Masui H, Wakabayashi I, Siogawa K, Koizumi N
Department of Public Health, Hyogo College of Medicine, Nishinomiya, Japan.
Pharmacology. 2002 May;65(1):10-7. doi: 10.1159/000056180.
Ethanol is known to decrease the gallbladder contractility. The purpose of this study was to clarify the mechanism of tolerance to the inhibitory action of ethanol on the gallbladder contractility. Male guinea pigs were fed ethanol (3%) or calorie-matched sucrose in the drinking water for 4 weeks. Then, the gallbladder was isolated, and its isometric tension was measured. The contractile responses to KCl, BAY K8644, histamine, and phorbol 12,13-dibutyrate in the normal medium were not different between the gallbladder strips from ethanol-fed and control guinea pigs. Ethanol at 25 mmol/l in vitro did not affect the contractile responses to KCl and BAY K8644 in the gallbladder strips from both ethanol-fed and control guinea pigs. On the other hand, ethanol at 25 mmol/l in vitro significantly inhibited the contractile responses to histamine and phorbol 12,13-dibutyrate in the gallbladder strips from the control guinea pigs, but it did not affect the contractile response to histamine and significantly augmented that to phorbol 12,13-dibutyrate in the strips from the ethanol-fed guinea pigs. Diphenhydramine, a selective H(1) receptor antagonist, abolished the histamine contraction in gallbladder strips from both control and ethanol-fed guinea pigs, while cimetidine, a selective H(2) receptor antagonist, did not affect histamine contraction, implying that histamine-induced contraction of guinea pig gallbladders is mediated only by H(1) receptors. Verapamil (1 micromol/l) completely inhibited the phorbol 12,13-dibutyrate-induced contraction of the strips from both ethanol-fed and control guinea pigs. The histamine-induced contraction was partly inhibited in the absence of Ca(2+) in the medium. In the gallbladder strips from both ethanol-fed and control guinea pigs, ethanol at 25 mmol/ in vitro did not affect the histamine-induced contraction in the absence of extracellular Ca(2+). Tolerance to the inhibitory action of ethanol developed selectively on contractile responses to histamine and phorbol 12,13-dibutyrate. Chronic ethanol administration produces tolerance to in vitro gallbladder contractility mediated by the Ca(2+) entry through L-type Ca(2+) channels linked with protein kinase C activation.
已知乙醇会降低胆囊收缩力。本研究的目的是阐明对乙醇抑制胆囊收缩力作用产生耐受性的机制。雄性豚鼠在饮用水中摄入乙醇（3%）或热量匹配的蔗糖，持续4周。然后，分离胆囊并测量其等长张力。在正常培养基中，来自摄入乙醇的豚鼠和对照豚鼠的胆囊条对氯化钾、BAY K8644、组胺和佛波醇12,13 - 二丁酸酯的收缩反应没有差异。体外25 mmol/l的乙醇对来自摄入乙醇的豚鼠和对照豚鼠的胆囊条对氯化钾和BAY K8644的收缩反应没有影响。另一方面，体外25 mmol/l的乙醇显著抑制对照豚鼠胆囊条对组胺和佛波醇12,13 - 二丁酸酯的收缩反应，但不影响对组胺的收缩反应，且显著增强了来自摄入乙醇的豚鼠胆囊条对佛波醇12,13 - 二丁酸酯的收缩反应。选择性H(1)受体拮抗剂苯海拉明消除了来自对照和摄入乙醇的豚鼠胆囊条中的组胺收缩，而选择性H(2)受体拮抗剂西咪替丁不影响组胺收缩，这意味着组胺诱导的豚鼠胆囊收缩仅由H(1)受体介导。维拉帕米（1 μmol/l）完全抑制了来自摄入乙醇的豚鼠和对照豚鼠胆囊条中佛波醇12,13 - 二丁酸酯诱导的收缩。在培养基中无Ca(2+)时，组胺诱导的收缩受到部分抑制。在来自摄入乙醇的豚鼠和对照豚鼠的胆囊条中，体外25 mmol/l的乙醇在无细胞外Ca(2+)时不影响组胺诱导的收缩。对乙醇抑制作用的耐受性选择性地出现在对组胺和佛波醇12,13 - 二丁酸酯的收缩反应上。长期给予乙醇会产生对体外胆囊收缩力的耐受性，这种收缩力是由通过与蛋白激酶C激活相关的L型Ca(2+)通道的Ca(2+)内流介导的。
