title: Enhanced basal contractility but reduced excitation-contraction coupling efficiency and beta-adrenergic reserve of hearts with increased Cav1.2 activity.
abstract: Cardiac remodeling during heart failure development induces a significant increase in the activity of the L-type Ca(2+) channel (Cav1.2). However, the effects of enhanced Cav1.2 activity on myocyte excitation-contraction (E-C) coupling, cardiac contractility, and its regulation by the beta-adrenergic system are not clear. To recapitulate the increased Cav1.2 activity, a double transgenic (DTG) mouse model overexpressing the Cavbeta2a subunit in a cardiac-specific and inducible manner was established. We studied cardiac (in vivo) and myocyte (in vitro) contractility at baseline and upon beta-adrenergic stimulation. E-C coupling efficiency was evaluated in isolated myocytes as well. The following results were found: 1) in DTG myocytes, L-type Ca(2+) current (I(Ca,L)) density, myocyte fractional shortening (FS), peak Ca(2+) transients, and sarcoplasmic reticulum (SR) Ca(2+) content (caffeine-induced Ca(2+) transient peak) were significantly increased (by 100.8%, 48.8%, 49.8%, and 46.8%, respectively); and 2) cardiac contractility evaluated with echocardiography [ejection fraction (EF) and (FS)] and invasive intra-left ventricular pressure (maximum dP/dt and -dP/dt) measurements were significantly greater in DTG mice than in control mice. However, 1) the cardiac contractility (EF, FS, dP/dt, and -dP/dt)-enhancing effect of the beta-adrenergic agonist isoproterenol (2 microg/g body wt ip) was significantly reduced in DTG mice, which could be attributed to the loss of beta-adrenergic stimulation on contraction, Ca(2+) transients, I(Ca,L), and SR Ca(2+) content in DTG myocytes; and 2) E-C couplng efficiency was significantly lower in DTG myocytes. In conclusion, increasing Cav1.2 activity by promoting its high-activity mode enhances cardiac contractility but decreases E-C coupling efficiency and the adrenergic reserve of the heart.
authors.affiliation: Cardiovascular Research Center and Dept. of Physiology, Temple Univ. School of Medicine, 3400 N. Broad St., Philadelphia, PA 19140, USA.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Tang
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Li
authors.forename: Yinzheng
authors.initials: Y
authors.lastname: Guan
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ai
authors.forename: Christopher
authors.initials: C
authors.lastname: Szeto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Shuping
authors.initials: S
authors.lastname: Ge
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D056966:Excitation Contraction Coupling / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D021122:Protein Subunits; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013318:Stroke Volume; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D021122:Protein Subunits; D011943:Receptors, Adrenergic, beta; D002110:Caffeine; D007545:Isoproterenol; D002118:Calcium