Mechanisms of pH preservation during global ischemia in preconditioned rat heart: roles for PKC and NHE.
Ischemic preconditioning (PC) attenuates cardiac acidosis during global ischemia. This adaptation to ischemia is detectable before other better known indexes of PC are manifested. Clarification of the endogenous mechanisms may provide insights into how protein kinase C (PKC) signaling might be linked to altered intracellular biochemistry. 31P NMR studies of isolated, buffer-perfused rat heart were performed to determine whether functionally cardioprotective PC by cyclic ischemia (CI) and alpha1-adrenergic stimuli [phenylephrine (PE)] attenuated acidosis during ischemia and, if so, whether this 1) involves a PKC-dependent pathway and is due to 2) decreased glycolytic proton production, 3) an increase in proton buffering, or 4) proton extrusion. At the end of 20 min of global ischemia, both CI-PC (pH = 6.86 +/- 0.14) and PE-PC (pH = 6.90 +/- 0.13) attenuated end-ischemic acidosis (control pH = 6.54 +/- 0.1). PKC blockade with chelerythrine (Chel) prevented the attenuation of ischemic acidosis by PC stimuli (end-ischemic pH: CI + Chel, 6.43 +/- 0.06; PE + Chel, 6.17 +/- 0.17). End-ischemic lactate accumulation was decreased in CI-PC hearts (7.54 +/- 0.5 vs. control, 14.61 +/- 2.1 micromol/g wet wt) but not in those preconditioned through the alpha1-adrenergic receptor (12.25 +/- 0.9 micromol/g wet wt). Physiologically relevant buffers were not increased in the preconditioned groups. Blockade of the Na+/H+ exchanger [NHE; with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) or HOE-694] eliminated the attenuation of ischemic acidosis seen with PC stimuli (pH: CI + EIPA, 6.5 +/- 0.1; PE + EIPA, 6.46 +/- 0.2; PE + HOE-694, 6.26 +/- 0.15; not significantly different from control). We conclude that CI and alpha1-adrenergic PC stimuli attenuate ischemic acidosis, and this may involve the cardiac amiloride-sensitive NHE. The signaling pathways of both these two stimuli appear to involve PKC.
Rehring
T F
TF
Department of Surgery, University of Colorado, Denver, Colorado 80262, USA.
Shapiro
J I
JI
Cain
B S
BS
Meldrum
D R
DR
Cleveland
J C
JC
Harken
A H
AH
Banerjee
A
A
D000138:Acidosis / Q000209:etiology / Q000517:prevention & control*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D006146:Guanidines / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D019157:Ischemic Preconditioning, Myocardial; D007700:Kinetics; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D010656:Phenylephrine / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D006146:Guanidines; D010710:Phosphates; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D010656:Phenylephrine; D000584:Amiloride; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; C039614:ethylisopropylamiloride