Laboratório de Tecnologia Farmacêutica (LTF), Universidade Federal da Paraíba - UFPB, João Pessoa, PB - Brazil.
Basic Clin Pharmacol Toxicol. 2011 Dec;109(6):465-75. doi: 10.1111/j.1742-7843.2011.00749.x. Epub 2011 Aug 8.
Rotundifolone is the major constituent of the essential oil of Mentha x villosa Hudson. In preliminary studies, rotundifolone induced significant hypotensive, bradycardic and vasorelaxant effects in rats. Thus, to gain more insight into the pharmacology of rotundifolone, the aim of this study was to characterize the molecular mechanism of action involved in relaxation produced by rotundifolone. The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements and whole-cell patch-clamp techniques. Rotundifolone relaxed phenylephrine-induced contractions in a concentration-dependent manner. Pre-treatment with KCl (20 mM), charybdotoxin (10(-7) M) or tetraethylammonium (TEA 10(-3) or 3 × 10(-3) M) significantly attenuated the relaxation effect induced by rotundifolone. Additionally, whole-cell patch-clamp recordings were made in mesenteric smooth muscle cells and showed that rotundifolone significantly increased K(+) currents, and this effect was abolished by TEA (10(-3) M), suggesting the participation of BK(Ca) channels. Furthermore, rotundifolone inhibited the vasoconstriction induced by CaCl(2) in depolarizing nominally Ca(2+) -free medium and antagonized the contractions elicited by an L-type Ca(2+) channel agonist, S(-)-Bay K 8644 (2 × 10(-7) M), indicating that the vasodilatation involved inhibition of Ca(2+) influx through L-type voltage-dependent calcium channels (Ca(v) type-L). Additionally, rotundifolone inhibited L-type Ca(2+) currents (I(Ca) L), affecting the voltage-dependent activation of I(Ca) L and steady-state inactivation. Our findings suggest that rotundifolone induces vasodilatation through two distinct but complementary mechanisms that clearly depend on the concentration range used. Rotundifolone elicits an increase in the current density of BK(Ca) channels and causes a shift in the steady-state inactivation relationship for Ca(v) type-L towards more hyperpolarized membrane potentials.
旋覆花酮是绵马贯众挥发油的主要成分。在初步研究中，旋覆花酮在大鼠体内表现出显著的降压、减慢心率和血管舒张作用。因此，为了更深入地了解旋覆花酮的药理学特性，本研究旨在研究旋覆花酮引起的舒张作用的作用机制。采用等长张力测量和全细胞膜片钳技术，在大鼠肠系膜动脉中研究了旋覆花酮的舒张作用。旋覆花酮以浓度依赖的方式松弛去甲肾上腺素诱导的收缩。用 KCl（20 mM）、蟾毒灵（10(-7) M）或四乙铵（TEA 10(-3) 或 3 × 10(-3) M）预处理可显著减弱旋覆花酮诱导的舒张作用。此外，在肠系膜平滑肌细胞中进行全细胞膜片钳记录显示，旋覆花酮显著增加 K(+)电流，而 TEA（10(-3) M）可使该作用失活，表明参与了 BK(Ca)通道。此外，旋覆花酮抑制去极化的无钙介质中由 CaCl(2) 诱导的血管收缩，并拮抗由 L 型钙通道激动剂 S(-)-Bay K 8644（2 × 10(-7) M）引起的收缩，表明血管舒张涉及抑制通过 L 型电压依赖性钙通道（Ca(v) type-L）的 Ca(2+)内流。此外，旋覆花酮抑制 L 型 Ca(2+)电流（I(Ca) L），影响 I(Ca) L 的电压依赖性激活和稳态失活。我们的研究结果表明，旋覆花酮通过两种截然不同但互补的机制引起血管舒张，这两种机制显然取决于所使用的浓度范围。旋覆花酮引起 BK(Ca) 通道电流密度增加，并导致 Ca(v) type-L 的稳态失活关系向更超极化的膜电位转移。
