Ca 2+ sensitization and diastolic function of normal and stunned porcine myocardium

Abstract

Ca 2+ sensitizers prolong myofibrillar force development in vitro and might therefore aggravate relaxation abnormalities of stunned myocardium. This is the first in vivo study of the effects of the thiadiazinone derivative EMD 60263 ((+)-5-(l-(alpha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-on), a Ca 2+-sensitizing agent with negligible phosphodiesterase III inhibitory activity, on diastolic function of regionally stunned myocardium. After producing stunning by two sequences of 10-min coronary artery occlusion and 30 min of reperfusion, anaesthetised pigs received either saline ( n=7) or 1.5 and 3.0 mg/kg of EMD 60263 ( n=8) or its enantiomer EMD 60264 ( n=6), which lacks the Ca 2+-sensitizing properties but shares the bradycardiac action via inhibition of the delayed inward rectifier K + current. In stunned myocardium, systolic shortening was reduced to 46±4% of baseline ( P<0.05) and mean rate of half end-diastolic segment lengthening, an index for diastolic function, to 35±4%; systolic shortening and mean rate of half end-diastolic lengthening of remote normal myocardium remained unchanged. Saline did not affect these parameters in stunned or normal myocardium. EMD 60264 did not affect systolic shortening but decreased mean rate of half end-diastolic lengthening in normal myocardium to 61±8% and in stunned myocardium to 16±5% of baseline. During saline and EMD 60264, normal and stunned segments started to lengthen immediately after minimal segment length was reached (Δ T=0). Low dose EMD 60263 restored systolic shortening of the stunned region with no effect on Δ T. The high dose increased systolic shortening above baseline and Δ T to 210±30 ms in both regions. Consequently, mean rate of half end-diastolic lengthening increased to 66±11% in stunned, while decreasing to 55±3% in normal myocardium. After elimination of bradycardia, Δ T and hence mean rate of half end-diastolic lengthening recovered in stunned myocardium, but in normal myocardium the latter remained depressed because Δ T persisted. In conclusion, both doses of EMD 60263 improved systolic as well as diastolic function of stunned myocardium. The high dose delayed relaxation of normal myocardium without adversely affecting systolic function.