title: Impaired beta-adrenergic response and decreased L-type calcium current of hypertrophied left ventricular myocytes in postinfarction heart failure.
abstract: Infarct-induced heart failure is usually associated with cardiac hypertrophy and decreased  -adrenergic responsiveness. However, conflicting results have been reported concerning the density of L-type calcium current (I Ca(L)), and the mechanisms underlying the decreased  -adrenergic inotropic response. We determined I Ca(L) density, cytoplasmic calcium ([Ca2+]i) transients, and the effects of  -adrenergic stimulation (isoproterenol) in a model of postinfarction heart failure in rats. Left ventricular myocytes were obtained by enzymatic digestion 8-10 weeks after infarction. Electrophysiological recordings were obtained using the patch-clamp technique. [Ca2+]i transients were investigated via fura-2 fluorescence.  -Adrenergic receptor density was determined by [ H]-dihydroalprenolol binding to left ventricle homogenates. Postinfarction myocytes showed a significant 25% reduction in mean I Ca(L) density (5.7   0.28 vs 7.6   0.32 pA/pF) and a 19% reduction in mean peak [Ca2+]i transients (0.13   0.007 vs 0.16   0.009) compared to sham myocytes. The isoproterenol-stimulated increase in I Ca(L) was significantly smaller in postinfarction myocytes (Emax: 63.6   4.3 vs 123.3   0.9% in sham myocytes), but EC50 was not altered. The isoproterenol-stimulated peak amplitude of [Ca2+]i transients was also blunted in postinfarction myocytes. Adenylate cyclase activation through forskolin produced similar I Ca(L) increases in both groups.  -Adrenergic receptor density was significantly reduced in homogenates from infarcted hearts (Bmax: 93.89   20.22 vs 271.5   31.43 fmol/mg protein in sham myocytes), while Kd values were similar. We conclude that postinfarction myocytes from large infarcts display reduced I Ca(L) density and peak [Ca2+]i transients. The response to  -adrenergic stimulation was also reduced and was probably related to  -adrenergic receptor down-regulation and not to changes in adenylate cyclase activity.
authors.affiliation: Departamento de Cardiologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
authors.forename: R M
authors.initials: RM
authors.lastname: Saraiva
authors.forename: N G B
authors.initials: NG
authors.lastname: Chedid
authors.forename: C C
authors.initials: CC
authors.lastname: Quintero H
authors.forename: L E
authors.initials: LE
authors.lastname: Díaz G
authors.forename: M O
authors.initials: MO
authors.lastname: Masuda
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000262:Adenylyl Cyclases; D007545:Isoproterenol