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

1998 Fiscal Year Final Research Report Summary

• Project/Area Number: 08670755
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Akita University
• Principal Investigator: ABE Toyohiko Akita Univ.School of Med.Assistant Professor, 医学部, 講師 (30231963)
• Co-Investigator(Kenkyū-buntansha): KIBIRA Hitoshi Akita Univ.School of Med.Research Fellow, 医学部, 助手 (80234334) ; SAITO Takashi Akita Univ.School of Med.Assistant Professor, 医学部, 講師 (90178484) ; MIURA Mamoru Akita Univ.School of Med.Professor, 医学部, 教授 (10006710)
• Project Period (FY): 1996 – 1998
• Keywords: TNF-alpha / neural stunning

Research Abstract

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) 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.