MDIMP, a novel cardiac Ca²⁺ channel blocker with atrial selectivity

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• 作者：Mireille Aline Santamaria-Herrera^a ; Erick Benjamí ; n Rí ; os-Pé ; rez^a ; Juan Antonio Manuel de la Rosa^a ; Maricela Garcí ; a-Castañ ; eda^a ; Diana Stephanie Osornio-Garduñ ; o^a ; Roberto Ramos-Mondragó ; n^a ; ^c ; Teresa Mancilla-Percino^b ; Guillermo Avila^a ; ^{gavila@cinvestav.mx" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Ion channels ; Intracellular Ca2+ ; Cardiac myocyte ; Excitation-contraction coupling ; Ca2+-induced Ca2+ release
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 June 2016
• 年：2016
• 卷：781
• 期：Complete
• 页码：218-228
• 全文大小：1231 K

文摘

In cardiac muscle cells both T-and L-type Ca²⁺ channels (TTCCs and LTCCs, respectively) are expressed, and the latter are relevant to a process known as excitation-contraction coupling (ECC). Evidence obtained from docking studies suggests that isoindolines derived from α-amino acids bind to the LTCC Ca_V1.2. In the present study, we investigated whether methyl (S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate (MDIMP), which is derived from L-leucine, modulates both Ca²⁺ channels and ECC. To this end, mechanical properties, as well as Ca²⁺ transients and currents, were all investigated in isolated cardiac myocytes. The effects of MDIMP on Ca_V1.2 (transiently expressed in 293T/17 cells) were also studied. In this system, evidence was found for an inhibitory action that develops and recovers in min, with an IC₅₀ of 450 µM. With respect to myocytes: atrial-TTCCs, atrial-LTCCs, and ventricular-LTCCs were also inhibited, in that order of potency. Accordingly, Ca²⁺ transients, contractions, and window currents of LTCCs were all reduced more strongly in atrial cells. Interestingly, while the modulation of LTCCs was state-independent in these cells, it was state-dependent, and dual, on the ventricular ones. Furthermore, practically all of the ventricular LTCCs were closed at resting membrane potentials. This could explain their resistance to MDIMP, as they were affected in only open or inactivated states. All these features in turn explain the preferential down-regulation of the atrial ECC. Thus, our results support the view that isoindolines bind to Ca²⁺ channels, improve our knowledge of the corresponding structure-function relationship, and may be relevant for conditions where decreased atrial activity is desired.