Recruitment of inotropic reserve in “stunned” myocardium by the cardiotonic agent AR-L 57

Abstract

Contractile dysfunction of reversibly injured, reperfused myocardium can be enhanced by inotropic interventions. A decrease in the Ca-sensitivity of contractile proteins with slow recovery during reperfusion has been suggested as a potential mechanism underlying this postischemic dysfunction. We therefore tested the effects of the cardiotonic agent AR-L 57 (1 mg/kg i.v.) in six anesthetized, vagotomized dogs during constant atrial pacing at 192 +/- 6 beats/min. Before ischemia, AR-L 57 increased left ventricular pressure from 131 +/- 22 to 138 +/- 21 mm Hg and maximum dP/dt from 3,022 +/- 1,427 to 4,337 +/- 2,608 mm Hg/s. Mean systolic thickening velocity of the posterior myocardium was increased from 8.9 +/- 1.1 to 11.7 +/- 1.1 mm/s. After release of a 15 min LCX-occlusion which caused complete regional akinesia, baseline function in the posterior myocardium was severely depressed and only gradually returned towards control values over 8 h of reperfusion. AR-L 57 increased systolic thickening velocity at 10 min, 4 and 8 h reperfusion to a similar extent as before ischemia. With reference to a purported Ca-sensitizing mechanism underlying the positive inotropic action of AR-L 57, our data suggest no change in the Ca-sensitivity of reperfused myocardium.

Recruitment of a time-dependent inotropic reserve by postextrasystolic potentiation in normal and reperfused myocardium

“…The equally pronounced stepwise increases in regional contractility in normal and stunned myocardium suggest no change in the myocardial Cakinetics of excitation-contraction coupling in rcperfused myocardium in situ. An unchanged Ca-sensitivity of reperfused myocardium was also suggested by a previous study from our laboratory in which the recruitment of an inotropic reserve by the purported Ca-sensitizer AR-L 57 was identical in normal and reperfused myocardium of anesthetized dogs (25). However, as transcellular and intracellular Ca-fluxes were not measured directly in these studies, this conclusion remains speculative at present.…”

“…In contrast, in canine in situ preparations there was no diminished contractile response to intracoronary calcium (30) or to the purported Ca-sensitizer AR-L 57 (25) in reperfused myocardium. The analysis of regional contractile effects of postextrasystolic potentiation with constant prematurity and three different postextrasystolic time intervals could provide further insight into the Cakinetics of excitation-contraction coupling in situ.…”

“…Previous studies from our laboratory using similar experimental preparations demonstrated either an increase (13,24) or no change (23,25) in non-ischemic systolic myocardial function during regional myocardial ischemia. Apparently, the effect of regional myocardial ischemia on non-ischemic systolic myocardial function is variable.…”

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“…Despite numerous efforts, the cellular mechanism of myocardial stunning is not fully understood [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Stunned myocardium remains responsive to positive inotropic agents such as catecholamines [2], increased extracellular Ca 2+ concentration [3], phosphodiesterase III (PDE III) inhibitors (e.g.…”

“…Stunned myocardium remains responsive to positive inotropic agents such as catecholamines [2], increased extracellular Ca 2+ concentration [3], phosphodiesterase III (PDE III) inhibitors (e.g. AR-L 57) [4] and the so-called Ca 2+ sensitizers (e.g. thiadiazinone derivatives [+]EMD 57033 [5] and [+]EMD 60263 [6]).…”