Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy.
Pharmacol Res. 2011 Mar;63(3):199-206. doi: 10.1016/j.phrs.2010.10.010. Epub 2010 Oct 14.
AT(1) receptor antagonists (ARBs) are drugs widely used for preventing and/or treating major cardiovascular diseases. Some of these drugs also show AT(1) receptor-independent effects that may have patho-physiological significance, such as Peroxisome Proliferator-Activated Receptors gamma (PPARγ) stimulation. Here we investigated the effect of telmisartan (that also stimulates PPARγ) on vasomotor responses of femoral arteries isolated from rat, in comparison to losartan. Femoral artery segments were mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE) and acetylcholine (ACh) after 30-min incubation in the absence or presence of 30 μM telmisartan or 30 μM losartan. Vasomotor responses were not significantly changed by losartan, whereas telmisartan reduced vasoconstriction to PE and increased vasodilatation to ACh. Incubation with 0.1 mM N(G)-nitro-l-arginine abolished relaxation to ACh in untreated controls as well as in losartan-treated preparations, but did not in telmisartan-treated preparations (were 20% relaxation subsisted); this residual relaxing effect was abolished by indomethacin and by endothelium removal. Incubation with 30 μM GW9662 (PPARγ antagonist), 10 μM PD123319 (AT(2) antagonist) or 30 μM A779 (angiotensin(1-7)/Mas antagonist) did not change the effect of telmisartan on vasomotor responses in preparations with intact endothelium. We conclude that telmisartan modifies constriction and dilatation of isolated arteries in an endothelium-dependent manner, involving both nitric oxide and prostanoid production. The present effect of telmisartan, however, does not seem to involve PPARγ, AT(2) or angiotensin(1-7)/Mas.
血管紧张素受体拮抗剂（ARBs）是广泛用于预防和/或治疗主要心血管疾病的药物。其中一些药物还表现出血管紧张素受体非依赖性作用，这些作用可能具有病理生理意义，例如过氧化物酶体增殖物激活受体γ（PPARγ）的刺激。在这里，我们研究了替米沙坦（也刺激 PPARγ）对大鼠离体股动脉血管舒缩反应的影响，并与氯沙坦进行了比较。股动脉段在带有金属丝的肌动描记器中安装，并在不存在或存在 30μM 替米沙坦或 30μM 氯沙坦的情况下，用累积浓度的苯肾上腺素（PE）和乙酰胆碱（ACh）进行 30 分钟孵育后进行挑战。血管舒缩反应不受氯沙坦的影响，而替米沙坦则减少了对 PE 的血管收缩，并增加了对 ACh 的血管舒张。在未处理的对照组以及氯沙坦处理的制剂中，用 0.1mM N（G）-硝基-L-精氨酸孵育会消除 ACh 的松弛作用，但在替米沙坦处理的制剂中则没有（仍存在 20%的松弛作用）；这种残留的松弛作用被吲哚美辛和内皮去除所消除。用 30μM GW9662（PPARγ拮抗剂）、10μM PD123319（AT2 拮抗剂）或 30μM A779（血管紧张素（1-7）/Mas 拮抗剂）孵育不会改变替米沙坦对完整内皮制剂中血管舒缩反应的作用。我们得出结论，替米沙坦以依赖内皮的方式调节离体动脉的收缩和舒张，涉及一氧化氮和前列腺素的产生。然而，替米沙坦的这种作用似乎不涉及 PPARγ、AT2 或血管紧张素（1-7）/Mas。
