THE ROLE OF SUBSTANCE-P IN MYOCARDIAL DYSFUNCTION DURING ISCHEMIA ANDREPERFUSION

Impairment of myocardial contraction (''myocardial stunning'') occurs during reperfusion after short ischemic periods. Substance P (SP) is w idely distributed in heart and can be released by various stimuli incl uding myocardial hypoxia. Our previous study shows SP has a negative i notropic effect in guinea pig heart. The objective of this study was t o investigate whether SP contributes to the myocardial stunning after brief global ischemia. Guinea pig hearts in a Langendorff preparation were subjected to 15 min of global ischemia followed by 60 min reperfu sion. Experiments were performed without and with pretreatment with ne urokinin-1 (NK1) receptor antagonists, spantide (10(-6) M) or CP-99,99 4-01 (10(-6) M) in order to study the role of SP. Experiments were als o performed in hearts which were perfused with atropine, phentolamine, and nadolol (10(-6) M each) to examine the role of neurotransmitters and autonomic receptors. A group of hearts obtained from capsaicin-pre treated guinea pigs was also investigated. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), hear t rate, and perfusion pressure were monitored. At the end of reperfusi on, the LVDP of control hearts recovered to only 55 +/- 6% (+/- SEM) o f preischemic baseline and the LVEDP increased significantly (P > 0.05 ). With pretreatment with spantide or CP-99,994-01, LVDP recovered to 88 +/- 2% or 78 +/- 2% of the preischemic baseline, respectively. The LVEDP of these hearts was not different from preischemic baseline and much smaller than in control hearts. There were no differences in hear t rate and perfusion pressure compared to baseline among all groups. S imilar results were obtained in hearts perfused with autonomic blocker s. However, recoveries of LVDP and LVEDP were faster in hearts perfuse d with autonomic blockers during the first 10 min of reperfusion. Pret reatment with capsaicin also significantly improved recovery of LVDP a nd LVEDP. In conclusion, substance P is involved in postischemic myoca rdial dysfunction and neurokinin-1 receptors mediate this action. The NK1 receptor antagonists may be useful in prevention of ''myocardial s tunning''.