Possible mechanisms involved in the vasorelaxant effect produced by clobenzorex in aortic segments of rats

Clobenzorex is a metabolic precursor of amphetamine indicated for the treatment of obesity. Amphetamines have been involved with cardiovascular side effects such as hypertension and pulmonary arterial hypertension. The aim of the present study was to investigate whether the direct application of 10–9–10–5 M clobenzorex on isolated phenylephrine-precontracted rat aortic rings produces vascular effects, and if so, what mechanisms may be involved. Clobenzorex produced an immediate concentration-dependent vasorelaxant effect at the higher concentrations (10–7.5–10–5 M). The present outcome was not modified by 10–6 M atropine (an antagonist of muscarinic acetylcholine receptors), 3.1×10–7 M glibenclamide (an ATP-sensitive K+ channel blocker), 10–3 M 4-aminopyridine (4-AP; a voltage-activated K+ channel blocker), 10–5 M indomethacin (a prostaglandin synthesis inhibitor), 10–5 M clotrimazole (a cytochrome P450 inhibitor) or 10–5 M cycloheximide (a general protein synthesis inhibitor). Contrarily, the clobenzorex-induced vasorelaxation was significantly attenuated (P<0.05) by 10–5 M L-NAME (a direct inhibitor of nitric oxide synthase), 10–7 M ODQ (an inhibitor of nitric oxide-sensitive guanylyl cyclase), 10–6 M KT 5823 (an inhibitor of protein kinase G), 10–2 M TEA (a Ca2+-activated K+ channel blocker and non-specific voltage-activated K+ channel blocker) and 10–7 M apamin plus 10–7 M charybdotoxin (blockers of small- and large-conductance Ca2+-activated K+ channels, respectively), and was blocked by 8×10–2 M potassium (a high concentration) and removal of the vascular endothelium. These results suggest that the direct vasorelaxant effect by clobenzorex on phenylephrine-precontracted rat aortic rings involved stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.苄甲苯丙胺（Clobenzorex）是苯丙胺（amphetamine）的代谢前体，临床适应症为肥胖症治疗。苯丙胺类药物可引发高血压、肺动脉高压（pulmonary arterial hypertension）等心血管不良反应。本研究旨在探究：将浓度为10⁻⁹~10⁻⁵ M的苄甲苯丙胺直接作用于经去氧肾上腺素（phenylephrine）预收缩的离体大鼠主动脉环时，是否可产生血管效应；若可产生，则其潜在作用机制为何。当浓度处于10⁻⁷.⁵~10⁻⁵ M区间时，苄甲苯丙胺可即刻产生浓度依赖性的血管舒张（vasorelaxant）效应。10⁻⁶ M阿托品（atropine，毒蕈碱型乙酰胆碱受体拮抗剂）、3.1×10⁻⁷ M格列本脲（glibenclamide，ATP敏感性钾通道阻滞剂）、10⁻³ M 4-氨基吡啶（4-aminopyridine，4-AP，电压门控钾通道阻滞剂）、10⁻⁵ M吲哚美辛（indomethacin，前列腺素合成抑制剂）、10⁻⁵ M克霉唑（clotrimazole，细胞色素P450抑制剂）以及10⁻⁵ M环己酰亚胺（cycloheximide，通用蛋白质合成抑制剂）均未对本研究的观测结果产生显著影响。与之相反，10⁻⁵ M L-NAME（一氧化氮合酶直接抑制剂）、10⁻⁷ M ODQ（一氧化氮敏感性鸟苷酸环化酶抑制剂）、10⁻⁶ M KT 5823（蛋白激酶G抑制剂）、10⁻² M四乙铵（TEA，钙激活钾通道阻滞剂与非特异性电压门控钾通道阻滞剂），以及10⁻⁷ M蜂毒明肽（apamin，小电导钙激活钾通道阻滞剂）联合10⁻⁷ M蝎毒素（charybdotoxin，大电导钙激活钾通道阻滞剂）可显著减弱苄甲苯丙胺诱导的血管舒张效应（P<0.05）；而8×10⁻² M高浓度钾离子以及去除血管内皮（vascular endothelium）则可完全阻断该效应。本研究结果表明，苄甲苯丙胺对经去氧肾上腺素预收缩的离体大鼠主动脉环所产生的直接血管舒张效应，依赖于NO/cGMP/PKG/钙激活钾通道通路的激活。