Park S J, Boulanger C M, Kirchengast M, Vanhoutte P M
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030-3498.
J Cardiovasc Pharmacol. 1994 Sep;24(3):517-22. doi: 10.1097/00005344-199409000-00022.
We performed experiments to determine the effects of the combined 5-hydroxytryptamine2 (5-HT2) receptor and Ca2+ channel antagonist LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)]amino-2-isopropyl-2(3.4.5-trimethoxy phenyl)-valeronitril-hydrochloride) on vascular smooth muscle (VSM) and endothelium in isolated porcine coronary arteries. Rings with and without endothelium were suspended in conventional organ chambers for measurement of isometric force. LU49938 inhibited contractions evoked by serotonin, norepinephrine (NE), and prostaglandin F2 alpha (PGF2 alpha) in a concentration-dependent and noncompetitive manner. The lower concentrations of LU49938 (10(-7) and 10(-6) M) did not affect contractions to serotonin in the presence of ketanserin. However, a higher concentration of LU49938 (10(-5) M) significantly decreased the concentration-response curve to the monoamine in the presence of ketanserin. These finding suggest that LU49938 has a dual inhibitory effect on contractions: selective inhibition of 5-HT2 receptor and nonselective inhibition of the contractile process in VSM. The mechanism of this nonselective inhibition of VSM is likely to be related to inhibition of Ca2+ entry because LU49938 inhibited responses to several agonists. The time course and degree of relaxation caused by LU49938 were comparable in rings with and without endothelium in control solution or after incubation with nitro-L-arginine and/or indomethacin. LU49938 did not affect endothelium-dependent relaxations induced by serotonin and bradykinin. These results suggest that LU49938 does not affect endothelium-dependent responses in porcine coronary artery.
我们进行了实验，以确定5-羟色胺2（5-HT2）受体和钙通道拮抗剂LU49938（(2S)-5-[N-甲基-N-(正己基)]氨基-2-异丙基-2(3,4,5-三甲氧基苯基)-戊腈盐酸盐）对离体猪冠状动脉血管平滑肌（VSM）和内皮的影响。将有内皮和无内皮的血管环悬挂在传统器官浴槽中以测量等长力。LU49938以浓度依赖性和非竞争性方式抑制血清素、去甲肾上腺素（NE）和前列腺素F2α（PGF2α）诱发的收缩。较低浓度的LU49938（10^(-7)和10^(-6) M）在酮色林存在时不影响对血清素的收缩。然而，较高浓度的LU49938（10^(-5) M）在酮色林存在时显著降低了对单胺的浓度-反应曲线。这些发现表明，LU49938对收缩有双重抑制作用：对5-HT2受体的选择性抑制和对VSM收缩过程的非选择性抑制。这种对VSM的非选择性抑制机制可能与抑制钙内流有关，因为LU49938抑制了对几种激动剂的反应。在对照溶液中或用硝基-L-精氨酸和/或吲哚美辛孵育后，有内皮和无内皮的血管环中，LU49938引起的舒张时间进程和程度相当。LU49938不影响血清素和缓激肽诱导的内皮依赖性舒张。这些结果表明，LU49938不影响猪冠状动脉中的内皮依赖性反应。
