In vivo evidence that EMD 57033 restores myocardial responsiveness to intracoronary Ca2+ in stunned myocardium

Despite ample in vitro evidence that myofilament Ca2+-responsiveness of stu nned myocardium is decreased, in vivo data are inconclusive. Conversely, wh ile Ca2+-sensitizing agents increase myofilament Ca2+-responsiveness in vit ro, it has been questioned whether this also occurs in vivo. We therefore t ested 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 normaliz ing the responsiveness to Ca2+. Studies were performed under beta-adrenocep tor blockade to minimize the contribution of the phosphodiesterase-III inhi bitory 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 reperfusi on. In non-stunned propranolol-treated myocardium, the Ca2+ infusions doubl ed 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 mmH g 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 m m(-2) (P < 0.05) and restored responsiveness to added Ca2+. These in vivo f indings are consistent with the in vitro observations that myofilament Ca2-responsiveness of stunned myocardium is reduced and that EMD 57033 increas es contractility by enhancing myofilament Ca2+-responsiveness. (C) 2000 Els evier Science B.V. All rights reserved.