选择性鸟苷酸环化酶抑制剂及收缩水平对胃底氮能舒张的影响。

Influence of a selective guanylate cyclase inhibitor, and of the contraction level, on nitrergic relaxations in the gastric fundus.

作者信息

Lefebvre R A

机构信息

Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.

出版信息

Br J Pharmacol. 1998 Aug;124(7):1439-48. doi: 10.1038/sj.bjp.0701992.

DOI:10.1038/sj.bjp.0701992

PMID:9723956

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565545/

Abstract

The influence of the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) on non-adrenergic non-cholinergic (NANC) relaxations and the possible role of a nerve-derived hyperpolarizing factor in NANC relaxation were investigated in the rat gastric fundus. 2. ODQ (10(-6) and 10(-5) M) concentration-dependently inhibited the short-lasting relaxations by NO (2 x 10(-6) M-10(-4) M) administered as a bolus without influencing the relaxation by 3 x 10(-8) M isoprenaline. The relaxation by an infusion of NO was reduced to the same extent by 10(-6) and 10(-5) M ODQ. 3. The electrically induced short-lasting and sustained relaxations (40 V, 1 ms, 0.5-16 Hz, 10 s trains at 2 min interval or cumulative increase in the frequency every 2 min) in NANC conditions were inhibited to a similar extent by 10(-6) and 10(-5) M ODQ, and by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 3 x 10(-4) M). 4. ODQ (10(-6) M) and L-NAME (3 x 10(-4) M), administered after 5, 10 or 20 min of long-term stimulation, reversed the relaxation to a similar extent (approximately 50% at 2 Hz and 20% at 8 Hz). 5. When the tissues were contracted to 40% of maximum by adapting the concentration of prostaglandin F2alpha (PGF2alpha), the inhibitory effect of 3 x 10(-4) M L-NAME on relaxations induced by train and cumulative stimulation was the same as when tissues were contracted with 3 x 10(-7) M PGF2alpha. 6. The findings of this study illustrate that the relaxation by exogenous and endogenous NO in the rat gastric fundus is due to activation of soluble guanylate cyclase. During long-term electrical stimulation, the partial contribution of NO to NANC relaxation is maintained but it is small at higher frequencies of stimulation. Evidence for the contribution of a nerve-derived hyperpolarizing factor to NANC relaxation was not obtained.

摘要

研究了可溶性鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮（ODQ）对大鼠胃底非肾上腺素能非胆碱能（NANC）舒张的影响，以及神经源性超极化因子在NANC舒张中可能发挥的作用。2. ODQ（10⁻⁶和10⁻⁵ M）浓度依赖性地抑制了一次性给予的NO（2×10⁻⁶ M - 10⁻⁴ M）所引起的短暂舒张，而不影响3×10⁻⁸ M异丙肾上腺素所引起的舒张。通过输注NO所产生的舒张被10⁻⁶和10⁻⁵ M ODQ降低到相同程度。3. 在NANC条件下，电诱导的短暂和持续舒张（40 V，1 ms，0.5 - 16 Hz，每隔2分钟进行10秒的串刺激或每隔2分钟频率逐渐增加）被10⁻⁶和10⁻⁵ M ODQ以及NO合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME；3×10⁻⁴ M）以相似程度抑制。4. 在长期刺激5、10或20分钟后给予ODQ（10⁻⁶ M）和L-NAME（3×10⁻⁴ M），使舒张逆转到相似程度（2 Hz时约为50%，8 Hz时约为20%）。5. 当通过调整前列腺素F2α（PGF2α）的浓度使组织收缩至最大收缩力的40%时，3×10⁻⁴ M L-NAME对串刺激和累积刺激诱导的舒张的抑制作用与用3×10⁻⁷ M PGF2α使组织收缩时相同。6. 本研究结果表明，大鼠胃底中外源性和内源性NO所引起的舒张是由于可溶性鸟苷酸环化酶的激活。在长期电刺激期间，NO对NANC舒张的部分贡献得以维持，但在较高刺激频率下其作用较小。未获得神经源性超极化因子对NANC舒张有贡献的证据。