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1.
Int. j. morphol ; 38(1): 215-221, Feb. 2020. graf
Article in English | LILACS | ID: biblio-1056424

ABSTRACT

The potential inhibitory effect of the insulin mimicking agent, vanadium on type 2 diabetes mellitus (T2DM)induced alterations to the aorta ultrastructure associated with the suppression of dyslipedima and biomarkers of inflammation has not been investigated before. Therefore, we tested whether vanadium can protect against aortic injury induced secondary to T2DM possibly via the inhibition of blood lipid and inflammatory biomarkers. T2DM was induced in rats by a high-fat diet and streptozotocin (50 mg/ kg), and the treatment group started vanadium treatment five days post diabetic induction and continued until being sacrificed at week 10. Using light and electron microscopy examinations, we observed in the model group substantial damage to the aorta tissue such as damaged endothelium, degenerative cellular changes with vacuolated cytoplasm and thickened internal elastic lamina that were substantially ameliorated by vanadium. Administration of vanadium to diabetic rats also significantly (p<0.05) reduced blood levels of glucose, hyperlipidemia and biomarkers of inflammation (TNF-a, IL-6). We conclude that vanadium protects against T2DM-induced aortic ultrastructural damage in rats, which is associated with the inhibition of blood sugar and lipid and inflammatory biomarkers.


El potencial efecto inhibidor del agente imitador de la insulina, el vanadio en las alteraciones inducidas por la diabetes mellitus tipo 2 (DM2) en la ultraestructura de la aorta, asociada con la supresión de dislipidemia y los biomarcadores de inflamación no se ha investigado anteriormente. El objetivo fue estudiar las propiedades del vanadio para proteger contra la lesión aórtica inducida a la DM2, a través de la inhibición de los lípidos sanguíneos y los biomarcadores inflamatorios. La DM2 fue inducida en ratas con una dieta alta en grasas y estreptozotocina (50 mg / kg), y el grupo de tratamiento fue sometido a un régimen continuo con vanadio, cinco días después de la inducción diabética hasta ser sacrificadas en la semana 10. Se utilizaron exámenes de luz y microscopía electrónica en el grupo modelo y se observó un daño sustancial al tejido de la aorta, como también en el endotelio; los cambios celulares degenerativos con citoplasma vacuolado y lámina elástica interna engrosada mejoró sustancialmente con vanadio. La administración de vanadio a ratas diabéticas también redujo significativamente (p <0,05) los niveles sanguíneos de la glucosa, hiperlipidemia y los biomarcadores de inflamación (TNFa, IL-6). En conclusión, el vanadio protege contra el daño ultraestructural aórtico inducido por T2DM en ratas, que es asociado con la inhibición del azúcar en la sangre y los biomarcadores de lípidos y de inflamatorios.


Subject(s)
Animals , Male , Rats , Aorta/drug effects , Vanadium/administration & dosage , Diabetes Mellitus, Type 2/complications , Aorta/injuries , Aorta/ultrastructure , Aortic Diseases/etiology , Vanadium/pharmacology , Rats, Sprague-Dawley , Microscopy, Electron, Transmission , Disease Models, Animal , Dyslipidemias/drug therapy , Inflammation/drug therapy
2.
Braz. j. med. biol. res ; 53(2): e9304, 2020. tab, graf
Article in English | LILACS | ID: biblio-1055489

ABSTRACT

Metabolic syndrome is a multifaceted condition associated with a greater risk of various disorders (e.g., diabetes and heart disease). In a rat model of metabolic syndrome, an acute in vitro application of rosuvastatin causes relaxation of aortic rings. Since the outcome of a subchronic rosuvastatin treatment is unknown, the present study explored its effect on acetylcholine-induced vasorelaxation of aortic rings from rats with metabolic syndrome. Animals were submitted to a 16-week treatment, including a standard diet, a cafeteria-style diet (CAF-diet), or a CAF-diet with daily rosuvastatin treatment (10 mg/kg). After confirming the development of metabolic syndrome in rats, aortic segments were extracted from these animals (those treated with rosuvastatin and untreated) and the acetylcholine-induced relaxant effect on the corresponding rings was evaluated. Concentration-response curves were constructed for this effect in the presence/absence of L-NAME, ODQ, KT 5823, 4-aminopyridine (4-AP), tetraethylammonium (TEA), apamin plus charybdotoxin, glibenclamide, indomethacin, clotrimazole, and cycloheximide pretreatment. Compared to rings from control rats, acetylcholine-induced vasorelaxation decreased in rings from animals with metabolic syndrome, and was maintained at a normal level in animals with metabolic syndrome plus rosuvastatin treatment. The effect of rosuvastatin was inhibited by L-NAME, ODQ, KT 5823, TEA, apamin plus charybdotoxin, but unaffected by 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. In conclusion, the subchronic administration of rosuvastatin to rats with metabolic syndrome improved the acetylcholine-induced relaxant response, involving stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.


Subject(s)
Animals , Male , Rats , Aorta/drug effects , Vasodilation/drug effects , Endothelium, Vascular/drug effects , Acetylcholine/pharmacology , Metabolic Syndrome/physiopathology , Rosuvastatin Calcium/pharmacology , Vasodilator Agents , Endothelium, Vascular/physiopathology , Rats, Wistar , Disease Models, Animal
3.
Bol. latinoam. Caribe plantas med. aromát ; 18(2): 204-222, mar. 2019. ilus
Article in English | LILACS | ID: biblio-1007819

ABSTRACT

To explore the mechanistic basis behind smooth muscle relaxant prospective of Bismarckia nobilis in gastrointestinal, respiratory and cardiovascular ailments. The methanolic extract of B. nobilis and sub-fractions have been evaluated in vitro rabbit isolated tissues, in vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice. The B. nobilis extract relaxed spontaneous and K+(80 mM)- induced contractions in rabbit isolated jejunum preparations, CCh (1 µM) and K+ (80 mM)-induced contractions in tracheal and bladder preparations, PE (1 µM) and K+ (80 mM)-induced concentrations in aorta preparations, likewise verapamil. Spasmolytic activity of dichloromethane fraction is stronger as compared to aqueous fraction. In vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice further supported spasmolytic activity. B. nobilis extract possess anti-spasmodic, anti-diarrheal, airway relaxant and vasodilator activities possible mediated through calcium channel blocking mechanism, justifying therapeutic utility of B. nobilis in diarrhea, asthma and hypertension.


El objetivo de trabajo fue explorar el mecanismo de acción relacionado con el efecto relajante del músculo liso inducido por Bismarckia nobilis (B. nobilis) en enfermedades gastrointestinales, respiratorias y cardiovasculares. El extracto metanólico de B. nobilis y subfracciones fue evaluado in vitro en tejidos aislados de conejos. Además se evaluó diarrea in vivo inducida con aceite de ricino en ratas y la actividad de harina de carbón vegetal en ratones. El extracto de B. nobilis relajó tanto las contracciones espontáneas como las inducidas por K+(80 mM) en preparaciones de yeyuno aisladas de conejos, las contracciones inducidas por PE (1 µM) y K+(80 mM) inducidas en preparaciones de aorta; de manera similar a verapamilo. La actividad espasmolítica de la fracción de diclorometano es más potente en comparación con la fracción acuosa. La diarrea inducida in vivo por el aceite de ricino en ratas y la actividad de la harina de carbón vegetal en ratones apoyaron aún más la actividad espasmolítica. El extracto de B. nobilis posee actividades antiespasmódicas, antidiarreicas, relajantes de las vías respiratorias y vasodilatadoras, posibles a través del mecanismo de bloqueo de los canales de calcio, lo que justifica la utilidad terapéutica de B. nobilis en la diarrea, el asma y la hipertensión.


Subject(s)
Animals , Rabbits , Rats , Plant Extracts/pharmacology , Anti-Asthmatic Agents/pharmacology , Arecaceae , Antidiarrheals/pharmacology , Antihypertensive Agents/pharmacology , Aorta/drug effects , Asthma/metabolism , Trachea/drug effects , Calcium Channel Blockers/pharmacology , Diarrhea/metabolism , Methanol , Hypotension/metabolism , Jejunum/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects
4.
Clin. biomed. res ; 38(2): 141-150, 2018.
Article in Portuguese | LILACS | ID: biblio-1025547

ABSTRACT

Introdução: Os anticoncepcionais orais vêm sofrendo alterações em suas concentrações de estrogênio e progestogênio, baseando-se no fato de que doses mais baixas estão associadas a menor incidência de alterações metabólicas e de efeitos adversos, como o comprometimento da morfologia e função da artéria aorta. O objetivo deste estudo é avaliar a influência dos anticoncepcionais nas propriedades morfofuncionais da artéria aorta, através do método histoquímico, demonstrando sua utilidade nas análises histopatológicas. Métodos: Para tanto, foram utilizadas 15 ratas divididas em 3 grupos; Grupo controle (GC), cujos animais não receberam tratamento hormonal; Grupo 2 (G2), onde os animais receberam tratamento diário de 15 µg de etinilestradiol + 60 µg de gestodeno; e Grupo 3 (G3), que recebeu 30 µg de etinilestradiol + 75 µg de gestodeno. Após o tratamento, os animais foram eutanasiados e as artérias retiradas para análise histológica. Resultados: Os valores encontrados com a técnica de coloração histológica de hematoxilina e eosina (HE), bem como na coloração específica em histoquímica com Alcian Blue, demonstram que no G3, tratados com uma dosagem superior de hormônio, 8% das ratas tem aumento relevante da espessura de suas artérias, ou seja, superior ao G2, que recebeu dosagem menor de hormônio, e GC, o qual não recebeu nenhum tipo de tratamento. Conclusão: Este estudo demonstra que existem relações entre o espessamento das artérias, de ratas submetidas a dosagens de etinilestradiol e gestodeno, com a grande quantidade de mucopolissacarídeos depositados entre as túnicas das artérias. (AU)


Introduction: Pharmacological development of hormonal contraceptives has been undergoing changes in estrogen and progesterone doses, based on the fact that lower doses are associated with a lower incidence of metabolic changes and adverse effects, such as impairment of morphology and function of the aortic artery. The aim of this study is to evaluate the influence of contraceptives on the morphofunctional properties of the aortic artery, using the histochemical method, demonstrating its usefulness in histopathological analyzes. Methods: For this purpose, 15 rats were divided into 3 groups; Control group (GC), whose animals did not receive hormonal treatment; Group 2 (G2), where the animals received a daily treatment of 15 µg of ethinylestradiol + 60 µg of gestodene; and Group 3 (G3), whose animals received 30 µg of ethinylestradiol + 75 µg of gestodene. After treatment, the animals were sacrificed and the arteries removed for histologic analysis. Results: The values found, with HE measurements and Alcian Blue histochemical staining, showed that in G3, treated with a higher hormone dosage, there are 8% of the rats with a relevant increase in the thickness of their arteries, that is, higher than that of G2, which received lower dosage of hormone and that of GC, which received no treatment. Conclusion: This study demonstrates that there are relations between the thickening of the arteries of rats submitted to dosages of ethinylestradiol and gestodene with the great amount of mucopolysaccharides deposited between the tunics of the arteries. (AU)


Subject(s)
Animals , Female , Rats , Aorta/drug effects , Aorta/physiopathology , Ethinyl Estradiol/adverse effects , Ethinyl Estradiol/pharmacology , Rats , Contraceptives, Oral/adverse effects , Disease Models, Animal
5.
Arq. bras. cardiol ; 108(4): 315-322, Apr. 2017. graf
Article in English | LILACS | ID: biblio-838719

ABSTRACT

Abstract Background: The practice of exercise in short bouts repeated throughout the day may be an alternative strategy to lift people out of physical inactivity. Objective: to evaluate if accumulated exercise, as occurs in continuous exercise training, improve endothelial function in rat aorta. Methods: Wistar male rats were divided into three groups: continuous exercise (CEx, 1 hour on the treadmill) or accumulated exercise (AEx, 4 bouts of 15 minutes / day) for 5 days/week for 8 weeks, or sedentary (SED). During the training period, body weight gain and increase in exercise performance were recorded. On sacrifice day, aorta was dissected into rings (3-5 mm) and mounted on the organ bath. Results: Fitness was significantly greater in CEx and AEx rats as compared with SED animals. In addition, compared with the SED group, CEx animals had a lower body mass gain, and the aorta obtained from these animals had reduced contractile response to norepinephrine and greater acetylcholine-induced relaxation. These results were not observed in ACEx animals. Conclusions: Both CEx and AEx improved fitness, but only CEx led to reduced body weight gain and improved endothelial function.


Resumo Fundamento: A prática de exercícios em sessões curtas que se repetem ao longo do dia pode ser uma alternativa para tirar as pessoas da inatividade física. Objetivo: Verificar se o exercício acumulado, tal como ocorre com o treinamento com exercício contínuo, melhora a função endotelial na aorta de ratos. Métodos: Ratos Wistar machos foram divididos em 3 grupos: treinamento com exercício contínuo (ExC; 1 hora em esteira) ou com exercício acumulado (ExA; 4 sessões de 15 minutos ao longo do dia) por 5 dias/semana, durante 8 semanas, ou grupo sedentário (SED). Durante o treinamento, foram registrados o ganho de peso corporal e desempenho na esteira. No dia do sacrifício, anéis (3-5 mm) da aorta foram obtidos e montados em banho de órgãos. Resultados: Animais ExC e ExA mostraram aptidão física significativamente maior em comparação com os SED. Paralelamente, em comparação com SED, animais ExC tiveram menor ganho de massa corporal, e aortas retiradas desses animais mostraram respostas contrácteis à noradrenalina reduzidas e maior relaxamento induzido pela acetilcolina. Esses resultados não foram observados no grupo ExA. Conclusões: Tanto o ExC quanto o ExA melhoraram a aptidão física, mas somente o ExC foi capaz de reduzir o ganho de peso corporal dos animais e melhorar a função endotelial.


Subject(s)
Animals , Male , Aorta/physiology , Physical Conditioning, Animal/methods , Endothelium, Vascular/physiology , Physical Fitness/physiology , Aorta/drug effects , Physical Conditioning, Animal/physiology , Vasoconstrictor Agents/pharmacology , Endothelium, Vascular/drug effects , Weight Loss/physiology , Acetylcholine/pharmacology , Random Allocation , Norepinephrine/pharmacology , Thiobarbituric Acid Reactive Substances/analysis , Rats, Wistar , Models, Animal
6.
Pakistan Journal of Pharmaceutical Sciences. 2017; 30 (1): 199-203
in English | IMEMR | ID: emr-185759

ABSTRACT

The aim of this experimental work was to explore the potential pharmacological activities of Gaultheria trichophylla Royle in hyperactive respiratory and vascular conditions. Gaultheria trichophylla was extracted with solvents, phytochemical detection tests were performed, and rabbit trachea and aorta strips were used to evaluate its effects on airways and vascular smooth muscles. Qualitative phytochemical tests showed the presence of flavonoids, alkaloids, anthraquinones, saponins, terpenoids, and condensed tannins. The methanol extract caused inhibition [EC[50] values of 3.12 mg/mL] of carbachol [1 micro M] and partial relaxation of K[+][80 mM] caused contractions in tracheal strips. The chloroform extract was comparatively more potent against carbachol than K[+] induced contraction with EC[50] values of 0.64 and 2.26 mg/mL, respectively. However, the n-hexane extract showed more potency against K[+] than cabachol induced contractions, as in case with verapamil, with EC[5]0 values of 0.61 and 6.58 mg/mL, respectively. In isolated prepared trachea, the extracts displaced the carbachol concentration response curves and maximum response was suppressed. In rabbit aorta preparations, methanol and n-hexane extracts partially relaxed phenylephrine [1 micro M] and K[+] induced vasoconstrictions. However, the chloroform extract inhibited phenylephrine induced contractions and exhibited a vasoconstrictor effect at lower concentrations and a relaxant effect at higher concentrations against K[+] precontractions. The data indicates that, in addition to others, the extracts of G .trichophylla possess verapamil like Ca[++] channel blocking components which explain the possible role of this plant in respiratory and vascular conditions


Subject(s)
Adult , Animals, Laboratory , Female , Male , Phytochemicals/pharmacology , Phytotherapy , Plants, Medicinal , Muscle, Smooth, Vascular/drug effects , Aorta/drug effects , Calcium Channel Blockers
8.
Professional Medical Journal-Quarterly [The]. 2012; 19 (3): 341-345
in English | IMEMR | ID: emr-131441

ABSTRACT

To evaluate the effect of tocotrienols on intimal thickening in ascending aorta of cholesterol-fed rabbits. Randomized control trial. The Anatomy department of Army Medical College, Rawalpindi, from March 2009 to February 2010. Thirty, male, New Zealand white rabbits were randomly divided into three equal groups. Group- I was fed normal lab diet for six weeks. For the similar period, group-II and III were given 2% high cholesterol diet. However, group-III diet was also supplemented with tocotrienols [6 mg/kg body weight/day]. By the end of study, aorta was removed from each animal. Cross sections from ascending aorta were processed and embedded in paraffin. Light microscopic examination was performed in H and E and Verhoeff elastic stained slides. Tunica intima in group-I appeared as single layer of squamous endothelial cells, lying on a thin layer of loose connective tissue. High cholesterol diet in group-II induced marked atherosclerotic changes which were characterized by extensive intimal thickening with raised fatty streaks, pools of extracellular lipids, proliferation of smooth muscles and deposition of connective tissue matrix. Intimal thickening was also observed in group-III, but lesions were of lesser degree than group-II [P<0.05]. Histomorphometric analysis revealed significantly [P<0.001] higher thickness of intima in group-II and in group-III when either was compared with group-I. However, thickness of intima was 35% lesser [P<0.05] in group-III than group-II. Tocotrienols has significant potential in suppressing the intimal thickening of aorta in cholesterol-fed rabbits


Subject(s)
Male , Animals, Laboratory , Tunica Intima/drug effects , Aorta/drug effects , Rabbits , Cholesterol , Random Allocation , Microscopy, Polarization , Atherosclerosis
9.
Article in English | WPRIM | ID: wpr-194084

ABSTRACT

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an important role in vascular functions, including vasorelaxation. We here investigated the pharmacological effect of the natural product syringaresinol on vascular relaxation and eNOS-mediated NO production as well as its underlying biochemical mechanism in endothelial cells. Treatment of aortic rings from wild type, but not eNOS-/- mice, with syringaresinol induced endothelium-dependent relaxation, which was abolished by addition of the NOS inhibitor NG-monomethyl-L-arginine. Treatment of human endothelial cells and mouse aortic rings with syringaresinol increased NO production, which was correlated with eNOS phosphorylation via the activation of Akt and AMP kinase (AMPK) as well as elevation of intracellular Ca2+ levels. A phospholipase C (PLC) inhibitor blocked the increases in intracellular Ca2+ levels, AMPK-dependent eNOS phosphorylation, and NO production, but not Akt activation, in syringaresinol-treated endothelial cells. Syringaresinol-induced AMPK activation was inhibited by co-treatment with PLC inhibitor, Ca2+ chelator, calmodulin antagonist, and CaMKKbeta siRNA. This compound also increased eNOS dimerization, which was inhibited by a PLC inhibitor and a Ca2+-chelator. The chemicals that inhibit eNOS phosphorylation and dimerization attenuated vasorelaxation and cGMP production. These results suggest that syringaresinol induces vasorelaxation by enhancing NO production in endothelial cells via two distinct mechanisms, phosphatidylinositol 3-kinase/Akt- and PLC/Ca2+/CaMKKbeta-dependent eNOS phosphorylation and Ca2+-dependent eNOS dimerization.


Subject(s)
Animals , Aorta/drug effects , Enzyme Activation/drug effects , Furans/pharmacology , Gene Deletion , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Lignans/pharmacology , Mice , Mice, Inbred C57BL , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide Phospholipase C/metabolism , Phosphorylation/drug effects , Protein Multimerization/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Vasodilation/drug effects
10.
Article in English | WPRIM | ID: wpr-110117

ABSTRACT

Cinnamyl alcohol (CAL) is known as an antipyretic, and a recent study showed its vasodilatory activity without explaining the mechanism. Here we demonstrate the vasodilatory effect and the mechanism of action of CAL in rat thoracic aorta. The change of tension in aortic strips treated with CAL was measured in an organ bath system. In addition, vascular strips or human umbilical vein endothelial cells (HUVECs) were used for biochemical experiments such as Western blot and nitrite and cyclic guanosine monophosphate (cGMP) measurements. CAL attenuated the vasoconstriction of phenylephrine (PE, 1 microM)-precontracted aortic strips in an endothelium-dependent manner. CAL-induced vasorelaxation was inhibited by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; 10(-4) M), methylene blue (MB; 10(-5) M) and 1 H-[1,2,4]-oxadiazolole-[4,3-a] quinoxalin-10one, (ODQ; 10(-6) or 10(-7) M) in the endothelium-intact aortic strips. Atrial natriuretic peptide (ANP; 10(-8) or 10(-9) M) did not affect the vasodilatory effect of CAL. The phosphorylation of endothelial nitric oxide synthase (eNOS) and generation of nitric oxide (NO) were stimulated by CAL treatment in HUVECs and inhibited by treatment with L-NAME. In addition, cGMP and PKG1 activation in aortic strips treated with CAL were also significantly inhibited by L-NAME. Furthermore, CAL relaxed Rho-kinase activator calpeptin-precontracted aortic strips, and the vasodilatory effect of CAL was inhibited by the ATP-sensitive K+ channel inhibitor glibenclamide (Gli; 10(-5) M) and the voltage-dependent K+ channel inhibitor 4-aminopyridine (4-AP; 2 x 10(-4) M). These results suggest that CAL induces vasorelaxation by activating K+ channels via the NO-cGMP-PKG pathway and the inhibition of Rho-kinase.


Subject(s)
Animals , Aorta/drug effects , Atrial Natriuretic Factor/pharmacology , Cyclic GMP/metabolism , Cyclic GMP-Dependent Protein Kinases/metabolism , Dipeptides/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Male , Methylene Blue/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Oxadiazoles/pharmacology , Phenylephrine/pharmacology , Phosphorylation , Potassium Channel Blockers/pharmacology , Potassium Channels/agonists , Propanols/pharmacology , Quinoxalines/pharmacology , Rats , Rats, Sprague-Dawley , Signal Transduction , Vasoconstriction/drug effects , Vasodilation/drug effects , rho-Associated Kinases/antagonists & inhibitors
11.
Braz. j. med. biol. res ; 44(5): 438-444, May 2011. ilus
Article in English | LILACS | ID: lil-586505

ABSTRACT

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.


Subject(s)
Animals , Male , Rats , Aorta/drug effects , Endothelium, Vascular/drug effects , Fluorobenzenes/pharmacology , Hydroxymethylglutaryl CoA Reductases/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Pyrimidines/pharmacology , Sulfonamides/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology , Aorta/enzymology , Cycloheximide/pharmacology , Fluorobenzenes/chemistry , Nitric Oxide Synthase Type II/pharmacology , Pyrimidines/chemistry , Rats, Wistar , Sulfonamides/chemistry , Tetraethylammonium/pharmacology , Vasodilation/physiology
12.
Braz. j. med. biol. res ; 44(5): 445-452, May 2011. ilus, tab
Article in English | LILACS | ID: lil-586508

ABSTRACT

Gadolinium (Gd) blocks intra- and extracellular ATP hydrolysis. We determined whether Gd affects vascular reactivity to contractile responses to phenylephrine (PHE) by blocking aortic ectonucleoside triphosphate diphosphohydrolase (E-NTPDase). Wistar rats of both sexes (260-300 g, 23 females, 7 males) were used. Experiments were performed before and after incubation of aortic rings with 3 µM Gd. Concentration-response curves to PHE (0.1 nM to 0.1 mM) were obtained in the presence and absence of endothelium, after incubation with 100 µM L-NAME, 10 µM losartan, or 10 µM enalaprilat. Gd significantly increased the maximum response (control: 72.3 ± 3.5; Gd: 101.3 ± 6.4 percent) and sensitivity (control: 6.6 ± 0.1; Gd: 10.5 ± 2.8 percent) to PHE. To investigate the blockade of E-NTDase activity by Gd, we added 1 mM ATP to the bath. ATP reduced smooth muscle tension and Gd increased its relaxing effect (control: -33.5 ± 4.1; Gd: -47.4 ± 4.1 percent). Endothelial damage abolished the effect of Gd on the contractile responses to PHE (control: 132.6 ± 8.6; Gd: 122.4 ± 7.1 percent). L-NAME + Gd in the presence of endothelium reduced PHE contractile responses (control/L-NAME: 151.1 ± 28.8; L-NAME + Gd: 67.9 ± 19 percent AUC). ATP hydrolysis was reduced after Gd administration, which led to ATP accumulation in the nutrient solution and reduced ADP concentration, while adenosine levels remained the same. Incubation with Gd plus losartan and enalaprilat eliminated the pressor effects of Gd. Gd increased vascular reactivity to PHE regardless of the reduction of E-NTPDase activity and adenosine production. Moreover, the increased reactivity to PHE promoted by Gd was endothelium-dependent, reducing NO bioavailability and involving an increased stimulation of angiotensin-converting enzyme and angiotensin II AT1 receptors.


Subject(s)
Animals , Female , Male , Rats , Aorta/drug effects , Gadolinium/pharmacology , Phenylephrine/pharmacology , Vasoconstriction/drug effects , Vasodilation/drug effects , Antihypertensive Agents/pharmacology , Aorta/physiology , Dose-Response Relationship, Drug , Enalaprilat/pharmacology , Endothelium, Vascular/drug effects , Losartan/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Rats, Wistar , Vasoconstriction/physiology , Vasodilation/physiology
13.
Invest. clín ; 51(4): 467-477, dic. 2010. ilus
Article in Spanish | LILACS | ID: lil-630905

ABSTRACT

La disfunción endotelial (DE) se presenta en pacientes con hipercolesterolemia, hipertensión arterial, obesidad y diabetes mellitus. Evidencias sugieren un papel de los glicosaminoglicanos en la DE. Evaluamos el efecto del sulodexide (SLD), un glicosaminoglicano utilizado en el tratamiento de la albuminuria y la enfermedad isquémica en pacientes diabéticos, sobre la relajación arterial y los cambios morfológicos en un modelo experimental de diabetes tipo 1. La diabetes se indujo a ratas Sprague Dawley administrando estreptozotocina (STZ), 60 mg/kg, i.v. Los animales fueron distribuidos en los siguientes grupos: I= control, II= diabéticas, III: control + sulodexide, IV= diabéticas + sulodexide (15 mg/kg/día s.c). A los 3 meses fueron sacrificados, las aortas extraídas para evaluar la relajación vascular inducida por acetilcolina (Ach) y nitroprusiato de sodio en anillos precontraídos con fenilefrina. Fueron evaluadas histológicamente mediante microscopía de luz y coloraciones diversas. El SLD in vitro no modificó la tensión basal de los anillos arteriales en reposo o precontraídos con fenilefrina. La diabetes disminuyó la capacidad de relajación arterial en respuesta a la Ach en un 28,8-35,1% vs control, efecto que fue prevenido por SLD. No se observó diferencia significativa en la relajación inducida por nitroprusiato sódico entre los grupos. El estudio histológico en los animales diabéticos mostró alteraciones estructurales, particularmente en la íntima y la adventicia, cambios que fueron prevenidos por el tratamiento con SLD. Nuestros resultados apoyan la potencial utilidad terapéutica del SLD en el tratamiento de la disfunción endotelial.


Endothelial dysfunction (ED) is observed in patients with hypercholesterolemia, arterial hypertension, obesity and diabetes mellitus. Recent evidences suggest the involvement of glycosaminoglycans(GSG) in ED. We evaluated the effect of sulodexide (SLD), a natural GSG used in albuminuria and ischemic diabetes treatment, on arterial relaxation and vascular morphological changes in a diabetic type I model. Diabetes was induced, in Sprague-Dawley rats by streptozotocine (STZ) administration, 60 mg, iv. Rats were divided into four groups; I: control, II: diabetics, III: control + SLD, IV: diabetics treated with SLD (15 mg/day). After three months, phenylephrine precontracted aortic rings were used to evaluate acetylcholine (ACh) and sodium nitroprusside (NPS) relaxation capacities. Light microscopy of aorta was done with several staining procedures. In vitro, SLD did not change smooth muscle tone in resting or phenylephrine precontracted aortic rings. In diabetic rats, ACh relaxation was 28.8-35.1% lower than in control rats. Diabetic rats treated with SLD showed aortic ACh relaxation similar to control rats. No significative statistical difference was found in endothelium-independent NPS relaxation, between the different groups. Light microscopy histological studies revealed important morphological alterations, particularly in intima and adventitia layers of aortic artery; those changes were dramatically reversed in SLD treated rats. Our experiments support the conclusion that SLD is a potential drug for improving endothelial dysfunction in diabetes.


Subject(s)
Animals , Male , Rats , Aorta/drug effects , Aortic Diseases/prevention & control , Diabetes Mellitus, Experimental/drug therapy , Diabetic Angiopathies/prevention & control , Endothelium, Vascular/drug effects , Glycosaminoglycans/therapeutic use , Hypoglycemic Agents/therapeutic use , Vasodilation/drug effects , Acetylcholine/pharmacology , Aorta/pathology , Aorta/physiopathology , Aortic Diseases/etiology , Aortic Diseases/pathology , Aortic Diseases/physiopathology , Drug Evaluation, Preclinical , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/physiopathology , Diabetic Angiopathies/etiology , Diabetic Angiopathies/pathology , Diabetic Angiopathies/physiopathology , Endothelium, Vascular/ultrastructure , Glycosaminoglycans/metabolism , Glycosaminoglycans/pharmacology , Hypoglycemic Agents/pharmacology , Nitroprusside/pharmacology , Rats, Sprague-Dawley , Tunica Intima/drug effects , Tunica Intima/ultrastructure
14.
Iranian Journal of Basic Medical Sciences. 2010; 13 (1): 195-201
in English | IMEMR | ID: emr-93112

ABSTRACT

Four novel losartan analogues 5a-d were synthesized by connecting a dihydropyridine nucleus to imidazole ring. The effects of 5a and 5b on angiotensin receptors [AT1] and L-type calcium channels were investigated on isolated rat aorta. Aortic rings were pre-contracted with 1 microM Angiotensin II or 80 mM KC1 and relaxant effects of losartan, nifedipine, 5a and 5b were evaluated by cumulative addition of these drugs to the bath solution. The results showed that compounds 5a and 5b have both L-type calcium channel and AT1 receptor blocking activity. Their effects on AT1 receptors are 1000 and 100, 000 times more than losartan respectively. The activity of compound 5b on L-type calcium channel is significantly less than nifedipine but compound 5a has comparable effect with nifedipine. Finally we concluded that these two new Compounds can be potential candidates to be used as effective antihypertensive agents


Subject(s)
Animals, Laboratory , Antihypertensive Agents , Calcium Channel Blockers , Angiotensins , Aorta/drug effects , Rats , Treatment Outcome
15.
Arab Journal of Pharmaceutical Sciences. 2010; 4 (2): 91-98
in Arabic | IMEMR | ID: emr-98776

ABSTRACT

The vasodilator effect of Pelargonium odoratissimum was investigated using isolated rat aortic rings. Eethanolic extract has shown a profound relaxing effect on noradrenaline-precontracted aortic rings. There was a difference in the effect in the absence or presence of endothelium. Relaxing effect of the ethanolic extract was obviously more potent in the presence of endothelium. These data clearly indicate that relaxing effect of Pelargonium odoratissimum is partially endothelium-dependent


Subject(s)
Animals , Aorta/drug effects , Rats , Plant Extracts , Endothelium/drug effects
16.
Article in English | WPRIM | ID: wpr-214627

ABSTRACT

Arginase competitively inhibits nitric oxide synthase (NOS) via use of the common substrate L-arginine. Arginase II has recently reported as a novel therapeutic target for the treatment of cardiovascular diseases such as atherosclerosis. Here, we demonstrate that piceatannol-3'-O-beta-D-glucopyranoside (PG), a potent component of stilbenes, inhibits the activity of arginase I and II prepared from mouse liver and kidney lysates, respectively, in a dose-dependent manner. In human umbilical vein endothelial cells, incubation of PG markedly blocked arginase activity and increased NOx production, as measured by Griess assay. The PG effect was associated with increase of eNOS dimer ratio, although the protein levels of arginase II or eNOS were not changed. Furthermore, isolated mice aortic rings treated with PG showed inhibited arginase activity that resulted in increased nitric oxide (NO) production upto 78%, as measured using 4-amino-5-methylamino-2',7'-difluorescein (DAF-FM) and a decreased superoxide anions up to 63%, as measured using dihydroethidine (DHE) in the intact endothelium. PG showed IC50 value of 11.22 microM and 11.06 microM against arginase I and II, respectively. PG as an arginase inhibitor, therefore, represents a novel molecule for the therapy of cardiovascular diseases derived from endothelial dysfunction and may be used for the design of pharmaceutical compounds.


Subject(s)
Animals , Aorta/drug effects , Arginase/antagonists & inhibitors , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Enzyme Activation/drug effects , Glucosides/chemistry , Humans , Mice , Mice, Inbred C57BL , Nitrates/metabolism , Nitric Oxide/biosynthesis , Nitric Oxide Synthase Type III/metabolism , Nitrites/metabolism , Reactive Oxygen Species/metabolism , Rheum/chemistry , Stilbenes/chemistry
17.
Braz. j. med. biol. res ; 42(1): 87-93, Jan. 2009. ilus, tab, graf
Article in English | LILACS | ID: lil-505424

ABSTRACT

Nitric oxide (NO) donors produce NO-related activity when applied to biological systems. Among its diverse functions, NO has been implicated in vascular smooth muscle relaxation. Despite the great importance of NO in biological systems, its pharmacological and physiological studies have been limited due to its high reactivity and short half-life. In this review we will focus on our recent investigations of nitrosyl ruthenium complexes as NO-delivery agents and their effects on vascular smooth muscle cell relaxation. The high affinity of ruthenium for NO is a marked feature of its chemistry. The main signaling pathway responsible for the vascular relaxation induced by NO involves the activation of soluble guanylyl-cyclase, with subsequent accumulation of cGMP and activation of cGMP-dependent protein kinase. This in turn can activate several proteins such as K+ channels as well as induce vasodilatation by a decrease in cytosolic Ca2+. Oxidative stress and associated oxidative damage are mediators of vascular damage in several cardiovascular diseases, including hypertension. The increased production of the superoxide anion (O2-) by the vascular wall has been observed in different animal models of hypertension. Vascular relaxation to the endogenous NO-related response or to NO released from NO deliverers is impaired in vessels from renal hypertensive (2K-1C) rats. A growing amount of evidence supports the possibility that increased NO inactivation by excess O2- may account for the decreased NO bioavailability and vascular dysfunction in hypertension.


Subject(s)
Animals , Rats , Cyclic GMP-Dependent Protein Kinases/drug effects , Muscle, Smooth, Vascular/drug effects , Nitric Oxide Donors/pharmacology , Ruthenium/pharmacology , Aorta/drug effects , Calcium Channels/drug effects , Calcium Channels/physiology , Cyclic GMP-Dependent Protein Kinases/metabolism , Hypertension, Renal/physiopathology , Muscle Relaxation , Muscle, Smooth, Vascular/enzymology , Muscle, Smooth, Vascular/physiopathology , Nitric Oxide/metabolism , Potassium Channels/drug effects , Potassium Channels/physiology , Ruthenium/chemistry , Signal Transduction/drug effects , Time Factors , Vasodilation/drug effects , Vasodilation/physiology
18.
Arab Journal of Pharmaceutical Sciences. 2009; 4 (1): 31-41
in Arabic | IMEMR | ID: emr-134513

ABSTRACT

The vasodilator effect of Achilea was investigated using isolated rabbit aortic rings. Both ethanolic and aqueous extracts have shown a profound relaxing effect on phenyl ephrine-precontracted aortic rings. There was no difference in the effect in the absence or presence of endothelium. Anyway, the ethanolic extract was obviously more potent than aqueous and therefore it was then chosen to continue the study to investigate the role of potassium channels. The K+ channels blockers, Glibenclamide and TEA, partially inhibited the relaxing effect of Achillea. On the other side, the ethanolic extract has also shown a relaxing effect on aortic rings precontracted by high concentration of K[+] ions [35mM]. These data clearly indicate that relaxing effect of Achillea is not endothelium-dependent but it is related to K+ channels


Subject(s)
Animals, Laboratory , Aorta/drug effects , Rabbits , Plant Extracts , Ethanol , Relaxation
19.
Yonsei Medical Journal ; : 414-421, 2009.
Article in English | WPRIM | ID: wpr-110993

ABSTRACT

PURPOSE: Fentanyl was reported to inhibit the alpha1-adrenoceptor agonist-induced contraction. The goal of this in vitro study was to identify the alpha1-adrenoceptor subtype primarily involved in the fentanyl-induced attenuation of phenylephrine-induced contraction in isolated endothelium-denuded rat aorta. MATERIALS AND METHODS: Aortic rings were suspended in order to record isometric tension. Concentration-response curves for phenylephrine (10-9 to 10-5 M) were generated in the presence or absence of one of the following drugs: fentanyl (3x10-7, 10-6, 3x10-6 M), 5-methylurapidil (3x10-8, 10-7, 3x10-7 M), chloroethylclonidine (10-5 M) and BMY 7378 (3x10-9, 10-8, 3x10-8 M). Phenylephrine concentration-response curves were generated in the presence or absence of fentanyl in rings pretreated with either 3x10-9 M prazosin, 10-9 M 5-methylurapidil or 3x10-9 M BMY 7378. RESULTS: Fentanyl (10-6, 3x10-6 M) attenuated phenylephrine-induced contraction in the rat aorta. 5-Methylurapidil and BMY 7378 produced a parallel rightward shift in the phenylephrine concentration-response curve. The pA2 values for 5-methylurapidil and BMY 7378 were estimated to be 7.71 +/- 0.15 and 8.99 +/- 0.24, respectively. Fentanyl (10-6 M) attenuated phenylephrine-induced contraction in rings pretreated with 10-9 M 5-methylurapidil, but did not alter the rings when pretreated with 3x10-9 M BMY 7378. Pretreatment of the rings with chloroethylclonidine showed a 72.9 +/- 2.3% reduction in phenylephrine-induced maximal contraction. CONCLUSION: The results suggest that fentanyl attenuates phenylephrine-induced contraction by inhibiting the pathway involved in the alpha1D-adrenoceptor-mediated contraction of the rat aorta.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Animals , Aorta/drug effects , Clonidine/analogs & derivatives , Fentanyl/pharmacology , Male , Phenylephrine/pharmacology , Piperazines/pharmacology , Rats , Rats, Sprague-Dawley , Vasoconstriction/drug effects
20.
Egyptian Journal of Histology [The]. 2008; 31 (2): 396-405
in English | IMEMR | ID: emr-86284

ABSTRACT

Soya was proposed to improve endothelial dysfunction in ovariectomized rats, perhaps through a mechanism similar to estrogen. The present work aimed at studying the changes in the aorta of ovariectomized rats and demonstrating the comparable effects of soya bean to estrogen replacement therapy [ERT] on the aorta by histological and immunohistochemical methods. Thirty nine female albino rats were divided into four groups. Group I [control], included 9 rats. Group II included 10 ovariectomized rats. Rats of group III were left ovariectomized for six months and received estrogen replacement for two months later. Rats of group IV were left ovariectomized for six months and received dietary soya for two months later. Aortic sections were subjected to H and E, estrogen receptor [ER] and nitric oxide [NO] immunohistochemical staining. The media thickness and the optical density of NO immunoreactive cytoplasm of endothelial cells were assessed. In group II, strong esinophilic cytoplasm, dark nuclei, dislodged nuclei of endothelial cells besides focal denuded endothelial lining were noted. In addition, dark nuclei and perinuclear cytoplasmic vacuolation were seen in smooth muscle cells. Most of the elastic fibers were straight. ER immunoexpression was cytoplasmic in some fields, however, most fields exhibited-ve reaction. Faint cytoplasmic NO immunoreaction was recorded. Highly significant increase in media thickness and highly significant decrease in NO optical density were reported. In group III, most of the elastic fibers were straight, while other structural elements were comparable to the control. In group IV, few elastic fibers were straight and minimal increase in media thickness was observed. It could be concluded that dietary soya improved the changes recorded in the wall of the aorta of ovariectomized rats, which could suggest soya as a preferable therapeutic substitute to estrogen which was claimed to have side effects on the female genital tract. This suggestion was reinforced by less apoptotic endothelial cell nuclei and fewer straightened elastic fibers of the media


Subject(s)
Female , Animals, Laboratory , Estrogens , Ovariectomy , Aorta/drug effects , Immunohistochemistry , Nitric Oxide , Rats , Estrogen Replacement Therapy
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