Inhibition of PLC improves postischemic recovery in isolated rat heart

The Ca2+-dependent PLC converts phosphatidylinositol 4,5-bisphosphate to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Because these products modulate Ca2+ movements in the myocardium, PLC may also contribute to a self-perpetuating cycle that exacerbates cardiomyocyte Ca2+-ov...

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Published inAmerican journal of physiology. Heart and circulatory physiology Vol. 56; no. 6; pp. H2598 - H2605
Main Authors ASEMU, Girma, DHALLA, Naranjan S, TAPPIA, Paramjit S
Format Journal Article
LanguageEnglish
Published Bethesda, MD American Physiological Society 01.12.2004
Subjects
Biological and medical sciences
Blood pressure
Calcium
Drug therapy
Fundamental and applied biological sciences. Psychology
Heart
Heart attacks
Phosphates
Vertebrates: cardiovascular system
Heart
Sarcolemma
Rat
Calcium antagonist
Rodentia
U-73122
Cardiovascular disease
Recovery
Vertebrata
Mammalia
Ischemia
Aralkylamine
Verapamil
Circulatory system
Hemodynamics
Inhibition
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Summary:The Ca2+-dependent PLC converts phosphatidylinositol 4,5-bisphosphate to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]. Because these products modulate Ca2+ movements in the myocardium, PLC may also contribute to a self-perpetuating cycle that exacerbates cardiomyocyte Ca2+-overload and subsequent cardiac dysfunction in ischemia-reperfusion (I/R). Although we have reported that I/R-induced changes in PLC isozymes might contribute to cardiac dysfunction, the present study was undertaken to examine the beneficial effects of the PLC inhibitor, U-73122, as well as determining the role of Ca2+ on the I/R-induced changes in PLC isozymes. Isolated rat hearts were subjected to global ischemia 30 min, followed by 5 or 30 min of reperfusion. Pretreatment of hearts with U-73122 (0.5 microM) significantly inhibited DAG and Ins(1,4,5)P3 production in I/R and was associated with enhanced recovery of cardiac function as indicated by measurement of left ventricular (LV) end-diastolic pressure (EDP), LV diastolic pressure (LVDP), maximum rate of pressure development (+dP/dtmax), and maximum rate of LV pressure decay (-dP/dtmax). Verapamil (0.1 microM) partially prevented the increase in sarcolemmal (SL) PLC-{beta}1 activity in ischemia and the decrease in its activity during the reperfusion phase as well as elicited a partial protection of the depression in SL PLC-{delta}1 and PLC-{gamma}1 activities during the ischemic phase and attenuated the increase during the reperfusion period. Although these changes were associated with an improved myocardial recovery after I/R, verapamil was less effective than U-73122. Perfusion with high Ca2+ resulted in the activation of the PLC isozymes studied and was associated with a markedly increased LVEDP and reduced LVDP, +dP/dtmax, and -dP/dtmax. These results suggest that inhibition of PLC improves myocardial recovery after I/R. [PUBLICATION ABSTRACT]
ISSN:0363-6135
1522-1539