CICLETANINE AND REPERFUSION INJURY - IS THERE ANY CORRELATION BETWEEN ARRHYTHMIAS, 6-KETO-PGF1-ALPHA, THROMBOXANE-B2, AND MYOCARDIAL ION SHIFTS (NA+,K+,CA2+, AND MG2+) INDUCED BY ISCHEMIA REPERFUSION IN ISOLATED RAT-HEART

We studied the effects of cicletanine, an antihypertensive drug, on reperfusion arrhythmias in relation to 6-keto-PGF(1-alpha, thromboxane B2 (TXB2), and ion shifts (Na+, K+, Ca2+, and Mg2+) induced by ischemia and reperfusion in hearts isolated from spontaneously hypertensive rats. Hearts were subjected to 30-min global ischemia followed by 10-min reperfusion. 6-keto-PGF1-alpha and TXB2 concentrations were determined by radioimmuno-assay (RIA) from coronary effluents, and myocardial Na+, K+, Ca2+, and Mg2+ contents were measured by atomic absorption spectrophotometry from myocardial tissue. Two basic protocols were used: (a) acute administration when 3, 10, 30, or 100 mg/L cicletanine was included in the perfusion buffer; and (b) chronic application, in which rats received cicletanine 3, 10, 30, or 100 mg/kg/day orally for 14 days. Acute administration of the drug in low concentrations (3 or 10 mg/L), significantly increased endogenous 6-keto-PGF1-alpha production before ischemia and during reperfusion, whereas higher doses of cicletanine (30 or 100 mg/L) as well as chronic application of the drug failed to increase production of 6-keto-PGF1-alpha in the myocardium. TXB2 production was not influenced by either acute or chronic treatment with the drug. Neither treatment changed myocardial ion contents in comparison with control values (Na+ = 45 +/- 4, K+ = 252 +/- 7, Ca2+ = 1.4 +/- 0.1, and Mg2+ = 12.5 +/- 0.3 mmol/kg dry weight) in nonischemic hearts. Thirty-minute ischemia resulted in a two- and fourfold accumulation of myocardial Na+ and Ca2+ and a 50% decrease in both K+ and Mg2+. After 10-min reperfusion, myocardial ion contents were similar to the values of 30-min ischemia, and all hearts showed fibrillation in the untreated group. Both acute and chronic administration of cicletanine protected the heart against reperfusion arrhythmias and ion shifts (30 and 100 mg/L or mg/kg/day). Although the data we report do not show any correlation between the antiarrhythmic effect of cicletanine and 6-keto-PGF1-alpha release, they do indicate a close correlation between antiarrhythmic activity of the drug and myocardial ion shifts induced by ischemia and reperfusion. Our results indicate that cicletanine is able to modify the ischemia- and reperfusion-induced deleterious ion shifts and consequently to protect the heart against life-threatening arrhythmias.