Effects Of Endothelin-1 And Tumor Necrosis Factor-α On L-type Calcium Current In Guinea Pig Ventricular Myocytes On Acute Ischemia Conditions

Tumor necrosis factor-α (TNF- α)is a pro-inflammatory cytokine produced primarily by macrophages.Current data indicate that adult myocytes can also release TNF- α in a variety of cardiac disease ,such as ischemic heart disease,congestive heart failure,myocarditis,et al.Elevated TNF- a in serum and myocardium contributes to the injury of myocytes and myocardial dysfunction,it plays an important role in the pathophysiological changes of these diseases.However, the exact mechanism for the TNF a -induced cardiac dysfunction is not clear. Thus,we studied the effect of TNF- a on the L-type Ca2+ channel current (Ica-0 (using the whole cell patch clamp technique)in isolated guinea pig ventricular myocytes in normal Tyrode solution and imitating ischemia condition. We tried to elucidate the mechanism underlying negative inotropic actions of TNF- a .Endothelin-1 (ET-1), a strong vasoconstrictor peptide ,is shown to produce arrhythmogenesis and prominent positive inotropic effects in myocardium.Elevated levels of ET-1 have been reported in acutemyocardial infarction,angina pectoris and congestive heart failure.lt is closely associated with these cardiovascular pathophysiological disorders.But the electrophysiologic effects of ET-1 on cardiac cells are not well known.In present study,we used whole cell patch clamp to determine the effect of ET-1 on the L-type Ca2+ channel current )in isolated guinea pig ventricular myocytes in normal Tyrode solution and imitating ischemia condition. We want to detect the potent mechanism mediating the pathophysiological actions on myocardium of ET-1. Results:1. Under imitating acute ischemia condition, the peaks of ICa-L were decreased obviously by 25.65 + 4.29% compared with the controled group.There was no any significant changes on maxium active voltage and Ica-L -V relationship curve.2. Under normal Tyrode solution,the application of TNF- a (lOOU/mK 300U/mK 5OOU/ml) did not produce any detectable alterations in Ica-L. Under imitating acute ischemia ,TNF- a increased the inhibitory effects of ischemia on Ica-L with dose-dependence, the peaks of Ica-L were decreased by 46.51 ?3.54% , 62.71 ?2.98% > 80.68 ?3.69% without any significant change on maxium active voltage and Ica.L -V relationship curve.3. Under normal Tyrode solution,the application of ET-l(5nM^10nM, 50nM) obviously increased the peaks of ICB-L by 25.55 ?.65%,44.98?1.68%, 72.00?.55%. While under imitating acute ischemia, ET-1 did not produce any significant changes on Ica-L inhibited by ischemia. There was no any significant changes on maxium active voltage and Ica.L -V relationship curve,either. Conclusion:1. Under imitating acute ischemia condition, the ICa-L was inhibited prominiently.2. Under normal Tyrode solution, TNF- a did not produce any detectable alterations in ICa-L Under imitating acute ischemia ,TNF- a increased the inhibitory effects of ischemia on Ica-L with dose-dependence.3. Under normal Tyrode solution, ET-1 has a significant enhancement on Ica-L ?While under imitating acute ischemia, ET-1 did not produce any significant changes on Ica-L inhibited by ischemia.4. .There was no any significant changes on maxium active voltage and Ica-L -V relationship curve when ET-1 and TNF- a are applicated on the guinea pig ventricular cells in normal Tyrode solution or imitating acute ischemia condition.