A Peripheral Site of Action for the Attenuation of Baroreflex-Mediated Bradycardia by Intravenous μ-Opioid Agonists

We previously reported that i.v. DAMGO (Tyr-D-Ala-Gly-NMePhe-Gly-ol), a selective μ-opioid agonist, causes an increase in blood pressure with no change in heart rate in unanesthetized sheep and subsequently demonstrated that DAMGO attenuates baroreflex-mediated bradycardia. To determine the site and mechanism by which μ-agonists inhibit baroreflex sensitivity, we have carried out further investigations by using DAMGO and another μ-agonist, DALDA (Tyr-D-Arg-Phe-Lys-NH 2 ). The bradycardic response to norepinephrine (NE) was significantly blunted after i.v. DAMGO or DALDA in both nonpregnant and pregnant sheep. In contrast, the tachycardic response to sodium nitroprusside (SNP) remained unchanged in the presence of DAMGO or DALDA. In view of the highly restricted distribution of DALDA across the blood-brain barrier (BBB), we hypothesized that the blunting of reflex-mediated bradycardia by μ-opioid agonists can occur peripherally. Pretreatment with the quaternary opioid antagonist, naloxone methiodide (NM), completely blocked the attenuation of baroreflex sensitivity by DAMGO and DALDA in both nonpregnant and pregnant animals. These data suggest that in addition to central mechanisms, μ-opioid agonists can inhibit baroreflex sensitivity at a peripheral site, most likely by inhibiting vagal influence on heart-rate control rather than by acting directly at baroreceptors.