Sousa Joana B, Fresco Paula, Diniz Carmen
REQUIMTE/FARMA, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal; MedinUP- Centro de Investigação Farmacológica e Inovação Medicamentosa, Portugal.
REQUIMTE/FARMA, Laboratório de Farmacologia, Departamento de Ciências do Medicamento, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira n° 228, 4050-313 Porto, Portugal; MedinUP- Centro de Investigação Farmacológica e Inovação Medicamentosa, Portugal.
Neurochem Int. 2015 Jan;80:7-13. doi: 10.1016/j.neuint.2014.11.001. Epub 2014 Nov 8.
The present study intends to clarify if endothelium dysfunction impairs vascular sympathetic neurotransmission. Electrically-evoked tritium overflow (100 pulses/5 Hz) was evaluated in arteries (intact and denuded) or exhibiting some degree of endothelium dysfunction (spontaneously hypertensive arteries), pre-incubated with [(3)H]-noradrenaline in the presence of enzymes (nitric oxide synthase (NOS); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; xanthine oxidase; cyclooxygenase; adenosine kinase) inhibitors and a nucleoside transporter inhibitor. Inhibition of endothelial nitric oxide synthase with L-NIO dihydrochloride reduced tritium overflow in intact arteries whereas inhibition of neuronal nitric oxide synthase with Nω-Propyl-L-arginine hydrochloride was devoid of effect showing that only endothelial nitric oxide synthase is involved in vascular sympathetic neuromodulation. Inhibition of enzymes involved in reactive oxygen species or prostaglandins production with apocynin and allopurinol or indomethacin, respectively, failed to alter tritium overflow. A facilitation or reduction of tritium overflow was observed in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or of 5-iodotubericidin, respectively, but only in intact arteries. These effects can be ascribed to a tonic inhibitory effect mediated by A1 receptors. In denuded and hypertensive arteries, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (SCH 58261) reduced tritium overflow, suggesting the occurrence of a tonic activation of A2A receptors. When endogenous adenosine bioavailability was increased by the nucleoside transporter inhibitor, S-(4-Nitrobenzyl)-6-thioinosine, tritium overflow increased in intact, denuded and hypertensive arteries. Among the endothelium-derived substances studied that could alter vascular sympathetic transmission only adenosine/adenosine receptor mediated mechanisms were clearly impaired by endothelium injury/dysfunction.
本研究旨在阐明内皮功能障碍是否会损害血管交感神经传递。在预先用[³H] - 去甲肾上腺素在酶（一氧化氮合酶（NOS）；烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶；黄嘌呤氧化酶；环氧化酶；腺苷激酶）抑制剂和核苷转运体抑制剂存在下孵育的动脉（完整和去内皮）或表现出一定程度内皮功能障碍（自发性高血压动脉）中，评估电诱发的氚溢出（100个脉冲/5Hz）。用L - NIO二盐酸盐抑制内皮型一氧化氮合酶可降低完整动脉中的氚溢出，而用Nω - 丙基 - L - 精氨酸盐酸盐抑制神经元型一氧化氮合酶则无作用，表明只有内皮型一氧化氮合酶参与血管交感神经调节。分别用阿朴吗啡和别嘌呤醇或吲哚美辛抑制参与活性氧或前列腺素产生的酶，未能改变氚溢出。分别在存在8 - 环戊基 - 1,3 - 二丙基黄嘌呤（DPCPX）或5 - 碘杀结核菌素的情况下观察到氚溢出的促进或减少，但仅在完整动脉中。这些作用可归因于A1受体介导的强直性抑制作用。在去内皮和高血压动脉中，7 - （2 - 苯乙基） - 5 - 氨基 - 2 - （2 - 呋喃基） - 吡唑并[4,3 - e] - 1,2,4 - 三唑并[1,5 - c]嘧啶（SCH 58261）降低了氚溢出，提示A2A受体存在强直性激活。当通过核苷转运体抑制剂S - （4 - 硝基苄基） - 6 - 硫代肌苷增加内源性腺苷的生物利用度时，完整、去内皮和高血压动脉中的氚溢出均增加。在所研究的可能改变血管交感神经传递的内皮衍生物质中，只有腺苷/腺苷受体介导的机制因内皮损伤/功能障碍而明显受损。
