The antiarrhythmic effect of centrally administered rilmenidine involves muscarinic receptors, protein kinase C and mitochondrial signalling pathways.
OBJECTIVE
We have previously demonstrated that stimulation of imidazoline receptors in the CNS prevented halothane-adrenaline arrhythmias during halothane anaesthesia and that stimulation of the vagus nerve may be critical to this effect. However, details of the mechanism(s) involved are not yet available. The present study was designed to examine the role of muscarinic receptors, protein kinase C (PKC), ATP-sensitive potassium channels (K(ATP)) and the mitochondrial permeability transition pore (MPTP) in the antiarrhythmic effect of rilmenidine, an imidazoline receptor agonist.


METHODS
Rats were anaesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of adrenaline was defined as the lowest dose producing three or more premature ventricular contractions within a 15-s period. We confirmed that centrally administered rilmenidine prevented halothane-adrenaline arrhythmias and then examined the antiarrhythmic effect of rilmenidine in the presence of atropine methylnitrate, a muscarinic receptor antagonist, calphostin C, a PKC inhibitor, HMR-1098, a sarcolemmal K(ATP) inhibitor, 5-hydroxydecanoic acid, a mitochondrial K(ATP) inhibitor or atractyloside, an MPTP opener.


RESULTS
The antiarrhythmic effect of rilmenidine was significantly inhibited by atropine methylnitrate, calphostin C, 5-hydroxydecanoic acid and atractyloside, but the effects of HMR-1098 in our model were not clear.


CONCLUSIONS
The present results suggest that muscarinic receptors, PKC, mitochondrial K(ATP) channels and MPTP may be crucial components of the mechanism involved in the antiarrhythmic effect of rilmenidine given into the CNS.
Iwasaki
M
M
Department of Anesthesiology, Osaka University Medical School, Osaka, Japan. miwasaki@anes.med.osaka-u.ac.jp
Hayashi
Y
Y
Kamibayashi
T
T
Yamatodani
A
A
Mashimo
T
T
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control*; D004837:Epinephrine; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D010080:Oxazoles / Q000494:pharmacology*; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D000077769:Rilmenidine
D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D054086:KATP Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010080:Oxazoles; D011976:Receptors, Muscarinic; D011493:Protein Kinase C; D000077769:Rilmenidine; D004837:Epinephrine