The authors studied the reduction in anesthetic requirement (MAC) and the hemodynamic effects of the highly selective alpha 2-adrenergic agonist azepexole in isoflurane-anesthetized dogs. Eleven male beagles were anesthetized with isoflurane in oxygen. After a 2-h equilibration period, they determined isoflurane MAC and baseline hemodynamic function. Azepexole (at 0.1, 0.3, and 1.0 mg/kg) was administered via a right atrial port over 15 min, while each dog was given isoflurane at the MAC dose for that animal. Twenty minutes after the end of infusion, at a time when hemodynamic variables were stable, they reassessed hemodynamic function. They then determined isoflurane MAC again. In other experiments, dogs were pretreated with either idazoxan (the alpha 2-adrenergic antagonist; n = 5) or naloxone (the opiate antagonist; n = 7) prior to the administration of azepexole. Isoflurane MAC was determined before and after each dose of azepexole. Isoflurane MAC decreased as the dose of azepexole increased, to the extent that at the highest dose (1 mg/kg) the decrement in MAC was more than 85%. This reduction of MAC caused by azepexole could be completely prevented by pretreatment with idazoxan, while naloxone was without effect. Azepexole did not change mean arterial blood pressure, but caused heart rate and cardiac output to progressively decrease. The MAC-reducing effect of azepexole appears to be mediated by alpha 2 adrenoreceptors. Given the extent of the reduction of MAC, it is unlikely that inhibition of central noradrenergic neurotransmission through agonism of presynaptic alpha 2 adrenoreceptors is the sole explanation, since complete disruption of central noradrenergic tracts decreases MAC by only 40%.(ABSTRACT TRUNCATED AT 250 WORDS)