Contribution of protein kinases in the ischemic-induced dysfunction of cardiac sympathic innervation

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A brief period of myocardial ischemia is capable of producing transient dysfunction of cardiac sympathetic innervation. Tumor necrotizing facter-a (TNF-a) is a multifunctional cytokine that is also produced during myocardial ischemia and reperfusion. While TNF-a is reported to be a neurotrophic factor in the central nervous system, the protective role of TNF-a in cardiac neural stunning has not been determined. We examined the hypothesis that TNF-a attenuates post-ischemic reductions in sympathetic coronary constriction. Mongreldogs were anesthetized with a-chloralose and instrumented for recordings of heart rate (HR), arterial pressure (AP), LV dP dt, % segment length (%SL) and LAD and LCX coronary flow velocities (Doppler). After bilateral vagotomy and b-adrenergic blockade by propranolol, LAD was occluded for 15 min followed by reperfusion. Bilateral electrical stimulation of ansa subclavia was performed to evaluate % change in coronary resistance to sympathetic stimulation (D%CVR) … More before and after release of 15 min LAD occlusion. Intracoronary administration of TNF-a (6 ug/kg/min, n=6) or vehicle (n=5) was started 15 min before coronary occlusion to 5 min after reperfusion, In another dogs with intracoronary administration of anti-TNF-a antibody (60 nl/kg/mm, n=6) or vehicle (n=5), *%CVR was also estimated before and after release of 7 min LAD occlusion.Results : 1) Sympathetic stimulation produced transient increase in coronary resistance in both LAD and LCX beds. *%CVR in the LAD bed before (40*8%, MSE) and 15 min after reperfusion (38*8%) was not different in dogs treated with TNF-a . This contrasts with the change in LAD resistance from dogs with vehicle (38*5% before and 162% after reperfusion ; p<0.05). 2) *%CVR in the LAD bed after release of 7 min LAD occlusion was not affected in dogs with vehicle, while it was decreased with anti-TNF-a antibody(38*5% before and 19* 8% after reperfusion ; p<0.05).We conclude that TNF-a protects against post-ischemic neural stunning of sympathetic coronary innervation. Less