Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction-induced chronic left ventricular dysfunction.
1. It is unknown how cardiac stimulation by Ca(2+) sensitization modulates the cardiovascular response to exercise when left ventricular (LV) function is chronically depressed following a myocardial infarction. We therefore investigated the effects of EMD 57033 at rest and during exercise and compared these to those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan. 2. Pigs were chronically instrumented for measurement of cardiovascular performance. At the time of instrumentation, infarction was produced by coronary artery ligation (MI, n=12). Studies in MI were performed in the awake state, 2 - 3 weeks after infarction. 3. MI were characterized by a lower resting cardiac output (18%), stroke volume (30%) and LVdP/dt(max) (18%), and a doubling of LV end-diastolic pressure, compared to normal pigs (N, n=13). 4. In 11 resting MI, intravenous EMD 57033 (0.2 - 0.8 mg kg(-1) min(-1)) increased LVdP/dt(max) (57+/-5%) and stroke volume (26+/-6%) with no effect on heart rate, LV filling pressure, and myocardial O(2)-consumption, similar to N. 5. In MI, the effects of EMD 57033 (0.4 mg kg(-1) min(-1), IV) on stroke volume and LVdP/dt(max) were maintained during treadmill exercise up to 85% of maximal heart rate, while heart rate was lower compared to control exercise (all P<0.05). In contrast, the effects of EMD57033 gradually waned in N at increasing intensity of exercise. 6. Compared to N, the cardiostimulatory effects of pimobendan (20 microg kg(-1) min(-1), IV) were blunted in MI both at rest and during exercise compared to N. 7. In conclusion, the positive inotropic actions of the Ca(2+) sensitizer EMD 57033 are unmitigated in resting and exercising MI compared to N, while those of the mixed Ca(2+)-sensitizer/phosphodiesterase-III inhibitor pimobendan are blunted.
Duncker
D J
DJ
Experimental Cardiology, Thoraxcenter, Erasmus University Rotterdam, Rotterdam, The Netherlands. Duncker@tch.fgg.eur.nl
Haitsma
D B
DB
Liem
D A
DA
Heins
N
N
Stubenitsky
R
R
Verdouw
P D
PD
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002908:Chronic Disease; D005080:Exercise Test / Q000187:drug effects*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology*; D013552:Swine; D013829:Thiadiazines / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology
D002316:Cardiotonic Agents; D011724:Pyridazines; D011804:Quinolines; D013829:Thiadiazines; C070609:EMD 53998; C041648:pimobendan; D002118:Calcium