In vivo evidence that EMD 57033 restores myocardial responsiveness to intracoronary Ca(2+) in stunned myocardium.

Abstract

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.

• Authors: S de Zeeuw, S A Trines, R Krams, D J Duncker, P D Verdouw
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 403 Issue 1-2 Pg. 99-109 (Sep 01 2000) ISSN: 0014-2999 [Print] Netherlands
• PMID: 10969150 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Quinolines
• Thiadiazines
• Vasodilator Agents
• EMD 53998
• Propranolol
• Calcium

Topics

• Animals
• Calcium (pharmacology)
• Cardiotonic Agents (pharmacology)
• Coronary Vessels (drug effects, physiopathology)
• Dose-Response Relationship, Drug
• Female
• Heart (drug effects, physiopathology)
• Hemodynamics (drug effects)
• Male
• Myocardial Stunning (metabolism, physiopathology)
• Propranolol (pharmacology)
• Quinolines (pharmacology)
• Stroke Volume (drug effects)
• Swine
• Thiadiazines (pharmacology)
• Vasodilator Agents (pharmacology)
• Ventricular Function, Left (drug effects)