Protection of neuronal uptake-1 inhibitors in ischemic and anoxic hearts by norepinephrine-dependent and -independent mechanisms.
Cardiac ischemia and anoxia induce massive norepinephrine (NE) release, which is mediated by a reverse operation of uptake-1 and can be suppressed by uptake-1 inhibitors. We studied effects of uptake-1 inhibitors on incidence of ventricular fibrillation (VF%) and myocardial contracture in perfused rat hearts under ischemic or anoxic conditions. NE release occurred in hearts during ischemia or anoxia and was largely inhibited by desipramine, imipramine, and cocaine. The generation of inositol 1,4,5-trisphosphate (InsP3) during reperfusion also was abolished by desipramine. During anoxia/reoxygenation, VF (93 and 71%, respectively) and myocardial contracture occurred and were significantly inhibited by desipramine and by NE depletion. Regional ischemia and reperfusion induced high VF% (86 and 100%, respectively), which was reduced or abolished by desipramine and imipramine at 0.03 and 0.3 microM. During the ischemic phase, cocaine was similarly antiarrhythmic, as was a combination of timolol and prazosin, but NE depletion was not. In NE-depleted hearts, cocaine or the combination of timolol and prazosin showed limited effect on VF%, whereas both desipramine and imipramine abolished VF. In anesthetized rats in vivo, ischemic VF% was reduced by desipramine (30 vs. 92%; p < 0.01). In conclusion, uptake-1 inhibitors protect hearts against ischemia/reperfusion- and anoxia/reoxygenation-induced arrhythmias, partly because of the inhibition of locally mediated NE release. Other actions of desipramine and imipramine may contribute to the overall efficacy.
Du
X J
XJ
Baker Medical Research Institute, Melbourne, Australia.
Woodcock
E A
EA
Little
P J
PJ
Esler
M D
MD
Dart
A M
AM
D018759:Adrenergic Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003891:Desipramine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D000860:Hypoxia / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology* / Q000627:therapeutic use; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism*; D015425:Myocardial Reperfusion; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D014693:Ventricular Fibrillation / Q000517:prevention & control*
D018759:Adrenergic Uptake Inhibitors; D018765:Dopamine Uptake Inhibitors; D015544:Inositol 1,4,5-Trisphosphate; D003042:Cocaine; D007099:Imipramine; D003891:Desipramine; D009638:Norepinephrine