In vivo evidence that EMD 57033 restores myocardial responsiveness to intracoronary Ca(2+) in stunned myocardium.
Despite ample in vitro evidence that myofilament Ca(2+)-responsiveness of stunned myocardium is decreased, in vivo data are inconclusive. Conversely, while Ca(2+)-sensitizing agents increase myofilament Ca(2+)-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 Ca(2+) of non-stunned myocardium and restores function of stunned myocardium by normalizing the responsiveness to Ca(2+). Studies were performed under beta-adrenoceptor blockade to minimize the contribution of the phosphodiesterase-III inhibitory actions of EMD 57033. Consecutive intracoronary Ca(2+) infusions were used to evaluate the contractile response (assessed by the left ventricular end-systolic elastance, E(es)) to added Ca(2+) of non-stunned myocardium and myocardium stunned by 15 min coronary artery occlusion and 30 min reperfusion. In non-stunned propranolol-treated myocardium, the Ca(2+) infusions doubled E(es) (baseline 6.9+/-0.9 mmHg mm(-2), n=8). Following Ca(2+)-washout, subsequent EMD 57033 infusion (0.1 mg kg(-1) min(-1), i.v.) tripled E(es) (P<0.05) and potentiated the Ca(2+)-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 Ca(2+)-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 Ca(2+). These in vivo findings are consistent with the in vitro observations that myofilament Ca(2+)-responsiveness of stunned myocardium is reduced and that EMD 57033 increases contractility by enhancing myofilament Ca(2+)-responsiveness.
de Zeeuw
S
S
Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, Netherlands.
Trines
S A
SA
Krams
R
R
Duncker
D J
DJ
Verdouw
P D
PD
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017682:Myocardial Stunning / Q000378:metabolism / Q000503:physiopathology*; D011433:Propranolol / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects; D013552:Swine; D013829:Thiadiazines / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D011804:Quinolines; D013829:Thiadiazines; D014665:Vasodilator Agents; C070609:EMD 53998; D011433:Propranolol; D002118:Calcium