RESUMO
To compare global endothelial function assessed by pulse wave analysis (PWA) using the ratio of endothelium dependent vasodilatation (EDV) to endothelium independent vasodilatation (EIV) in patients with hypercholesterolemia and controls. 92 subjects [46 hypercholesterolemics, 46 controls] were studied at standardized conditions. Baseline augmentation index (AIx) was assessed followed by the administration of 0.5 mg sublingual nitroglycerine, an endothelium independent vasodilator. AIx was assessed and the maximum change in AIx after nitroglycerine was recorded as EIV. After a washout period of 30 minutes, 400 µg of inhaled salbutamol, an endothelium dependent vasodilator was administered. AIx was assessed again and the maximum change in AIx after salbutamol was recorded as EDV. Global endothelial function was calculated as EDV:EIV ratio. EDV and EIV in patients with hypercholesterolemia compared to controls were 2.97 ± 3.95 and 6.65 ± 3.80 (p<0.001); and 13.41 ± 4.57 and 15.88 ± 4.78 (p=0.01) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls; 0.21 ± 0.38 and 0.44 ± 0.24 (p<0.001) respectively. EDV:EIV ratio was significantly reduced in patients with hypercholesterolemia compared to controls. PWA is a potential clinical tool to assess global endothelial function in patients with hypercholesterole
Assuntos
Humanos , Masculino , Feminino , Adulto , Endotélio/metabolismo , Análise de Onda de Pulso/métodos , Hipercolesterolemia , Pacientes , Vasodilatadores/efeitos adversosRESUMO
Previously, we showed that 1-nitro-2-phenylethene, a nitrostyrene derivative of 1-nitro-2-phenylethane, induced vasorelaxant effects in rat aorta preparations. Here, we studied mechanisms underlying the vasorelaxant effects of its structural analog, trans-4-chloro-ß-nitrostyrene (T4CN), in rat aortic rings. Increasing concentrations of T4CN (0.54-544.69 µm) fully and similarly relaxed contractions induced by phenylephrine (PHE, 1 µm) or KCl (60 mm) in endothelium-intact aortic rings with IC50 values of 66.74 [59.66-89.04] and 79.41 [39.92-158.01] µm, respectively. In both electromechanical and pharmacomechanical couplings, the vasorelaxant effects of T4CN remained unaltered by endothelium removal, as evidenced by the IC50 values (108.35 [56.49-207.78] and 65.92 [39.72-109.40] µm, respectively). Pretreatment of endothelium-intact preparations with L-NAME, ODQ, glibenclamide, or TEA did not change the vasorelaxant effect of T4CN. Under Ca2+ -free conditions, T4CN significantly reduced the phasic contractions induced by caffeine or PHE, as well as the contractions due to exogenous CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil). These results suggest that in rat aortic rings, T4CN induced vasorelaxation independently from the activation of soluble guanylate cyclase/cGMP pathway, an effect that may be related to the electrophilicity of the substituted chloro-nitrostyrene. This vasorelaxation seems to involve inhibition of both calcium influx from the extracellular milieu and calcium mobilization from intracellular stores mediated by IP3 receptors and by ryanodine-sensitive Ca2+ channels.
Assuntos
Aorta Torácica/efeitos dos fármacos , Estirenos/farmacologia , Vasodilatadores/farmacologia , Animais , Concentração Inibidora 50 , Masculino , Ratos , Ratos WistarRESUMO
8-Oxo-9-dihydromakomakine is a tetracyclic indole alkaloid extracted from leaves of the Chilean tree Aristotelia chilensis. The present study investigated the effects of this alkaloid on vascular response in tissues isolated from aortic segments obtained from normotensive rats. Our results showed that 8-oxo-9-dihydromakomakine induced a dose-dependent relaxation of aortic rings pre-contracted with phenylephrine (PE; 10-6 M). The vasorelaxation induced by 8-oxo-9-dihydromakomakine in rat aortic rings is independent of endothelium. The pre-incubation of aortic rings with 8-oxo-9-dehydromakomakine (10-4 M) significantly reduced the contractile response to KCl (p < 0.001) more than PE (p < 0.05). The highest dose of 8-oxo-9-dehydromakomakine (10-4 M) drastically reduced the contraction to KCl (6·10-2 M), but after that, PE (10-6 M) caused contraction (p < 0.05) in the same aortic rings. The addition of 8-oxo-9-dihydromakomakine (10-5 M) decreased the contractile response to tetraethylammonium (a voltage-dependent potassium channels blocker; TEA; 5 × 10-3 M; p < 0.01) and BaCl2 (a non-selective inward rectifier potassium channel blocker; 5 × 10-3 M; p < 0.001) in rat aorta. 8-oxo-9-dihydromakomakine (10-5 M) decreased the contractile response to PE in rat aorta in the presence or absence of ouabain (an inhibitor of Na,K-ATPase; 10-3 M; p < 0.05). These results could indicate that 8-oxo-9-dihydromakomakine partially reduces plasma membrane depolarization-induced contraction. In aortic rings depolarized by PE, 8-oxo-9-dihydromakomakine inhibited the contraction induced by the influx of extracellular Ca2+ in a Ca2+ free solution (p < 0.01). 8-oxo-9-dihydromakomakine reduced the contractile response to agonists of voltage-dependent calcium channels type L (Bay K6844; 10-8 M; p < 0.01), likely decreasing the influx of extracellular Ca2+ through the voltage-dependent calcium channels. This study provides the first qualitative analysis indicating that traditional folk medicine Aristotelia chilensis may be protective in the treatment of cardiovascular pathologies.
Assuntos
Aorta Torácica/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Magnoliopsida/química , Vasodilatadores/farmacologia , Animais , Aorta Torácica/fisiologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Alcaloides Indólicos/química , Masculino , Ouabaína/farmacologia , Fenilefrina/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Vasodilatação , Vasodilatadores/químicaRESUMO
1-Nitro-2-phenylethene (NPe) induces a more potent vasorelaxant effect in rat aorta than its structural analog 1-nitro-2-phenylethane, but mediated through a different mechanism, independent of soluble guanylate cyclase (sGC) stimulation. We hypothesized that introducing an electron donor into the aromatic moiety might stabilize NPe, enhancing its potency and/or interaction with sGC. Therefore, trans-4-methoxy-ß-nitrostyrene (T4MN) was synthesized, and mechanisms underlying its vasorelaxant effects were studied in rat aortic ring preparations. In endothelium-intact preparations, T4MN fully relaxed contractions induced by phenylephrine (PHE) with a potency similar to that of its parent drug, NPe. This vasorelaxant effect that was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, or MDL-12,330A, but was significantly reduced by tetraethylammonium, 4-aminopyridine, methyl blue, or ODQ. Under Ca2+-free conditions, T4MN did not alter contractions evoked by caffeine, but significantly reduced, in an ODQ-preventable manner, those induced by either PHE or extracellular Ca2+ restoration following depletion of intracellular Ca2+ stores in thapsigargin-treated aortic preparations. Under the same conditions, T4MN also reduced contractions induced by protein kinase C activator phorbol-12,13-dibutyrate with a potency similar to that evoked by this nitroderivative against PHE-induced contractions. In conclusion, T4MN induces potent vasorelaxation in rat aorta by stimulating the sGC-cGMP pathway through a NO-independent mechanism. Introduction of a methoxy group into the aromatic moiety apparently stabilizes NPe, thereby enhancing its interaction with sGC.
Assuntos
Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Guanilato Ciclase/química , Guanilato Ciclase/metabolismo , Estirenos/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/citologia , Aorta Torácica/metabolismo , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Masculino , Fenilefrina/farmacologia , Canais de Potássio/metabolismo , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Solubilidade , Estirenos/síntese química , Vasoconstrição/efeitos dos fármacosRESUMO
Mechanisms underlying the vasorelaxant effects of trans-4-methyl-ß-nitrostyrene (T4MeN) were studied in rat aortic rings. In endothelium-intact preparations, T4MeN fully and similarly relaxed contractions induced by phenylephrine (PHE) (IC50 = 61.41 [35.40-87.42] µmol/L) and KCl (IC50 = 83.50 [56.63-110.50] µmol/L). The vasorelaxant effect of T4MeN was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, tetraethylammonium, ODQ or MDL-12,330A. Under Ca2+ -free conditions, T4MeN significantly reduced with a similar potency: (i) phasic contractions induced by PHE, but not by caffeine; (ii) contractions due to CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil) or high KCl; (iii) contractions evoked by the restoration of external Ca2+ levels after depletion of intracellular Ca2+ stores in the presence of thapsigargin. In contrast, T4MeN was more potent at inhibiting contractions evoked by the tyrosine phosphatase inhibitor, sodium orthovanadate, than those induced by the activator of PKC, phorbol-12,13-dibutyrate. These results suggest that T4MeN induces an endothelium- independent vasorelaxation that appears to occur intracellularly through the inhibition of contractions that are independent of Ca2+ influx from the extracellular milieu but involve phosphorylation of tyrosine residues.
Assuntos
Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Estirenos/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/síntese química , Vasodilatadores/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Técnicas de Química Sintética , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Dibutirato de 12,13-Forbol/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Estirenos/química , Vanadatos/farmacologia , Vasodilatadores/químicaRESUMO
OBJECTIVES: Little is known about the relation of pubertal development on endothelial function and arterial elasticity in children and adolescents; therefore, we compared brachial artery flow-mediated dilation and carotid artery elasticity across Tanner (pubertal) stages in children and adolescents. STUDY DESIGN: Blood pressure, fasting lipids, glucose and insulin, body fat, insulin sensitivity adjusted for lean body mass, brachial flow-mediated dilation (percent dilation and area under the curve), endothelium-independent dilation (peak dilation and area under the curve), and carotid artery elasticity were evaluated across pubertal stages (Tanner I vs Tanner II-IV vs Tanner V) in 344 children and adolescents (184 males, 160 females; ages 6 to 21 years). RESULTS: One hundred twenty-four subjects (mean age 8.23 ± 0.15 years; 52 females) were Tanner stage I; 105 subjects (mean age 13.19 ± 0.17 years; 47 females) were Tanner stages II-IV; and 115 subjects (mean age 17.19 ± 0.16 years; 61 females) were Tanner stage V. There were no significant differences for any of the measures of vascular structure and function across pubertal stages. CONCLUSION: Results of the current study indicate that smooth-muscle and endothelial function, as well as carotid artery elasticity, do not differ throughout pubertal development and that accounting for pubertal stage when reporting vascular data in children and adolescents may be unnecessary.
Assuntos
Velocidade do Fluxo Sanguíneo , Artéria Braquial/fisiologia , Artéria Carótida Primitiva/fisiologia , Endotélio Vascular/fisiologia , Puberdade , Tecido Adiposo , Adolescente , Área Sob a Curva , Glicemia/metabolismo , Pressão Sanguínea , Composição Corporal/fisiologia , Criança , Estudos Transversais , Elasticidade , Feminino , Humanos , Insulina/sangue , Lipídeos/sangue , Masculino , Adulto JovemRESUMO
The relaxant effect of the methyl ester of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g, 6 rats for each experimental group) with and without endothelium precontracted with 1.0 µM phenylephrine. The methyl ester presented a slightly greater potency than rosuvastatin in relaxing aortic rings, with log IC50 values of -6.88 and -6.07 M, respectively. Unlike rosuvastatin, the effect of its methyl ester was endothelium-independent. Pretreatment with 10 µM indomethacin did not inhibit, and pretreatment with 1 mM mevalonate only modestly inhibited the relaxant effect of the methyl ester. Nω-nitro-L-arginine methyl ester (L-NAME, 10 µM), the selective nitric oxide-2 (NO-2) inhibitor 1400 W (10 µM), tetraethylammonium (TEA, 10 mM), and cycloheximide (10 µM) partially inhibited the relaxant effect of the methyl ester on endothelium-denuded aortic rings. However, the combination of TEA plus either L-NAME or cycloheximide completely inhibited the relaxant effect. Inducible NO synthase (NOS-2) was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with methyl ester-treated rings. In conclusion, whereas rosuvastatin was associated with a relaxant effect dependent on endothelium and hydroxymethylglutaryl coenzyme A reductase in rat aorta, the methyl ester of rosuvastatin exhibited an endothelium-independent and only slightly hydroxymethylglutaryl coenzyme A reductase-dependent relaxant effect. Both NO produced by NOS-2 and K+ channels are involved in the relaxant effect of the methyl ester of rosuvastatin.