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Ultra-low-dose methionine-enkephalin-arginine-phenylalanine improves vagal transmission (vagotonic) and decreases heart rate via [[delta].sub.1]-opioid receptors within the sinoatrial (SA) node. Higher doses activate [[delta].sub.2]-opioid receptors, interrapt vagal transmission (vagolytic), and reduce the bradycardia. Preconditioning-like occinsion of the nodal artery produced a vagotonic response that was reversed by the [[delta].sub.1]-antagonist 7-benzylidenaltrexone (BNTX). The following study tested the hypothesis that extended [[delta].sub.1]-opioid receptor stimulation reduces subsequent [[delta].sub.2]-receptor responses. The [[delta].sub.2]-agonist deltorphin II was introduced in the SA node by microdialysis to evaluate [[delta].sub.2] responses before and after infusion of the [[delta].sub.1]-agonist TAN-67. TAN-67 reduced the vagolytic effect of deltorphin by two-thirds. When the [[delta].sub.1]-antagonist BNTX was combined with TAN-67, the deltorphin response was preserved, suggesting that attrition of the prior response was mediated by [[delta].sub.1] activity. When TAN-67 was omitted in time control studies, some loss of [[delta].sub.2] responses was apparent in the absence of the 81 treatment. This loss was also eliminated by BNTX, suggesting that the attenuation of the response after deltorphin alone was also the result of [[delta].sub.1] activity. Additional studies tested TAN-67 alone in the absence of prior deltorphin. When time controls were conducted without the initial deltorphin treatment, a robust vagolytic response was observed. When TAN-67 preceded the delayed deltorphin, the vagolytic response was eroded, indicating an independent effect of TAN-67. BNTX infused afterward was unable to restore the [[delta].sub.2] response. These data support the conclusion that the loss of the [[delta].sub.2] response resulted from reduced [[delta].sub.2] activity mediated by continued [[delta].sub.1]-receptor stimulation and not the arithmetic consequence of increased competition from that same [[delta].sub.1] receptor. sinoatrial node

Methionine-enkephalin-arginine-phenylalanine (MEAP) introduced into the interstitium of the canine sinoatrial (SA) node by microdialysis interrupts vagal bradycardia. In contrast, raising endogenous MEAP by occluding the SA node artery improves vagal bradycardia. Both are blocked by the same [delta]-selective antagonist, naltrindole. We tested the hypothesis that vagal responses to intranodal enkephalin are bimodal and that the polarity of the response is both doseand opioid receptor subtype dependent. Ultralow doses of MEAP were introduced into the canine SA node by microdialysis. Heart rate frequency responses were constructed by stimulating the right vagus nerve at 1, 2, and 3 Hz. Ultralow MEAP infusions produced a 50-100% increase in bradycardia during vagal stimulation. Maximal improvement was observed at a dose rate of 500 fmol/min with an E[D.sub.50] near 50 fmol/min. Vagal improvement was returned to control when MEAP was combined with the [delta]-antagonist naltrindole. The dose of naltrindole (500 fmol/min) was previously determined as ineffective vs. the vagolytic effect of higher dose MEAP. When MEAP was later reintroduced in the same animals at nanomoles per minute, a clear vagolytic response was observed. The [[delta].sub.1]-selective antagonist 7-benzylidenenaltrexone (BNTX) reversed the vagal improvement with an E[D.sub.50] near 1 x [10.sup.-21] mol/min, whereas the [[delta].sub.2]-antagonist naltriben had no effect through [10.sup.-9] mol/min. Finally, the improved vagal bradycardia previously associated with nodal artery occlusion and endogenous MEAP was blocked by the selective [[delta].sub.1]-antagonist BNTX. These data support the hypothesis that opioid effects within the SA node are bimodal in character, that low doses are vagotonic, acting on [[delta].sub.1]-receptors, and that higher doses are vagolytic, acting on [[delta].sub.2]-receptors. heart rate; enkephalins; opiate receptors; microdialysis; parasympathetic nervous system

Ultra-low-dose methionine-enkephalin-arginine-phenylalanine improves vagal transmission (vagotonic) and decreases heart rate via δ1-opioid receptors within the sinoatrial (SA) node. Higher doses activate δ2-opioid receptors, interrupt vagal transmission (vagolytic), and reduce the bradycardia. Pre-conditioning-like occlusion of the nodal artery produced a vagotonic response that was reversed by the δ1-antagonist 7-benzylidenaltrexone (BNTX). The following study tested the hypothesis that extended δ1-opioid receptor stimulation reduces subsequent δ2-receptor responses. The δ2-agonist deltorphin II was introduced in the SA node by microdialysis to evaluate δ2 responses before and after infusion of the δ1-agonist TAN-67. TAN-67 reduced the vagolytic effect of deltorphin by two-thirds. When the δ1-antagonist BNTX was combined with TAN-67, the deltorphin response was preserved, suggesting that attrition of the prior response was mediated by δ1 activity. When TAN-67 was omitted in time control studies, some loss of δ2 responses was apparent in the absence of the δ1 treatment. This loss was also eliminated by BNTX, suggesting that the attenuation of the response after deltorphin alone was also the result of δ1 activity. Additional studies tested TAN-67 alone in the absence of prior deltorphin. When time controls were conducted without the initial deltorphin treatment, a robust vagolytic response was observed. When TAN-67 preceded the delayed deltorphin, the vagolytic response was eroded, indicating an independent effect of TAN-67. BNTX infused afterward was unable to restore the E2 response. These data support the conclusion that the loss of the δ2 response resulted from reduced δ2 activity mediated by continued δ1-receptor stimulation and not the arithmetic consequence of increased competition from that same receptor. [ABSTRACT FROM AUTHOR]

Methionine-enkephalin-arginine-phenylalanine (MEAP) introduced into the interstitium of the canine sinoatrial (SA) node by microdialysis interrupts vagal bradycardia. In contrast, raising endogenous MEAP by occluding the SA node artery improves vagal bradycardia. Both are blocked by the same δ-selective antagonist, naltrindole. We tested the hypothesis that vagal responses to intranodal enkephalin are bimodal and that the polarity of the response is both doseand opioid receptor subtype dependent. Ultralow doses of MEAP were introduced into the canine SA node by microdialysis. Heart rate frequency responses were constructed by stimulating the right vagus nerve at 1, 2, and 3 Hz. Ultralow MEAP infusions produced a 50-100% increase in bradycardia during vagal stimulation. Maximal improvement was observed at a dose rate of 500 fmol/min with an EDso near 50 fmol/min. Vagal improvement was returned to control when MEAP was combined with the δ-antagonist naltrindole. The dose of naltrindole (500 fmol/min) was previously determined as ineffective vs. the vagolytic effect of higher dose MEAP. When MEAP was later reintroduced in the same animals at nanomoles per minute, a clear vagolytic response was observed. The δ[sub 1]-selective antagonist 7-benzylidenenaltrexone (BNTX) reversed the vagal improvement with an EDso near 1 × 10[sup -21] mol/min, whereas the δ[sub 2]-antagonist naltriben had no effect through 10[sup -9] mol/min. Finally, the improved vagal bradycardia previously associated with nodal artery occlusion and endogenous MEAP was blocked by the selective δ[sub 1]-antagonist BNTX. These data support the hypothesis that opioid effects within the SA node are bimodal in character, that low doses are vagotonic, acting on δ[sub 1]-receptors, and that higher doses are vagolytic, acting on δ°2-receptors. [ABSTRACT FROM AUTHOR]