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1.
PLoS One ; 9(3): e91890, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24638017

RESUMO

The aim was to investigate the beneficial effects of clopidogrel in thoracic aorta function and structure and to characterize if P2Y12 receptors contribute to these effects. Male Sprague Dawley rats were infused with angiotensin II [(Ang II) 60 ng x min(-1), 14 days] or saline (control rats) and were simultaneously treated with clopidogrel (10 mg x kg(-1) x day(-1)) or vehicle. After 14 days, systolic blood pressure (mmHg) was similar in Ang II-hypertensive rats treated with clopidogrel or vehicle (199±9 vs. 190±11, respectively). Systolic blood pressure in control rats was not altered by clopidogrel treatment (128±1 vs. vehicle, 134±2). Endothelium-dependent relaxation induced by 2-MeS-ADP was decreased in aortas from vehicle-treated Ang II-hypertensive rats, compared to vehicle-treated control rats. This response was elicited via activation of P2Y1 and P2Y12 receptors. In the presence of L-NAME and indomethacin, 2-MeS-ADP induced contraction and this response was augmented in vehicle-treated Ang II-hypertensive rats, compared to vehicle-treated control rats. The contraction to 2-MeS-ADP was evoked by P2Y13 and P2Y12 receptor activation. Clopidogrel-treatment did not normalize relaxation or contractile responses induced by 2-MeS-ADP in aortas from Ang II-hypertensive rats. P2Y1 and P2Y12 protein expression was increased, whereas P2Y13 receptor expression was reduced in aorta from vehicle-treated Ang II-hypertensive rats. Endothelium-dependent relaxation upon acetylcholine-stimulation was reduced in vehicle-treated Ang II-hypertensive rats, and clopidogrel treatment was effective in improving endothelial function. Clopidogrel also prevented vascular remodeling, evidenced by augmented media thickness in aortas from Ang II-hypertensive rats. Clopidogrel has beneficial effects on the aortic endothelium of Ang II-hypertensive rats, but its effects do not seem to be directly related to the presence of P2Y12 receptors in this vessel.


Assuntos
Aorta/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Hipertensão/patologia , Hipertensão/fisiopatologia , Inibidores da Agregação Plaquetária/farmacologia , Ticlopidina/análogos & derivados , Remodelação Vascular/efeitos dos fármacos , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Animais , Aorta/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Clopidogrel , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Expressão Gênica , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/administração & dosagem , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos , Receptores Purinérgicos P2Y/genética , Receptores Purinérgicos P2Y/metabolismo , Tionucleotídeos/farmacologia , Ticlopidina/administração & dosagem , Ticlopidina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
2.
Clin Sci (Lond) ; 118(7): 463-71, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19811450

RESUMO

The P2Y12 receptor antagonist clopidogrel blocks platelet aggregation, improves systemic endothelial nitric oxide bioavailability, and has anti-inflammatory effects. Since P2Y12 receptors have been identified in the vasculature, we hypothesized that clopidogrel ameliorates angiotensin II (Ang II) -induced vascular functional changes by blockade of P2Y12 receptors in the vasculature. Male Sprague Dawley rats were infused with Ang II (60 ng.min-1) or vehicle for 14 days. The animals were treated with clopidogrel (10mg*kg-1*day-1) or vehicle. Vascular reactivity was evaluated in second-order mesenteric arteries. Clopidogrel treatment did not change systolic blood pressure [(mmHg) control-vehicle, 117+/-7.1 vs. control- Clopidogrel, 125+/-4.2; AngII-vehicle, 197+/-10.7 vs. AngII-Clopidogrel, 198+/-5.2], but it normalized increased phenylephrine-induced vascular contractions [(%KCl) vehicle-treated, 182.2+/-18 vs. Clopidogrel, 133+/-14%), as well as impaired vasodilation to acetylcholine [(%) vehicle-treated, 71.7+/-2.2 vs. Clopidogrel, 85.3+/-2.8) in Ang II-treated animals. Vascular expression of P2Y12 receptor was determined by western blot. Pharmacological characterization of vascular P2Y12 was performed with the P2Y12 agonist 2-MeS-ADP. Although 2-MeSADP induced endothelium-dependent relaxation [(Emax %) = 71%+/-12), as well as contractile vascular responses (Emax %= 83+/-12) these actions are not mediated by P2Y12 receptor activation. 2-MeS-ADP produced similar vascular responses in control and Ang II rats. These results indicate potential effects of Clopidogrel, such as improvement of hypertension-related vascular functional changes that are not associated with direct actions of clopidogrel in the vasculature, supporting the concept that activated platelets contribute to endothelial dysfunction, possibly via impaired NO bioavailability.


Assuntos
Hipertensão/fisiopatologia , Artérias Mesentéricas/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo , Ticlopidina/análogos & derivados , Acetilcolina/farmacologia , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Angiotensina II , Animais , Western Blotting , Clopidogrel , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiopatologia , Inibidores Enzimáticos/farmacologia , Hipertensão/induzido quimicamente , Técnicas In Vitro , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , NG-Nitroarginina Metil Éster/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y12 , Tionucleotídeos/farmacologia , Ticlopidina/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
3.
J Pharmacol Exp Ther ; 322(2): 678-85, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17494861

RESUMO

This study tested the hypothesis that adenosine, in murine corpora cavernosa, produces direct relaxation of smooth muscle cells and inhibition of contractile responses mediated by sympathetic nerve stimulation. Penes were excised from anesthetized male C57BL/6 mice, dissected, and cavernosal strips were mounted to record isometric force. Adenosine, 2-chloroadenosine (stable analog of adenosine), and 2-phenylaminoadenosine (CV1808) (A2(A)/A2(B) agonist) produced concentration-dependent relaxations of phenylephrine-contracted tissues. Relaxation to 2-chloroadenosine was inhibited, in a concentration-dependent manner, by 2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine (SCH58261; A2(A) antagonist; 10(-9)-10(-6) M) and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamida (MRS1706; A2(B) antagonist; 10(-8)-10(-6) M). The combination of both antagonists abrogated 2-chloroadenosine-induced relaxation. Electrical field stimulation (EFS; 1-32 Hz) of adrenergic nerves produced frequency-dependent contractions that were inhibited by compounds that increase adenosine levels, such as 5'-iodotubercidin (adenosine kinase inhibitor), erythro-9-(2-hydroxy-3-nonyl)adenine (adenosine deaminase inhibitor), and dipyridamole (inhibitor of adenosine transport). The adenosine A1 receptor agonist N(6)-cyclopentyladenosine (C8031) right-shifted contractile responses to EFS, with a significant inhibitory effect at 10(-6) M. Blockade of adenosine A1 receptors with 8-cyclopentyl-1,3-dipropylxanthine (C101) (10(-7) M) enhanced contractile responses to EFS and eliminated the inhibitory effects of 5'-iodotubercidin. Dipyridamole and 5'-iodotubercidin had no effect on adenosine-mediated relaxation. In summary, adenosine directly relaxes cavernosal smooth muscle cells, by the activation of A2(A)/A2(B) receptor subtypes. In addition, adenosine negatively modulates sympathetic neurotransmission, by A1 receptor subtype activation, in murine corpora cavernosa. Adenosine may subserve dual roles in modulating the physiological mechanisms of erection in mice.


Assuntos
Adenosina/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Ereção Peniana/efeitos dos fármacos , Receptores Purinérgicos P1/fisiologia , 2-Cloroadenosina/farmacologia , Adenosina/análogos & derivados , Agonistas do Receptor A2 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Atropina/farmacologia , Tosilato de Bretílio/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Inibidores Enzimáticos/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , NG-Nitroarginina Metil Éster/farmacologia , Ereção Peniana/fisiologia , Fenilefrina/farmacologia , Prazosina/análogos & derivados , Prazosina/farmacologia , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Purinas/farmacologia , Pirimidinas/farmacologia , Receptor A2A de Adenosina/fisiologia , Receptor A2B de Adenosina/fisiologia , Triazóis/farmacologia
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