Stimulation of reseptors for α
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 α
1-adrenergic agonist phenylephrine (PE) at 1 or l0, μmol/L, ET at 0.5 or 5nmol/L or AT at 1 or 10μmol/ L was infused selectively into the left coronary bed during 12min 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 10μmol/L PE(*p<0.05 vs control), from 8% in control to 8% and 42% with 0.5 and 5 nmol/L of ET. However, AT had no effect. The selective NHE inhibitor NOE642 at lμmol/L, infused concomitantly with l0pmol/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 l1cmol/L did not affect the proarrhythmic effects of PE. Infusion of a specific PKC inhibitor GF109203X(GF) at 30 or 300nmol/L, starting from 5 min before ischemia and maintained throughout ischemia concomitantly with l0, umol/L of PE, was partially effective in reducing VF incidence ; which reduced from 75% in control to 42% with 300nmol/L of GF. These results suggest that, in rat hearts subjected to regional low-flow ischemia and reperfusion, stimulation of a
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. (J Nippon Med Sch 1998; 65:276-283)
View full abstract