[Effect of phenylephrine, endothelin and angiotensin II on reperfusion arrhythmias. A role for Na+/H+ exchanger activation via protein kinase C].
Stimulation of receptors for alpha 1-adrenergic agonist, endothelin (ET) and angiotensin II (AT) activates the cardiac sarcolemmal Na+/H+ exchanger (NHE), perhaps via protein kinase C(PKC)-mediated pathway(s). We tested for the ability of these extracellular stimuli to exacerbate reperfusion arrhythmias and for the possible role of NHE activation and PKC in such phenomena. Isolated rat hearts (n = 12/group) were subjected to dual coronary perfusion. After 15 min of aerobic perfusion, flow to the left coronary bed was reduced to 5% of basal values for 12 min, and the same bed was then reperfused for 5 min. An alpha 1-adrenergic agonist phenylephrine (PE) at 1 or 10 mumol/L, ET at 0.5 or 5nmol/L or AT at 1 or 10mumol/L was infused selectively into the left coronary bed during 12 min of regional low flow ischemia. The incidence of reperfusion-induced ventricular fibrillation (VF) was increased from 17% in control to 33% and 75%* with 1 and 10 mumol/L PE(*p < 0.05 vs control) from 8% in control to 8% and 12% with 0.5 and 5 nmol/L of ET. However, AT had no effect. The selective NHE inhibitor NOE642 at 1 mumol/L, infused concomitantly with 10 mumol/L PE, reversed the proarrhythmic effects of PE; VF incidence was reduced from 67% to 8%*. However, glibenclamide (a blocker for the ATP-sensitive K+ channel) at 1 mumol/L did not affect the proarrhythmic effects of PE. Infusion of a specific PKC inhibitor GF109203X(GF) at 30 or 300 nmol/L, starting from 5 min before ischemia and maintained throughout ischemia concomitantly with 10 mumol/L of PE, was partially effective in reducing VF incidence; which reduced from 75% in control to 42% with 300 nmol/L of GF. These results suggest that, in rat hearts subjected to regional low-flow ischemia and reperfusion, stimulation of alpha 1-adrenergic receptor can exacerbate reperfusion-induced VF, whose mechanism(s) may involve NHE activation. Moreover, PKC activation does not appear to be the sole signaling mechanism for this phenomenon.
First Department of Medicine, Nippon Medical School, Tokyo, Japan.
D
D
Jia
M
M
Yasutake
Y
Y
Kusama
H
H
Kishida
H
H
Hayakawa
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D016232:Endothelins / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000209:etiology*; D010656:Phenylephrine / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000209:etiology*
D000316:Adrenergic alpha-Agonists; D016232:Endothelins; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; D010656:Phenylephrine; D011493:Protein Kinase C