin resistant state.
Assuntos
Angiotensina II/fisiologia , Pressão Sanguínea , Insulina/fisiologia , Síndrome Metabólica/fisiopatologia , Angiotensina II/administração & dosagem , Animais , Frutose , Hipotálamo/metabolismo , Injeções Intraventriculares , Insulina/administração & dosagem , Resistência à Insulina , Sistema de Sinalização das MAP Quinases , Masculino , Síndrome Metabólica/induzido quimicamente , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Vasoconstritores/administração & dosagem , Sistema Vasomotor/fisiopatologiaRESUMO
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
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
Ten pheochromocytoma patients, five with paroxysmal hypertension (Group 1), five with sustained hypertension (Group 2) and 15 normals were studied to determine the relationship between differential secretion of the catecholamines (CA) or differences in their sulphoconjugation and the hypertension patterns in these patients. Group 1 patients were studied in the normotensive period. A consistent finding in this study is that permanent hypertensive patients showed the highest free and conjugated norepinephrine (NE) levels while paroxysmal patients studied during the normotensive period showed the highest conjugated epinephrine (E) levels. Although no significant difference was found in levels of free plasma epinephrine in the Group 1 patients, in the ratio of total plasma E/NE, E was clearly predominant. No significant differences could be found in the degree of the per cent conjugation of individual catecholamines between both groups of patients. Group 1 showed a higher (P less than 0.05) E and a lower dopamine (DA) per cent conjugation than controls. In conclusion, although the dominant type of CA secreted seems to be the main factor in determining the hypertension pattern, sulphoconjugation ability may also play an important role.
Assuntos
Neoplasias das Glândulas Suprarrenais/sangue , Dopamina/sangue , Epinefrina/sangue , Hipertensão/sangue , Norepinefrina/sangue , Feocromocitoma/sangue , Adolescente , Neoplasias das Glândulas Suprarrenais/complicações , Adulto , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Feocromocitoma/complicaçõesRESUMO
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.