Prazosin reduces myocardial ischemia/reperfusion-induced Ca2+ overloading in rat heart by inhibiting phosphoinositide signaling.
The aim of this study was to establish whether or not alpha 1-adrenergic receptors are implicated in triggering phosphoinositide hydrolysis and intracellular Ca2+ accumulation during myocardial ischemia and reperfusion. In isolated perfused rat hearts, the selective alpha 1-receptor antagonist prazosin abolished the increase in radioactivity incorporation into cellular inositol phosphates induced by 30 min ischemia followed by 30 min reperfusion, and selectively blocked the degradation of phosphoinositides; only minor changes in the ischemia/reperfusion-induced loss of other classes of phospholipids were seen. In addition, a prazosin-induced decrease of ischemia/reperfusion Ca2+ overloading was documented in real-time recordings of epicardial cytosolic free Ca2+ in fura 2-loaded hearts. An inhibition of early ischemic Ca2+ rise was observed, as well as a lower peak of cytosolic free Ca2+ and a more rapid reversal to normal values during reperfusion. Moreover, alpha 1-adrenergic blockade resulted in a significant improvement in the recovery of myocardial function during reperfusion: an increased left ventricular developed pressure and maximum rate of rise of systolic pressure paralleled the decrease in time-averaged cytosolic Ca2+ and the increase in amplitude of Ca2+ transients, respectively. It is concluded that myocardial Ca2+ overloading during ischemia and reperfusion may be triggered by alpha 1-adrenergic receptor-induced polyphosphoinositide hydrolysis.
Moraru
I I
II
Department of Surgery, University of Connecticut School of Medicine, Farmington 06030-1110, USA.
Jones
R M
RM
Popescu
L M
LM
Engelman
R M
RM
Das
D K
DK
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D017725:Ventricular Pressure
D058668:Adrenergic alpha-1 Receptor Antagonists; D010716:Phosphatidylinositols; D010738:Type C Phospholipases; D002118:Calcium; D011224:Prazosin