RESUMO
Isoflavonoids have been largely studied due to their distinct biological activities identified thus far. Herein, we evaluated the activity of neovestitol, an isoflavonoid isolated from Brazilian red propolis, in acute and chronic inflammation. As for acute inflammation, we found that neovestitol reduced neutrophil migration, leukocyte rolling and adhesion, as well as expression of ICAM-1 in the mesenteric microcirculation during lipopolysaccharide-induced acute peritonitis. No changes were observed in the levels of TNF-α, CXCL1/KC and CXCL2/MIP-2 upon pretreatment with neovestitol. The administration of an inducible nitric oxide synthase (iNOS) inhibitor abolished the inhibitory effects of neovestitol in neutrophil migration and ICAM-1 expression. Nitrite levels increased upon treatment with neovestitol. No effects of neovestitol were observed on the chemotaxis of neutrophils in vitro. As for chronic inflammation, neovestitol also reduced the clinical score and joint damage in a collagen-induced arthritis model. There was no change in the frequency of IL-17-producing TCD4+ cells. In addition, pretreatment with neovestitol reduced the levels of IL-6. These results demonstrate a potential anti-inflammatory activity of neovestitol, which may be useful for therapeutic purposes and/or as a nutraceutical.
Assuntos
Artrite Experimental/prevenção & controle , Flavonoides/uso terapêutico , Interleucina-6/metabolismo , Óxido Nítrico/metabolismo , Peritonite/prevenção & controle , Própole/química , Doença Aguda , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/etiologia , Brasil , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doença Crônica , Citocinas/metabolismo , Flavonoides/química , Flavonoides/farmacologia , Guanidinas/farmacologia , Lipopolissacarídeos/toxicidade , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/metabolismo , Veias Mesentéricas/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Peritonite/etiologia , Própole/metabolismoRESUMO
OBJECTIVES: Experimental studies on sepsis have demonstrated that ethyl pyruvate is endowed with antioxidant and anti-inflammatory properties. This study aimed to investigate the effects of ethyl pyruvate on leukocyte-endothelial interactions in the mesenteric microcirculation in a live Escherichia coli-induced sepsis model in rats. METHODS: Male Wistar rats were administered an intravenous suspension of E. coli bacteria or were subjected to a sham procedure. Three hours after bacterial infusion, the rats were randomized into the following groups: a control group without treatment, a group treated with lactated Ringer's solution (4 mL/kg, i.v.), and a group treated with lactated Ringer's solution (4 mL/kg, i.v.) plus ethyl pyruvate (50 mg/kg). At 24 h after bacterial infusion, leukocyte-endothelial interactions were investigated using intravital microscopy, and the expression of P-selectin and intercellular adhesion molecule-1 was evaluated via immunohistochemistry. White blood cell and platelet counts were also determined at baseline and 3 h and 24 h after E. coli inoculation. RESULTS: The non-treated and lactated Ringer's solution-treated groups exhibited increases in the numbers of rolling leukocytes (â¼2.5-fold increase), adherent cells (â¼3.0-fold), and migrated cells (â¼3.5-fold) compared with the sham group. In contrast, treatment with Ringer's ethyl pyruvate solution reduced the numbers of rolling, adherent and migrated leukocytes to the levels observed in the sham group. Additionally, the expression of P-selectin and intercellular adhesion molecule-1 was significantly increased on mesenteric microvessels in the non-treated group compared with the sham group (p<0.001). The expression of both adhesion molecules was reduced in the other groups, with ethyl pyruvate being more effective than lactated Ringer's solution. Infusion of bacteria caused significant leukopenia (3 h), followed by leukocytosis with granulocytosis (24 h). There was also an intense and progressive reduction in the number of platelets. However, no differences were observed after treatment with the different solutions. CONCLUSIONS: The presented data suggest that ethyl pyruvate efficiently reduces the inflammatory response in the mesenteric microcirculation in an experimental model of sepsis induced by live E. coli and is associated, at least in part, with down-regulation of P-selectin and intercellular adhesion molecule-1.
Assuntos
Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Piruvatos/farmacologia , Sepse/tratamento farmacológico , Animais , Comunicação Celular/fisiologia , Modelos Animais de Doenças , Células Endoteliais/citologia , Infecções por Escherichia coli , Leucócitos/citologia , Masculino , Veias Mesentéricas/citologia , Microcirculação , Ratos , Ratos WistarRESUMO
OBJECTIVES: Experimental studies on sepsis have demonstrated that ethyl pyruvate is endowed with antioxidant and anti-inflammatory properties. This study aimed to investigate the effects of ethyl pyruvate on leukocyte-endothelial interactions in the mesenteric microcirculation in a live Escherichia coli-induced sepsis model in rats. METHODS: Male Wistar rats were administered an intravenous suspension of E. coli bacteria or were subjected to a sham procedure. Three hours after bacterial infusion, the rats were randomized into the following groups: a control group without treatment, a group treated with lactated Ringer’s solution (4 mL/kg, i.v.), and a group treated with lactated Ringer’s solution (4 mL/kg, i.v.) plus ethyl pyruvate (50 mg/kg). At 24 h after bacterial infusion, leukocyte-endothelial interactions were investigated using intravital microscopy, and the expression of P-selectin and intercellular adhesion molecule-1 was evaluated via immunohistochemistry. White blood cell and platelet counts were also determined at baseline and 3 h and 24 h after E. coli inoculation. RESULTS: The non-treated and lactated Ringer’s solution-treated groups exhibited increases in the numbers of rolling leukocytes (∼2.5-fold increase), adherent cells (∼3.0-fold), and migrated cells (∼3.5-fold) compared with the sham group. In contrast, treatment with Ringer’s ethyl pyruvate solution reduced the numbers of rolling, adherent and migrated leukocytes to the levels observed in the sham group. Additionally, the expression of P-selectin and intercellular adhesion molecule-1 was significantly increased on mesenteric microvessels in the non-treated group compared with the sham group (p<0.001). The expression of both adhesion molecules was reduced in the other groups, with ethyl pyruvate being more effective than lactated Ringer’s solution. Infusion of bacteria caused significant leukopenia (3 h), followed ...
Assuntos
Animais , Masculino , Ratos , Comunicação Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Piruvatos/farmacologia , Sepse/tratamento farmacológico , Comunicação Celular/fisiologia , Modelos Animais de Doenças , Infecções por Escherichia coli , Células Endoteliais/citologia , Leucócitos/citologia , Microcirculação , Veias Mesentéricas/citologia , Ratos WistarRESUMO
The mechanisms whereby testosterone increases cardiovascular risk are not clarified. However, oxidative stress and inflammation seem to be determinants. Herein, we sought to determine whether exogenous testosterone, at physiological levels, induces leucocyte migration, a central feature in immune and inflammatory responses and the mediating mechanisms. We hypothesized that testosterone induces leucocyte migration via NADPH oxidase (NADPHox)-driven reactive oxygen species (ROS) and cyclooxygenase (COX)-dependent mechanisms. Sixteen-week-old Wistar rats received an intraperitoneal injection (5 ml) of either testosterone (10(-7) mol/l) or saline. Rats were pre-treated with 5 ml of sodium salicylate (SS, non-selective COX inhibitor, 1.25 × 10(-3) mol/l, 1 h prior to testosterone or saline), flutamide (androgen receptor antagonist, 10(-5) mol/l), apocynin (NADPHox inhibitor, 3 × 10(-4) mol/l), N-[2-Cyclohexyloxy-4-nitrophenyl]methanesulfonamide (NS398, COX2 inhibitor, 10(-4) mol/l) or saline, 4 h before testosterone or saline administration. Leucocyte migration was assessed 24 h after testosterone administration by intravital microscopy of the mesenteric bed. Serum levels of testosterone were measured by radioimmunoassay. NADPHox activity was assessed in membrane fractions of the mesenteric bed by dihydroethidium (DHE) fluorescence and in isolated vascular smooth muscle cells (VSMC) by HPLC. NADPHox subunits and VCAM (vascular cell adhesion molecule) expression were determined by immunoblotting. Testosterone administration did not change serum levels of endogenous testosterone, but increased venular leucocyte migration to the adventia, NADPHox activity and expression (P < 0.05). These effects were blocked by flutamide. SS inhibited testosterone-induced leucocyte migration (P<0.05). Apocynin and NS398 abolished testosterone-induced leucocyte migration and NADPHox activity (P<0.05). Testosterone induces leucocyte migration via NADPHox- and COX2-dependent mechanisms and may contribute to inflammatory processes and oxidative stress in the vasculature potentially increasing cardiovascular risk.
Assuntos
Movimento Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Leucócitos/efeitos dos fármacos , NADPH Oxidases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Testosterona/farmacologia , Acetofenonas/farmacologia , Androgênios/farmacologia , Animais , Western Blotting , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Injeções Intraperitoneais , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Veias Mesentéricas/citologia , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/metabolismo , Microscopia de Vídeo/métodos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NADPH Oxidases/antagonistas & inibidores , Nitrobenzenos/farmacologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Superóxidos/metabolismo , Testosterona/administração & dosagemRESUMO
This study investigated the endothelium-dependent vasorelaxant effects of the essential oil of Ocimum gratissimum (EOOG) in aortas and mesenteric vascular beds isolated from rats. EOOG (3-300 µg/mL) relaxed the tonic contractions induced by phenylephrine (0.1 µmol/L) in isolated aortas in a concentration-dependent manner in both endothelium-containing and endothelium-denuded preparations. This effect was partially reversed by L-NAME (100 µmol/L) but not by indomethacin (10 µmol/L) or TEA (5 mmol/L). In mesenteric vascular beds, bolus injections of EOOG (30, 50, 100, and 300 ng) decreased the perfusion pressure induced by noradrenaline (6 µmol/L) in endothelium-intact preparations but not in those treated with deoxycholate. L-NAME (300 µmol/L) but not TEA (1 mmol/L) or indomethacin (3 µmol/L) significantly reduced the vasodilatory response to EOOG at all of the doses tested. Our data showed that EOOG exerts a dose-dependent vasodilatory response in the resistance blood vessels of rat mesenteric vascular beds and in the capacitance blood vessel, the rat aorta. This action is completely dependent on endothelial nitric oxide (NO) release in the mesenteric vascular beds but only partially dependent on NO in the aorta. These novel effects of EOOG highlight interesting differences between resistance and capacitance blood vessels.
Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Ocimum/química , Óleos Voláteis/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/enzimologia , Aorta Torácica/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/fisiologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/enzimologia , Veias Mesentéricas/metabolismo , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Norepinefrina/antagonistas & inibidores , Norepinefrina/metabolismo , Óleos Voláteis/química , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Wistar , Capacitância Vascular/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/antagonistas & inibidoresRESUMO
To investigate the venoconstrictor effect of angiotensin II (Ang II) in spontaneously hypertensive rats (SHR), we used preparations of mesenteric venular beds and the circular muscle of the portal veins. Vessels were tested with Ang II in the presence or absence of losartan, PD 123319, HOE 140, L-NAME, indomethacin, or celecoxib. In the mesenteric venular bed of SHR, the effect of Ang II (0.1 nmol) was nearly abolished by losartan and enhanced by HOE 140, indomethacin, and celecoxib, while PD123319 and L-NAME had no effect. In portal vein preparations, cumulative-concentration response curves (CCRC) to Ang II (0.1-100 nmol/L) exhibited a lower maximal response (E(max)) in SHR compared to Wistar rats. AT(1) receptor expression was similar in the two strains, while AT(2) receptor levels were lower in SHR portal veins when compared to Wistar. In SHR portal veins, losartan shifted the CCRC to Ang II to the right, while indomethacin and HOE 140 increased the E(max) to Ang II. PD 123319, celecoxib, and L-NAME had no effect. Taken together, our results suggest that Ang II-induced venoconstriction in SHR is mediated by activation of AT(1) receptors and this effect may be counterbalanced by kinin B(2) receptor and COX metabolites. Furthermore, our data indicate that there are different cellular and molecular mechanisms involved in the regulation of venous tonus of normotensive and hypertensive rats. These differences probably reflect distinct factors that influence arterial and venous bed in hypertension.
Assuntos
Angiotensina II/farmacologia , Hipertensão/fisiopatologia , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/fisiologia , Veia Porta/efeitos dos fármacos , Veia Porta/fisiologia , Vasoconstrição/efeitos dos fármacos , Animais , Masculino , Veias Mesentéricas/anatomia & histologia , Veia Porta/anatomia & histologia , Ratos , Ratos Endogâmicos SHR , Ratos WistarRESUMO
This study analyzes the effects of sodium tungstate and vanadyl sulphate in the fructose-overloaded rat, a model of metabolic syndrome. Fructose (9 weeks) increased blood pressure, triglycerydemia, glycemia, and reduced release of vasodilator prostaglandins (prostacyclin and prostaglandin E2 ) in the mesenteric vascular bed. Sodium tungstate prevented those alterations; meanwhile vanadyl sulfate only prevented the increase in glycemia. In conclusion, the present experiments showed that sodium tungstate is more effective than vanadyl sulfate for the treatment of experimental metabolic syndrome in rats.
Assuntos
6-Cetoprostaglandina F1 alfa/biossíntese , Pressão Sanguínea/efeitos dos fármacos , Dinoprostona/biossíntese , Síndrome Metabólica/tratamento farmacológico , Compostos de Tungstênio/farmacologia , Compostos de Vanádio/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Glicemia/análise , Determinação da Pressão Arterial , Cromatografia de Fase Reversa , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Frutose/administração & dosagem , Frutose/metabolismo , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/metabolismo , Síndrome Metabólica/metabolismo , Síndrome Metabólica/fisiopatologia , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Triglicerídeos/sangueRESUMO
BACKGROUND: In previous studies we reported an altered prostanoid (PR) release-pattern in mesenteric vessels in fructose (F)-overloaded rats, an experimental model of insulin resistance and hypertension. Dehydroepiandrosterone (DHEA) and its precursor Dehydroepiandrosterone sulfate (DHEA-S) are the most abundant circulating steroid hormones produced by the adrenal and recent studies in both cells and animals suggest that DHEA may have acute non-genomic actions that mimic both metabolic and vascular actions of insulin. AIM OF THE STUDY: This study was to analyze in F-overloaded rats, the effects of DHEA treatment on arterial blood pressure and the PR production in mesenteric vessels and aorta. METHODS: Male 6 week-old Sprague-Dawley rats were randomly divided in four groups: a control group (C), a DHEA (30 mg/kg/sc/48 h)-treated group (D), a fructose (10% w/v in drinking water)-fed group (F), and both treatments simultaneously group (FD). The systolic blood pressure (SBP) was measured by tail cuff method and glycemia and triglyderidemia were measured by enzymatic assays. The mesenteric beds of all groups were dissected, and incubated in Krebs solution. The PR released were measured by HPLC. RESULTS: F overload increased SBP and triglyceridemia and decreased the mesenteric vasodilatory PR release. DHEA treatment prevented the increment in SBP and triglyceridemia and decreased vasoconstrictor PR in F-treated rats. CONCLUSION: DHEA normalize the PGI(2)/TX ratio, diminished in F-overloaded rats, through the decrease in thromboxane (TX) production and this could be one of the mechanisms by which DHEA prevented the slight hypertension in F-animals.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Desidroepiandrosterona/farmacologia , Prostaglandinas/metabolismo , Tromboxanos/sangue , Triglicerídeos/sangue , Administração Oral , Animais , Pressão Sanguínea/fisiologia , Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/metabolismo , Modelos Animais de Doenças , Frutose/farmacologia , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Oxamniquine is an antiparasitic agent commonly used in therapeutics against Schistosoma mansoni. Although it is well tolerated, some adverse effects justify the search for new compounds with prolonged biological action, so that monomeric and polymeric oxamniquine prodrugs were designed. Synthetic results assisted by molecular modeling study showed the possibility to obtain the corresponding monomeric forms of the oxamniquine methacrylate (1) and oxamniquine acrylamide (2). Successful copolymerization procedure only occurred on the methacrylic compound, generating the oxamniquine methacrylate copolymer (3). Submitted to a preliminary in vivo biological evaluation, a similar oxamniquine profile was observed to the monomeric forms although an inadequate drug release may be responsible for the methacrylic copolymer failure.
Assuntos
Acrilamida/síntese química , Desenho de Fármacos , Metacrilatos/síntese química , Oxamniquine/síntese química , Pró-Fármacos/síntese química , Esquistossomicidas/uso terapêutico , Acrilamida/química , Acrilamida/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Masculino , Veias Mesentéricas/efeitos dos fármacos , Metacrilatos/química , Metacrilatos/uso terapêutico , Camundongos , Modelos Moleculares , Oxamniquine/química , Oxamniquine/uso terapêutico , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/síntese química , Relação Estrutura-AtividadeRESUMO
1. The mechanisms involved in the vasodilator actions of angiotensin II (Ang II) have not yet been completely elucidated. We investigated the potential mechanisms that seem to be involved in the Ang II vasodilator effect using rat isolated mesenteric vascular bed (MVB). 2. Under basal conditions, Ang II does not affect the perfusion pressure of MVB. However, in vessels precontracted with norepinephrine, Ang II induces vasodilation followed by vasoconstriction. Vasoconstrictor, but not the vasodilation of Ang II, is inhibited by AT(1) antagonist (losartan). The vasodilator effect of Ang II was not inhibited by AT(2), angiotensin IV and angiotensin 1-7 receptor antagonists alone (PD 123319, divalinal, A 779, respectively). 3. The vasodilator effect of Ang II is significantly reduced by endothelial removal (deoxycholic acid), but not by indomethacin. Inhibition of NO-synthase by N(G)-nitro-l-arginine methyl ester (l-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ) reduces the vasodilator effect of Ang II. This effect is also reduced by tetraethylammonium (TEA) or l-NAME, and a combination of l-NAME plus TEA increases the inhibitory effect of the antagonists alone. However, indomethacin does not change the residual vasodilator effect observed in vessels pretreated with l-NAME plus TEA. 4. In vessels precontracted with norepinephrine and depolarized with KCl 25 mm or treated with Ca(2+)-dependent K(+) channel blockers (charybdotoxin plus apamin), the effect of Ang II was significantly reduced. However, this effect is not affected by ATP and voltage-dependent K(+) channel blockers (glybenclamide and 4-aminopyridine). 5. Inhibition of kininase II with captopril significantly potentiates the vasodilator effect of bradykinin (BK) and Ang II in the rat MVB. The inhibitory effect of the B(2) receptor antagonist HOE 140 on the vasodilator effect of Ang II is further enhanced by PD 123319 and/or A 779. 6. The present findings suggest that BK plays an important role in the endothelium-dependent vasodilator effect of Ang II. Probably, the link between Ang II and BK release is modulated by receptors that bind PD 123319 and A 779.
Assuntos
Angiotensina II/farmacologia , Angiotensina I/fisiologia , Bradicinina/fisiologia , Fatores Relaxantes Dependentes do Endotélio/metabolismo , Fragmentos de Peptídeos/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Vasodilatação/fisiologia , Animais , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Veias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/fisiologia , Ratos , Ratos Wistar , Receptores de Angiotensina/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
1. The administration of streptozotocin (STZ) to 2-day old rats induced a non-insulin-dependent diabetes mellitus (NIDDM)-like state, with mild hyperglycaemia and no alterations in body weight at the adult age. 2. In the isolated and perfused mesenteric vascular bed of NIDDM animals, the constrictor responses to either noradrenaline (NA) or potassium chloride (KCl) were not modified as compared with age-matched non-diabetic controls. 3. The reduction in NA contractions induced by the cyclooxygenase inhibitor, 10 microM indomethacin in the control group was absent in the NIDDM rats. 4. The increase in the NA-induced contractions caused by endothelium removal was suppressed by indomethacin in the controls but not in the NIDDM group. 5. The prostanoid release from the mesenteric vascular beds of NIDDM rats was markedly reduced as compared with non-diabetic controls. Noradrenaline increased production of the constrictor prostaglandin (PG) F2alpha in control but not in NIDDM rats. 6. In summary, these results show that in STZ-induced NIDDM rats, there is an impairment of the prostanoid production, as well as a suppression of the role of prostanoids in the contractile effects of NA in the mesenteric vascular bed. These alterations are more severe than those previously observed in a model of insulin-dependent diabetes mellitus (IDDM), in which hyperglycaemia and reduction of body weight were more marked. The conclusion is that, in these models of diabetes and in the preparation studied, vascular alterations and modifications of glycaemia and body weight are not closely related.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Norepinefrina/farmacologia , Prostaglandinas/metabolismo , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 2/induzido quimicamente , Masculino , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/metabolismo , Prostaglandinas/biossíntese , Ratos , Ratos Wistar , Vasoconstrição/fisiologiaRESUMO
The roles of nitric oxide and of endothelium in the effects of the vasorelaxing agents acetylcholine and bradykinin on the production of prostanoids was studied in the isolated and perfused mesenteric vascular bed of the rat. Prostanoids were measured in the perfusate by high-performance liquid chromatography (HPLC). In the intact vascular bed, 1 microM bradykinin increased the release of 6-keto-prostaglandinF(1alpha) (stable metabolite of prostacyclin) and of prostaglandin E2 and 10 microM acetylcholine stimulated the efflux of prostacyclin only. In the de-endothelialized vascular bed, bradykinin increased the release of prostacyclin whereas acetylcholine increased the efflux of thromboxane. The inhibition of nitric oxide synthesis with 100 microM N(G)-nitro-L-arginine methyl ester prevented the effect of bradykinin but did not modify the effects of acetylcholine on prostanoid release. In addition, 100 microM L-arginine reversed the inhibitory effect of N(G)-nitro L-arginine methyl ester on bradykinin-stimulated prostaglandin production. It is concluded that acetylcholine and bradykinin stimulate prostanoid release in the rat mesenteric vascular bed with different patterns and through different mechanisms.
Assuntos
Acetilcolina/farmacologia , Bradicinina/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Prostaglandinas/metabolismo , 6-Cetoprostaglandina F1 alfa/metabolismo , Animais , Arginina/farmacologia , Dinoprosta/metabolismo , Dinoprostona/metabolismo , Endotélio Vascular/metabolismo , Epoprostenol/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Veias Mesentéricas/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Tromboxano B2/metabolismoRESUMO
1. The effects of niflumic acid, an inhibitor of calcium-activated chloride currents, were compared with the actions of the calcium channel blocker nifedipine on noradrenaline- and 5-hydroxytryptamine (5-HT)-induced pressor responses of the rat perfused isolated mesenteric vascular bed. 2. Bolus injections of noradrenaline (1 and 10 nmol) increased the perfusion pressure in a dose-dependent manner. Nifedipine (1 microM) inhibited the increase in pressure produced by 1 nmol noradrenaline by 31 +/- 5%. Niflumic acid (10 and 30 microM) also inhibited the noradrenaline-induced increase in perfusion pressure and 30 microM niflumic acid reduced the pressor response to 1 nmol noradrenaline by 34 +/- 6%. 3. The increases in perfusion elicited by 5-HT (0.3 and 3 nmol) were reduced by niflumic acid (10 and 30 microM) in a concentration-dependent manner and 30 microM niflumic acid inhibited responses to 0.3 and 3 nmol 5-HT by, respectively, 49 +/- 8% and 50 +/- 7%. Nifedipine (1 microM) decreased the pressor response to 3 nmol 5-HT by 44 +/- 9%. 4. In the presence of a combination of 30 microM niflumic acid and 1 microM nifedipine the inhibition of the pressor effects of noradrenaline (10 nmol) and 5-HT (3 nmol) was not significantly greater than with niflumic acid (30 microM) alone. Thus the effects of niflumic acid and nifedipine were not additive. 5. In Ca-free conditions the transient contractions induced by 5-HT (3 nmol) were not reduced by 30 microM niflumic acid, suggesting that this agent does not inhibit calcium release from the intracellular store or the binding of 5-HT to its receptor. 6. Niflumic acid 30 microM did not inhibit the pressor responses induced by KCl (20 and 60 mumol) which were markedly reduced by 1 microM nifedipine. In addition, 1 microM levcromakalim decreased pressor responses produced by 20 mumol KCl. These data suggest that niflumic acid does not block directly calcium channels or activate potassium channels. 7. It is concluded that niflumic acid selectively reduces a component of noradrenaline- and 5-HT-induced pressor responses by inhibiting a mechanism which leads to the opening of voltage-gated calcium channels. Our data suggest that the Ca(2+)-activated chloride conductance may play a pivotal role in the activation of voltage-gated calcium channels in agonist-induced constriction of resistance blood vessels.
Assuntos
Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Ácido Niflúmico/farmacologia , Norepinefrina/farmacologia , Serotonina/farmacologia , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/fisiologia , Veias Mesentéricas/fisiologia , Nifedipino/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Vasoconstritores/farmacologiaRESUMO
Norepinephrine-induced responses in isolated perfused mesenteric vascular bed from normotensive and renovascular hypertensive rats were examined in the presence of adenosine diphosphate (ADP, 2 x 10(-6) M). Responses to norepinephrine were significantly greater in vessels from hypertensive rats. Norepinephrine-induced contractions increased after the removal of endothelium. N omega-Nitro-L-arginine (L-NOARG), a potent inhibitor of nitric oxide formation, similarly increased contractions. The greatest responses were obtained, however, after treatment of the vascular segments with methylene blue. The presence of ADP caused significant endothelium-dependent decreases in contractions. Although decreases caused by ADP in vessels with endothelium after treatment with L-NOARG were not statistically significant, a tendency to decreased responses seems to suggest that L-NOARG diminishes but does not completely prevent the effect of ADP in mesenteric vessels. Methylene blue partially reduced the endothelium-dependent ADP-induced relaxant effects in sham-operated nephrectomized rats. A tendency to increased contractions to norepinephrine was observed in the presence of ADP after removal of endothelium. Thus, in the mesenteric resistance arteries of the rat under stimulation by ADP, it appears that nitric oxide released from L-arginine and the activity of soluble guanylate cyclase account only in part for the endothelium-dependent decreased responses to norepinephrine. When nitric oxide formation or soluble guanylate cyclase activity are depressed simultaneously with endothelium damage, ADP released from platelets or red blood cells may be an important factor that acts synergically with vasoconstrictor stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Difosfato de Adenosina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Hipertensão Renovascular/fisiopatologia , Animais , Pressão Sanguínea , Frequência Cardíaca , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Norepinefrina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
In rings of rat portal vein, endothelin-1, endothelin-2, and endothelin-3 caused graded slow contractions and potentiated spontaneous contractions. The apparent EC50 values and maximal responses to 30 nM endothelin were 1.4 nM and 0.96 g for endothelin-1, 5.2 nM and 0.65 g for endothelin-2, and 1.7 nM and 0.62 g for endothelin-3 (n = 4-12). At concentrations producing half the contraction triggered by 80 mM KCl, the order of potencies was endothelin-1 greater than U46619 = angiotensin II greater than bradykinin greater than substance P greater than phenylephrine. Longitudinal portal-mesenteric vein preparations developed very modest contractions to endothelin-1 (0.13 g at 30 nM; n = 5), but their responses to 80 mM KCl and phenylephrine were greater than those of rings. Responses of rings to endothelin-1 were profoundly reduced in Ca(2+)-free medium, but less inhibition was obtained after incubation with nicardipine (up to 1 microM) and/or nickel (up to 0.5 mM), phorbol (up to 0.3 microM), staurosporine (up to 10 nM), or cromakalim (3 microM). Indomethacin (5.6 microM) did not affect responses to endothelin-1. Cromakalim (0.1-3 microM) also relaxed rings constricted with 0.3 nM endothelin-1, and this effect was partially reversed by glibenclamide (3 microM). Thus, endothelins, especially endothelin-1, are potent constrictors of portal vein rings but not of portal-mesenteric vein strips. Their action appears to rely largely on Ca2+ influx from the external medium (only in part via L- and T-type Ca2+ channels) and activation of protein kinase C but not on eicosanoid generation.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Endotelinas/farmacologia , Veia Porta/fisiologia , Alcaloides/farmacologia , Animais , Benzopiranos/farmacologia , Cálcio/farmacologia , Cromakalim , Endotelinas/efeitos dos fármacos , Endotelinas/fisiologia , Glibureto/farmacologia , Indometacina/farmacologia , Masculino , Veias Mesentéricas/efeitos dos fármacos , Nicardipino/farmacologia , Forbóis/farmacologia , Proteína Quinase C/antagonistas & inibidores , Pirróis/farmacologia , Ratos , Ratos Endogâmicos , Estaurosporina , Vasoconstrição/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
The vasoconstrictor effects of endothelin-1 (ET-1) and norepinephrine (NE) were compared in the exteriorized rat mesentery in situ. ET-1 was 1,000 times more potent than NE in constricting both arterioles and venules. Vasoconstrictions induced by ET-1 lasted much longer than those caused by the catecholamine. At nonrelaxant doses, acetylcholine and sodium nitroprusside antagonized the constrictive response of microvessels to ET-1 and NE. However, larger doses of acetylcholine were necessary to inhibit the response to ET-1 than that to NE.
Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Peptídeos/farmacologia , Animais , Arteríolas/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotelinas , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Veias Mesentéricas/efeitos dos fármacos , Norepinefrina/farmacologia , Ratos , Ratos Endogâmicos , Vasoconstrição/efeitos dos fármacos , Vênulas/efeitos dos fármacosRESUMO
The contractile reactivity to norepinephrine, methoxamine, and verapamil of the perfused mesenteric vascular bed from sinoaortic denervated (SAD) and sham-operated (SO) rats was studied 3 to 30 days after surgery. A gradual but incomplete reduction of arterial hypertension was observed in SAD rats throughout the study. The norepinephrine- and methoxamine-induced dose-response curves were similar in both SAD and SO groups on day 3, but shifted to the left on days 7 and 15 and demonstrated a tendency to shift to the right at 30 days. Verapamil-induced vasodilation was similar in both groups. Enhanced mesenteric vascular responsiveness to endogenous catecholamines could contribute to the increased vascular resistance.