米力农在豚鼠离体模型中的变时作用:筛选新的作用机制的初步研究。

IF 2.6 4区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Piero Pollesello, Jouko Levijoki, Zoltán Papp
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引用次数: 0

摘要

米力酮是一种磷酸二酯酶(PDE)抑制剂,在服用米力酮后出现正性肌力反应,包括明显的正性变时效应。在这里,我们测试了米立酮是否仅仅通过PDE抑制或通过涉及其他药理靶点的协同作用来引起这种变时反应。在假定的辅助分子途径或离子通道抑制剂存在或不存在的情况下,在豚鼠右心房制剂中研究米立酮刺激心率的增加:即具有不同选择性的β受体阻滞剂(普萘洛尔、美托洛尔和卡维地洛尔)、α1受体阻滞剂(吡唑嗪)、小电导Ca2+活化K+ (SK)通道抑制剂(apamin)、l型Ca2+通道阻滞剂(维拉帕米和地尔硫卓)和不同的Na+通道阻滞剂(利多卡因、河蟹毒素和奎宁)。卡维地洛抑制β1、β2、α1和5-HT受体,将米力酮的正向变时作用限制在40%左右(p
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Chronotropic Effects of Milrinone in a Guinea Pig Ex Vivo Model: A Pilot Study to Screen for New Mechanisms of Action.

Abstract: Positive inotropic responses upon administration of milrinone, an inhibitor of the phosphodiesterase enzyme (PDE), involve a well-pronounced positive chronotropic effect. Here, we tested whether milrinone evokes this chronotropic response solely by PDE inhibition or by a concerted action that involve additional pharmacological targets. Milrinone-stimulated increases in heart rate were studied in right atrial preparations of guinea pig in the presence or absence of inhibitors of putative ancillary molecular pathways or ion channels: ie, β receptor blockers with distinct selectivities (propranolol, metoprolol, and carvedilol), α1 receptor blocker (prazosin), inhibitor of the small conductance Ca 2+ activated K + (SK) channels (apamin), L-type Ca 2+ channel blockers (verapamil and diltiazem), and different Na + channel blockers (lidocaine, tetrodotoxin, and quinidine). Carvedilol, which inhibits β1, β2, α1, and 5-HT receptors, limited the positive chronotropic effects of milrinone to about 40%, ( P < 0.01). In the presence of another nonselective blocker of the β receptors, propranolol, and blockers of the l -type Ca 2+ channels, only nonsignificant trends toward reductions of the milrinone effects were seen. The α1 receptor blocker prazosin did not limit the milrinone-evoked positive chronotropy. Blockers of Na + channels, SK channels, or the β1 receptor blocker, metoprolol also did not affect the positive chronotropy evoked by milrinone. We conclude that milrinone increases heart rate in response to adrenergic signaling, which besides PDE inhibition, may involve a 5-HT receptor-dependent component. Our exploratory approach paves the way to more focused experiments with the use of selective 5-HT receptor antagonists to confirm or reject the involvement of a specific 5-HT receptor-dependent pathway.

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来源期刊
CiteScore
5.10
自引率
3.30%
发文量
367
审稿时长
1 months
期刊介绍: Journal of Cardiovascular Pharmacology is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. The Journal encourages submission in all aspects of cardiovascular pharmacology/medicine including, but not limited to: stroke, kidney disease, lipid disorders, diabetes, systemic and pulmonary hypertension, cancer angiogenesis, neural and hormonal control of the circulation, sepsis, neurodegenerative diseases with a vascular component, cardiac and vascular remodeling, heart failure, angina, anticoagulants/antiplatelet agents, drugs/agents that affect vascular smooth muscle, and arrhythmias. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, application of drugs to gain novel insights into physiology or pathological conditions, clinical results with new and established agents, and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases. Please note that JCVP does not publish work based on biological extracts of mixed and uncertain chemical composition or unknown concentration.
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