ABSTRACT
RESUMO:Os receptores beta-adrenérgicos (beta-AR) integram um sistema proteico ternário: beta-AR, proteína G de acoplamento e enzimas como a adenilato-ciclase (AC) que produz o 3'-5' monofosfato de adenosina (AMPc). O principal mecanismo de ação do AMPc é a ativação da proteína quinase A (PKA), capaz de fosforilar inúmeros substratos. Em células endoteliais, a ativação dos beta-AR promove o aumento dos níveis citoplasmáticos de Ca+2 favorecendo a ligação do Ca+2 com a calmodulina e deste complexo com a enzima óxido nitrico sintase endotelial (eNOS), resultando na produção de NO. A ativação beta3-AR no músculo liso vascular e conseqüente ativação da PKA reduz a concentração citoplasmática de Ca+2 e a sua afinidade pela calmodulina, resultando no relaxamento vascular.. Os receptores beta-AR podem ser agrupados em beta-AR clássicos (beta1 e beta2) e beta-AR atípicos (beta3 e beta4), Os agonístas beta-AR são classificados em não seletivos (isoprenalina), seletivos beta1 (xamoterol) e seletivos beta2 (terbutalina, salbutamol) e podem ser usados em várias situações clínicas, como broncodilatadores ou como estimulantes cardíacos. O desenvolvimento de agonistas beta3-AR como BRL-37344, CGP 12177 e CL 316243, bem como de antagonistas beta-AR têm merecido especial atenção devido à sua eficácia no tratamento da hipertensão arterial, certas arritmias cardíacas e ísquemia cardiaca. A busca por antagonistas seletivos resultou na síntese de vários compostos como: atenolol, bisoprolol, betaxolol, practolol e CFP20712A (antagonistas beta1-AR seletivos), ICI 118551 (antagonista beta2-AR seletivo), SR59230A (antagonista beta3-AR seletivo), bupranolol e CGP20712A (antagonistas beta4-AR seletivos).
Subject(s)
Humans , Endothelium, Vascular , Receptors, Cyclic AMP , Receptors, Adrenergic, beta , VasodilationABSTRACT
The aim of this study was to investigate the role of the contractile agent on the relaxation induced by isoprenaline and the contribution of nitric oxide (NO) and cGMP to this relaxation. These studies were conducted in intact endothelium or denuded aortas contracted with the EC50 of norepinephrine (NE) or phenylephrine (Phe), and the relaxation induced by isoprenaline (non-selective beta-adrenoceptor agonist) or forskolin (activator of adenylyl-cyclase) was studied. The maximum effect (Emax) and pD2 were analysed. Isoprenaline and forskolin-induced relaxation were not changed by the endothelium removal in both NE and Phe-contracted aortas. However, L-NAME reduced the relaxation induced by isoprenaline (Emax from 94.48+/-2.30%, n=7 to 66.17+/-11.73%, n=7; pD2 from 7.56+/-0.10 to 6.08+/-0.15) only in NE-contracted aortas. The pD2 of isoprenaline was also reduced by ODQ (6.57+/-0.13), but not the Emax. The inhibitory effects of L-NAME and ODQ were reversed by yohimbine. L-NAME, ODQ and oxyhemoglobin had no effect on the relaxation induced by isoprenaline in Phe-contracted aortas. Taken together, these results suggest that norepinephrine, a non-selective alpha-adrenoceptor agonist can also activate alpha2-adrenoceptors sensitive to yohimbine in the endothelial cells, activating the NO-synthase and cGMP production which would potentiate the relaxation induced by isoprenaline. However, this pathway is not activated with Phe, the selective alpha1-adrenoceptors agonist.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Colforsin/pharmacology , Endothelium, Vascular/drug effects , Isoproterenol/pharmacology , Nitric Oxide/metabolism , Receptors, Adrenergic, alpha-1/drug effects , Vasodilation/drug effects , Animals , Aorta/drug effects , Drug Interactions , Endothelium, Vascular/metabolism , Male , NG-Nitroarginine Methyl Ester/pharmacology , Norepinephrine/pharmacology , Phenylephrine/pharmacology , Rats , Rats, WistarABSTRACT
Statins have cholesterol-independent effects including an increased vascular nitric oxide (NO) activity and are commonly used by patients with cardiovascular disease. Such patients frequently have erectile dysfunction, which may be treated with sildenafil, a selective inhibitor of phosphodiesterase type 5. Since statins and sildenafil can activate the NO-cGMP pathway, we investigated whether pre-treatment with atorvastatin (0, 5 and 30 mg/kg/day) for 2 weeks affects sildenafil (1 pM-100 mM)-induced relaxation of aortic rings isolated from Wistar rats. We also examined the hemodynamic consequences of this interaction in Wistar rats. Plasma nitrite/nitrate (NOx) concentrations were determined using an ozone-based chemiluminescence assay. While pre-treatment with atorvastatin increased the potency of sildenafil-induced vasorelaxation (P<0.01), no differences were observed in the maximum sildenafil-induced relaxation. Pre-incubation of aortic rings with NG-nitro-L-arginine methyl ester (L-NAME) reversed atorvastatin-induced increase in the potency of sildenafil relaxation. In addition, pre-treatment with atorvastatin enhanced plasma NOx concentrations and sildenafil-induced hypotension and tachycardia (all P<0.05). These results suggest that atorvastatin increases the vascular sensitivity to sildenafil through NO-mediated mechanisms.
