title: MDIMP, a novel cardiac Ca(2+) channel blocker with atrial selectivity.
abstract: In cardiac muscle cells both T-and L-type Ca(2+) 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 CaV1.2. 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 Ca(2+) channels and ECC. To this end, mechanical properties, as well as Ca(2+) transients and currents, were all investigated in isolated cardiac myocytes. The effects of MDIMP on CaV1.2 (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 450µM. With respect to myocytes: atrial-TTCCs, atrial-LTCCs, and ventricular-LTCCs were also inhibited, in that order of potency. Accordingly, Ca(2+) 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 Ca(2+) channels, improve our knowledge of the corresponding structure-function relationship, and may be relevant for conditions where decreased atrial activity is desired.
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
authors.forename: Mireille Aline
authors.initials: MA
authors.lastname: Santamaria-Herrera
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
authors.forename: Erick Benjamín
authors.initials: EB
authors.lastname: Ríos-Pérez
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
authors.forename: Juan Antonio Manuel
authors.initials: JA
authors.lastname: de la Rosa
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
authors.forename: Maricela
authors.initials: M
authors.lastname: García-Castañeda
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
authors.forename: Diana Stephanie
authors.initials: DS
authors.lastname: Osornio-Garduño
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, 2800 Plymouth Rd, 26-235N, Ann Arbor, MI 48109, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ramos-Mondragón
authors.affiliation: Department of Chemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico.
authors.forename: Teresa
authors.initials: T
authors.lastname: Mancilla-Percino
authors.affiliation: Department of Biochemistry, Cinvestav-IPN, AP 14-740, México City, DF 07000, Mexico. Electronic address: gavila@cinvestav.mx.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Avila
mesh_terms: D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D010421:Pentanoic Acids / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D054833:Isoindoles; C419385:L-type calcium channel alpha(1C); D010421:Pentanoic Acids; C000614834:methyl(S)-2-(1,3-dihydroisoindol-2-yl)-4-methylpentanoate
keywords: Ca(2+)-induced Ca(2+) release; Cardiac myocyte; Excitation-contraction coupling; Intracellular Ca(2+); Ion channels