In vivo evidence that EMD 57033 restores myocardial responsiveness to intracoronary Ca2+ in stunned myocardium
European Journal of Pharmacology , Volume 403 - Issue 1-2 p. 99- 109
Despite ample in vitro evidence that myofilament Ca2+-responsiveness of stunned myocardium is decreased, in vivo data are inconclusive. Conversely, while Ca2+-sensitizing agents increase myofilament Ca2+- responsiveness in vitro, it has been questioned whether this also occurs in vivo. We therefore tested in open-chest anesthetized pigs whether EMD 57033 (the (+) enantiomer of 5-[1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-6- quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one) increases responsiveness to Ca2+ of non-stunned myocardium and restores function of stunned myocardium by normalizing the responsiveness to Ca2+. Studies were performed under β-adrenoceptor blockade to minimize the contribution of the phosphodiesterase-III inhibitory actions of EMD 57033. Consecutive intracoronary Ca2+ infusions were used to evaluate the contractile response (assessed by the left ventricular end-systolic elastance, E(es)) to added Ca2+ of non-stunned myocardium and myocardium stunned by 15 min coronary artery occlusion and 30 min reperfusion. In non-stunned propranolol-treated myocardium, the Ca2+ infusions doubled E(es) (baseline 6.9 ± 0.9 mmHg mm- 2, n = 8). Following Ca2+-washout, subsequent EMD 57033 infusion (0.1 mg kg-1 min-1, i.v.) tripled E(es) (P < 0.05) and potentiated the Ca2+- induced increase in E(es) to 55.7 ± 10.0 mmHg mm-2 (P < 0.05). Stunning (n = 7) decreased E(es) to 5.3 ± 0.6 mmHg mm-2 (P > 0.10) and attenuated the Ca2+-induced increase in E(es) (P < 0.05). Subsequent infusion of EMD 57033 increased E(es) to 6.8 ± 1.8 mmHg mm-2 (P < 0.05) and restored responsiveness to added Ca2+. These in vivo findings are consistent with the in vitro observations that myofilament Ca2+-responsiveness of stunned myocardium is reduced and that EMD 57033 increases contractility by enhancing myofilament Ca2+-responsiveness. (C) 2000 Elsevier Science B.V.