Clozapine is a functional antagonist at cardiac human H2-histamine receptors.

IF 3.1 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Jonas M A Schlicht, Undine Ahlrep, Britt Hofmann, Uwe Kirchhefer, Joachim Neumann, Ulrich Gergs
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Abstract

Clozapine is an atypical antipsychotic (neuroleptic) drug. Clozapine binds to H2-histamine receptors in vitro. We wanted to test the hypothesis that clozapine might be a functional antagonist at human cardiac H2-histamine receptors. To that end, we studied isolated electrically stimulated left atrial preparations and spontaneously beating right atrial preparations from transgenic mice with cardiomyocyte-specific overexpression of the human H2-histamine receptor (H2-TG). For comparison, we used wild-type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium (HAP) obtained from patients during bypass surgery. After pre-stimulation with histamine, clozapine (up to 10 µM) concentration and time dependently decreased beating rate in right atrial preparations from H2-TG. Clozapine concentration dependently 1, 3, and 10 µM decreased histamine-stimulated force of contraction in HAP. Clozapine (10 µM) decreased also the isoprenaline-stimulated force of contraction in HAP. In summary, clozapine can antagonize the function of H2-histamine and β-receptors in the human heart.

氯氮平是心脏人h2 -组胺受体的功能性拮抗剂。
氯氮平是一种非典型抗精神病药物。氯氮平在体外与h2 -组胺受体结合。我们想测试氯氮平可能是人类心脏h2 -组胺受体的功能性拮抗剂的假设。为此,我们研究了从心肌细胞特异性过表达人h2 -组胺受体(H2-TG)的转基因小鼠中分离的电刺激左心房制剂和自发跳动右心房制剂。为了进行比较,我们使用野生型同窝小鼠(WT)。最后,我们测量了心脏搭桥手术患者右心房电刺激肌条的等距收缩力。在组胺预刺激后,氯氮平(浓度高达10µM)和时间依赖性地降低了H2-TG右心房制剂的心律。氯氮平浓度依赖于1、3和10µM降低组胺刺激的HAP收缩力。氯氮平(10µM)也能降低异丙肾上腺素刺激的HAP收缩力。综上所述,氯氮平可以拮抗心脏中h2 -组胺和β-受体的功能。
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来源期刊
CiteScore
6.20
自引率
5.60%
发文量
142
审稿时长
4-8 weeks
期刊介绍: Naunyn-Schmiedeberg''s Archives of Pharmacology was founded in 1873 by B. Naunyn, O. Schmiedeberg and E. Klebs as Archiv für experimentelle Pathologie und Pharmakologie, is the offical journal of the German Society of Experimental and Clinical Pharmacology and Toxicology (Deutsche Gesellschaft für experimentelle und klinische Pharmakologie und Toxikologie, DGPT) and the Sphingolipid Club. The journal publishes invited reviews, original articles, short communications and meeting reports and appears monthly. Naunyn-Schmiedeberg''s Archives of Pharmacology welcomes manuscripts for consideration of publication that report new and significant information on drug action and toxicity of chemical compounds. Thus, its scope covers all fields of experimental and clinical pharmacology as well as toxicology and includes studies in the fields of neuropharmacology and cardiovascular pharmacology as well as those describing drug actions at the cellular, biochemical and molecular levels. Moreover, submission of clinical trials with healthy volunteers or patients is encouraged. Short communications provide a means for rapid publication of significant findings of current interest that represent a conceptual advance in the field.
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