Cardiac enkephalins interrupt vagal bradycardia via delta 2-opioid receptors in sinoatrial node.
Local cardiac opioids appear to be important in determining the quality of vagal control of heart rate. Introduction of the endogenous opioid methionine-enkephalin-arginine-phenylalanine (MEAP) into the interstitium of the canine sinoatrial node by microdialysis attenuates vagally mediated bradycardia through a delta-opioid receptor mechanism. The following studies were conducted to test the hypothesis that a delta(2)-opiate receptor subtype mediates the interruption of vagal transmission. Twenty mongrel dogs were anesthetized and instrumented with microdialysis probes inserted into the sinoatrial node. Vagal frequency responses were performed at 1, 2, and 3 Hz during vehicle infusion and during treatment with the native agonist MEAP, the delta(1)-opioids 2-methyl-4aa-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aalpha-octahydroquinolino[2,3,3- g]isoquinoline (TAN-67) and [d-pen(2,5)]-enkephalin (DPDPE), and the delta(2) opioid deltorphin II. The vagolytic effects of intranodal MEAP and deltorphin were then challenged with the delta(1)- and delta(2)-opioid receptor antagonists 7-benzylidenenaltrexone (BNTX) and naltriben, respectively. Although the positive control deltorphin II was clearly vagolytic in each experimental group, TAN-67 and DPDPE were vagolytically ineffective in the same animals. In contrast, TAN-67 improved vagal bradycardia by 30-35%. Naltriben completely reversed the vagolytic effects of MEAP and deltorphin. BNTX was ineffective in this regard but did reverse the vagal improvement observed with TAN-67. These data support the hypothesis that the vagolytic effect of the endogenous opioid MEAP was mediated by delta(2)-opioid receptors located in the sinoatrial node. These data also support the existence of vagotonic delta(1)-opioid receptors also in the sinoatrial node.
Farias
Martin
M
Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
Jackson
Keith E
KE
Yoshishige
Darice
D
Caffrey
James L
JL
D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D001919:Bradycardia / Q000188:drug therapy* / Q000503:physiopathology*; D004285:Dogs; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D012849:Sinoatrial Node / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D000701:Analgesics, Opioid; D001597:Benzylidene Compounds; D009292:Narcotic Antagonists; D009842:Oligopeptides; D018847:Opioid Peptides; D011804:Quinolines; D017465:Receptors, Opioid, delta; C094142:TAN 67; C068868:naltrindole benzofuran; C060209:deltorphin II, Ala(2)-; C077358:7-benzylidenenaltrexone; D004744:Enkephalin, Methionine; D009271:Naltrexone; C027511:enkephalin-Met, Arg(6)-Phe(7)-; D020881:Enkephalin, D-Penicillamine (2,5)-