Anesthetized open-chest male Wistar rats were subjected to either 45 minutes of left coronary artery occlusion (phase 1a 10 minutes and phase 2b 35 minutes) and 2 hours of reperfusion in Experiment 1 or 10 minutes of
ischemia and 10 minutes of reperfusion in Experiment 2. In Experiment 1, saline or vehicle controls and the mu-specific
opioids dermorphin-H (Derm-H) and ([d-Ala2, N-Me-Phe4, Gly-ol5]
enkephalin (DAMAGO); the delta-1-specific
opioid d-Pen2,5enkephalin (
DPDPE);
nociceptin; and the delta-2-specific
opioids deltorphin-II (
Delt-II), Delt-Dvariant (Delt-Dvar), and
deltorphin-E (Delt-E) were infused 15 minutes prior to
ischemia. In Experiment 2,
DPDPE, Delt-D, Delt-Dvar, and Delt-E were infused at 15 minutes prior to
ischemia. The universal
opioid receptor antagonist naltrexone, the peripherally acting antagonist
naloxone methiodide, the selective δ1 antagonist 7-benzylidene
naltrexone maleate, and the specific δ2 antagonist
naltriben mesylate were infused 25 minutes prior to
ischemia.
RESULTS: In Experiment 1, pretreatment with the μ
opioids Derm-H and
DAMGO,
DPDPE, and
nociceptin at all doses tested did not reduce the incidence of
ischemia-induced arrhythmias compared to controls during 45 minutes of
ischemia. The δ2
opioids Delt-II (0.12 mg/kg), Delt-Dvar (0.3 mg/kg), and Delt-E (0.18 mg/kg) all demonstrated significant antiarrhythmic effects at the 150 nmol/kg dose compared to saline or vehicle controls. Nine of 19 animals treated with
Delt-II were tolerant without ventricular arrhythmias to the arrhythmogenic effect of
ischemia during the first 10 minutes of
ischemia (phase 1a) and 11 of 19 were without ventricular arrhythmias during the following 35 minutes of
ischemia (phase 1b).
Delt-II also decreased the incidence of
premature ventricular contractions and
ventricular tachycardia by almost half during phase 1a.
Delt-II did not affect the incidence of
ventricular fibrillation (VF). Pretreatment with Delt-Dvar and Delt-E completely blocked the incidence of VF in phase 1b. Delt-E also decreased
premature ventricular contractions by 50%, and the incidence of
ventricular tachycardia decreased over twofold in phase 1b of
ischemia. There was no enhanced tolerance by any of the delta-2
opioids to the arrhythmogenic effect of reperfusion after long-term
ischemia. In Experiment 2, after 10 minutes of
ischemia and 10 minutes of reperfusion,
Delt-II (0.12 mg/kg) reduced the incidence of
premature ventricular contractions and
ventricular tachycardia compared to controls, and completely blocked the incidence of VF following 10 minutes of reperfusion. Delt-Dvar and Delt-E were without effect, as was
DPDPE following 10 minutes of reperfusion. The antiarrhythmic effect of
Delt-II during 10 minutes of
ischemia and 10 minutes of reperfusion was completely blocked by the peripherally acting
opioid receptor inhibitor
naloxone methiodide and the selective delta-2
opioid receptor inhibitor
naltriben mesylate, but not by the selective delta-1 inhibitor 7-benzylidene
naltrexone maleate. The antagonists alone had no effect on arrhythmogenesis.
CONCLUSIONS: