Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia.
Basic Clin Pharmacol Toxicol. 2012 Jul;111(1):24-30. doi: 10.1111/j.1742-7843.2011.00855.x. Epub 2012 Jan 20.
The ATP-sensitive K(+) channels opener (K(ATP)CO), P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N″-3-pyridylguanidine], has been shown to cause relaxation of various isolated animal and human blood vessels by opening of vascular smooth muscle ATP-sensitive K(+) (K(ATP)) channels. In addition to the well-known effect on the opening of K(ATP) channels, it has been reported that vasorelaxation induced by some of the K(ATP)COs includes some other K(+) channel subtypes. Given that there is still no information on other types of K(+) channels possibly involved in the mechanism of relaxation induced by P1075, this study was designed to examine the effects of P1075 on the rat renal artery with endothelium and with denuded endothelium and to define the contribution of different K(+) channel subtypes in the P1075 action on this blood vessel. Our results show that P1075 induced a concentration-dependent relaxation of rat renal artery rings pre-contracted by phenylephrine. Glibenclamide, a selective K(ATP) channels inhibitor, partly antagonized the relaxation of rat renal artery induced by P1075. Tetraethylammonium (TEA), a non-selective inhibitor of Ca(2+)-activated K(+) channels, as well as iberiotoxin, a most selective blocker of large-conductance Ca(2+) -activated K(+) (BK(Ca)) channels, did not abolish the effect of P1075 on rat renal artery. In contrast, a non-selective blocker of voltage-gated K(+) (K(V)) channels, 4-aminopyridine (4-AP), as well as margatoxin, a potent inhibitor of K(V)1.3 channels, caused partial inhibition of the P1075-induced relaxation of rat renal artery. In addition, in this study, P1075 relaxed contractions induced by 20 mM K(+) , but had no effect on contractions induced by 80 mM K(+). Our results showed that P1075 induced strong endothelium-independent relaxation of rat renal artery. It seems that K(ATP), 4-AP- and margatoxin-sensitive K(+) channels located in vascular smooth muscle mediated the relaxation of rat renal artery induced by P1075.
ATP 敏感性钾（KATP）通道开放剂（KATPCO），P1075[N-氰基-N'-(1,1-二甲基丙基）-N″-3-吡啶基胍]，已被证明通过打开血管平滑肌 ATP 敏感性钾（KATP）通道，导致各种分离的动物和人类血管的松弛。除了对 KATP 通道开放的众所周知的作用外，据报道，一些 KATPCO 诱导的血管舒张包括其他一些 K+通道亚型。鉴于目前尚无关于可能参与 P1075 诱导的松弛机制的其他类型 K+通道的信息，本研究旨在研究 P1075 对大鼠带内皮和去内皮肾动脉的作用，并确定不同 K+通道亚型在 P1075 对该血管作用中的贡献。我们的结果表明，P1075 诱导苯肾上腺素预收缩的大鼠肾动脉环浓度依赖性松弛。选择性 KATP 通道抑制剂格列本脲部分拮抗 P1075 诱导的大鼠肾动脉松弛。四乙铵（TEA），一种非选择性钙激活钾（KCa）通道抑制剂，以及伊比罗毒素，一种最选择性的大电导钙激活钾（BKCa）通道阻断剂，并没有消除 P1075 对大鼠肾动脉的作用。相反，电压门控钾（Kv）通道的非选择性阻断剂 4-氨基吡啶（4-AP）以及玛格毒素，一种有效的 Kv1.3 通道抑制剂，部分抑制了 P1075 诱导的大鼠肾动脉松弛。此外，在这项研究中，P1075 松弛了 20 mM K+诱导的收缩，但对 80 mM K+诱导的收缩没有影响。我们的结果表明，P1075 诱导大鼠肾动脉强烈的内皮非依赖性松弛。似乎位于血管平滑肌中的 KATP、4-AP 和玛格毒素敏感的 K+通道介导了 P1075 诱导的大鼠肾动脉松弛。
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