NOREPINEPHRINE-INDUCED SUSTAINED MYOCARDIAL ADAPTATION TO ISCHEMIA ISDEPENDENT ON ALPHA(1)-ADRENOCEPTORS AND PROTEIN-SYNTHESIS

The authors have shown that stimulation of cardiac alpha(1)-adrenocept ors confers immediate cardioprotection in the isolated rat heart again st post-ischemic dysfunction, and have recently demonstrated that in v ivo treatment of rats with norepinephrine (NE) induces cardiac heat sh ock protein 72 and myocardial adaptation to ischemia 24 h after treatm ent, To characterize the delayed myocardial adaptive response induced by NE further, the present study examined its time course and effects of adrenoceptor antagonism and protein synthesis inhibition on this ad aptive response during optimal myocardial protection, Rats were treate d with NE (3.1 mu mol/kg, ip) or normal saline (0.4 ml, i.p.), and hea rts isolated at 2, 4, 24, 72 and 168 h after injection. Isolated heart s were subjected to 25 min of normothermic global ischemia and 40 min of reperfusion by the Langendorff technique, and left ventricular deve loped pressure (LVDP) was assessed, There was no difference in baselin e LVDP among groups, Post-ischemic LVDP recovered to 44.7+/-2.1 mmHg i n pooled saline control. LVDP was significantly improved in hearts iso lated al 4, 24 and 72 h after injection of NE (66.3+/-3.8, 68.6+/-2.7 and 72.6+/-8.3 mmHg, respectively, P<0.05 v control) but not in hearts isolated at 2 or 168 h. Effects of antecedent adrenoceptor antagonism and protein synthesis inhibition were examined in hearts isolated at 72 h after NE treatment. Prazosin pretreatment (2.4 mu mol/kg, i.p.) a bolished the delayed myocardial adaptive response induced by NE at 72 h (post-ischemic LVDP 48.3+/-6.1 mmHg, P>0.05 v, control) while propra nolol pretreatment (3.6 mu mol/kg i.p.) had no effect (post-ischemic L VDP 67.3+/-3.7 mmHg, P<0.05 v control), Cycloheximide pretreatment (3. 6 mu mol/kg, i.p.) also abolished the beneficial effect of NE at 72 h (postischemic LVDP 50.2+/-6.0 mmHg, P>0.05 v control). In conclusion, administration of NE to rats can induce delayed and sustained cardiopr otection against postischemic myocardial dysfunction, NE-induced myoca rdial adaptation to ischemia at 72 h is mediated by alpha(1)-adrenocep tors and appears to require protein synthesis. (C) 1996 Academic Press Limited