Ro 5-4864和PK 11195对大鼠十二指肠和输精管的作用。

Effects of Ro 5-4864 and PK 11195 in rat duodenum and vas deferens.

作者信息

Escubedo E, Pallas M, Nuñez C, Camarasa J

机构信息

Laboratory of Pharmacology and Pharmacognosy, Faculty of Pharmacy, University of Barcelona, Spain.

出版信息

Eur J Pharmacol. 1992 Jan 14;225(1):15-20. doi: 10.1016/0922-4106(92)90033-r.

DOI:10.1016/0922-4106(92)90033-r

PMID:1311686

Abstract

Ro 5-4864 and PK 11195 inhibit in a concentration-dependent manner carbachol-induced contractions in rat duodenum (IC50: 1.56 +/- 0.07 x 10(-5) M and 1.18 +/- 0.07 x 10(-5) M respectively). The antagonism is non-competitive and is not mediated by peripheral-type benzodiazepine receptors. The Ro 5-4864 effect is modulated by the calcium concentration of the Tyrode-Ringer solution. In the presence of 1 mM NaF/10 microM AlCl3, Ro 5-4864 and PK 11195 do not inhibit carbachol-induced contractions. Moreover, Ro 5-4864 and PK 11195 significantly relax AlF(4-)-induced contractions, with IC50 values of 2.01 +/- 0.12 x 10(-5) M and 1.28 +/- 0.11 x 10(-5) M respectively. This effect is also modulated by the calcium concentration of the medium. Pertussis toxin potentiates the antagonist effects of Ro 5-4864 and PK 11195 on carbachol-induced contractions, but cholera toxin does not affect them. Ro 5-4864 and PK 11195 inhibit 45Ca2+ uptake induced by KCl (120 mM) in rat vas deferens, but do not affect either basal 45Ca efflux or noradrenaline-induced 45Ca2+ efflux. Only high doses of PK 11195 (above 5 x 10(-5) M) are able to produce a slight reduction of the accumulation of inositol phosphates induced by methoxamine in rat vas deferens, while Ro 5-4864 has no significant effect. Finally, Ro 5-4864 and PK 11195 reduce calcium influx, but do not seem to be the only mechanism of the antagonistic effect on carbachol-induced contractions. An alteration of other second messengers, probably cyclic monophosphate nucleotides, may be involved.

摘要

Ro 5-4864和PK 11195以浓度依赖性方式抑制卡巴胆碱诱导的大鼠十二指肠收缩（IC50分别为1.56±0.07×10⁻⁵ M和1.18±0.07×10⁻⁵ M）。这种拮抗作用是非竞争性的，且不是由外周型苯二氮䓬受体介导的。Ro 5-4864的作用受台氏-林格溶液钙浓度的调节。在1 mM NaF/10 μM AlCl₃存在下，Ro 5-4864和PK 11195不抑制卡巴胆碱诱导的收缩。此外，Ro 5-4864和PK 11195能显著舒张AlF₄⁻诱导的收缩，IC50值分别为2.01±0.12×10⁻⁵ M和1.28±0.11×10⁻⁵ M。这种作用也受培养基钙浓度的调节。百日咳毒素增强Ro 5-4864和PK 11195对卡巴胆碱诱导收缩的拮抗作用，但霍乱毒素对其无影响。Ro 5-4864和PK 11195抑制KCl（120 mM）诱导的大鼠输精管45Ca²⁺摄取，但不影响基础45Ca外流或去甲肾上腺素诱导的45Ca²⁺外流。只有高剂量的PK 11195（高于5×10⁻⁵ M）能使甲氧明诱导的大鼠输精管肌醇磷酸积累略有减少，而Ro 5-4864无显著作用。最后，Ro 5-4864和PK 11195减少钙内流，但似乎不是对卡巴胆碱诱导收缩产生拮抗作用的唯一机制。可能涉及其他第二信使的改变，可能是环磷酸核苷酸。