Na+/H+ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor.
Activation of sarcolemmal Na+/H+ exchange has been proposed as a causal factor in reperfusion arrhythmogenesis. To test this hypothesis, we determined the antiarrhythmic efficacy of two structurally distinct but equipotent Na+H+ exchange inhibitors, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and the novel drug, 3-methylsulfonyl-4-piperidinobenzoyl guanidine (HOE-694), in isolated rat hearts (n = 12/group) subjected to independent dual coronary perfusion. After 15 min of aerobic perfusion of both beds, flow to the left coronary bed (LCB) was terminated for 10 min; this was followed by 5 min of reperfusion. Various concentrations of each drug were selectively infused into the LCB either during the 5-min period preceding ischemia plus during reperfusion or during reperfusion alone. With the former protocol, 0.01, 0.1, 1, and 10 microM EIPA reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from 92% in controls to 83, 83, 50, and 0% (P < 0.05); the number of hearts in sinus rhythm at the end of reperfusion was increased from 17 to 42, 25, 83 (P < 0.05), and 100% (P < 0.05). HOE-694, at the same concentrations, reduced VF incidence from 92% in control to 83, 58, 50, and 8% (P < 0.05); 25, 67, 75 (P < 0.05), and 100% (P < 0.05) of hearts were in sinus rhythm, compared with 17% of controls, at the end of reperfusion. Even when infused during reperfusion alone, both drugs afforded significant protection against reperfusion-induced VF, which did not differ significantly from that observed when the drugs were also given before ischemia. The similar antiarrhythmic efficacy of EIPA and HOE-694 is consistent with an arrhythmogenic role for activation of Na+/H+ exchange during early reperfusion.
Yasutake
M
M
Rayne Institute, St. Thomas' Hospital, London, United Kingdom.
Ibuki
C
C
Hearse
D J
DJ
Avkiran
M
M
D000584:Amiloride / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D003326:Coronary Circulation; D004562:Electrocardiography; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use; D006339:Heart Rate; D008297:Male; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013450:Sulfones / Q000008:administration & dosage / Q000627:therapeutic use; D014693:Ventricular Fibrillation / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D000584:Amiloride; C039614:ethylisopropylamiloride