Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
Orion Pharma, Espoo, Finland.
J Cardiovasc Pharmacol. 2019 Sep;74(3):218-224. doi: 10.1097/FJC.0000000000000700.
Relaxation and changes in the transmembrane potential of vascular smooth muscle induced by ORM-3819, a novel inodilating compound, were investigated in isolated porcine coronary arteries. Isometric tone was studied on arterial rings precontracted by KCl (30 mM), and resting membrane potential was investigated by a conventional microelectrode technique. ORM-3819 in the concentration range 0.38-230.6 µM evoked concentration-dependent relaxation with a maximum value of 58.1% and an effective concentration of the relaxing substance that caused 50% of maximum relaxation of 72.2 µM. The maximum hyperpolarization produced by ORM-3819 at a concentration of 120 µM (-2.6 ± 0.81 mV, N = 10) did not differ significantly from that induced by C-type natriuretic peptide (CNP), an endogenous hyperpolarizing mediator, at a concentration of 1.4 µM (-3.6 ± 0.38 mV, N = 17). The same effect elicited by the known inodilator levosimendan was less pronounced at a concentration of 3.7 µM: -1.82 ± 0.44 mV, N = 22 (P < 0.05 vs. CNP). The voltage-gated potassium channel inhibitor 4-aminopyridine, at a concentration of 5 mM, attenuated the relaxation induced by ORM-3819 at concentrations of 41.6 or 117.2 µM. These results suggest that ORM-3819 is a potent vasodilating agent able to relieve coronary artery vasospasm by causing hyperpolarization of vascular smooth muscle cells through processes involving activation of voltage-gated potassium channels.
在分离的猪冠状动脉中研究了新型血管扩张化合物 ORM-3819 对血管平滑肌跨膜电位的松弛作用和变化。通过 KCl（30mM）预收缩的动脉环研究等长张力，通过传统微电极技术研究静息膜电位。在 0.38-230.6µM 的浓度范围内，ORM-3819 诱发浓度依赖性松弛，最大值为 58.1%，引起 50%最大松弛的有效松弛物质浓度为 72.2µM。在 120µM 浓度下，ORM-3819 产生的最大超极化值（-2.6±0.81mV，N=10）与内源性超极化介质 C 型利钠肽（CNP）在 1.4µM 浓度下诱导的超极化值（-3.6±0.38mV，N=17）没有显著差异。在 3.7µM 浓度下，已知的血管扩张剂左西孟旦引起的相同作用不那么明显：-1.82±0.44mV，N=22（P<0.05 与 CNP 相比）。在 5mM 浓度下，电压门控钾通道抑制剂 4-氨基吡啶减弱了在 41.6 或 117.2µM 浓度下 ORM-3819 诱导的松弛作用。这些结果表明，ORM-3819 是一种有效的血管扩张剂，通过激活电压门控钾通道，导致血管平滑肌细胞超极化，从而缓解冠状动脉痉挛。
