Canine cardiac muscarinic receptors, G proteins, and adenylate cyclase after long-term morphine.
Short-term morphine stimulates vagal bradycardia. This led us to propose the hypothesis that chronically administered morphine would down-regulate myocardial muscarinic receptor systems. Dogs received morphine continuously for 2 weeks through an s.c. catheter, and cellular aspects of parasympathetic control of the heart were examined. Contrary to expectations, morphine increased muscarinic receptor density in the right atrium and left ventricle by 17 and 34%, respectively, with no change in the apparent affinity of the receptor (K(D)). Morphine also increased the expression of the G protein G(ialpha) by 115 and 233%, respectively, in right atrial and left ventricular sarcolemmal membranes. Morphine increased ventricular and atrial G(salpha) to a much lesser degree (49 and 25%). Morphine failed to alter basal or maximally stimulated (forskolin plus MnCl(2)) adenylate cyclase activity. The maximum cyclase activation by isoproterenol and the maximum inhibition by carbachol were similarly unaltered by morphine. Morphine reduced the ventricular but not atrial norepinephrine. Both long- and short-term morphine lowered tissue epinephrine content, suggesting that short-term morphine reduces extraneuronal uptake. Potential systemic and cellular models for myocardial adaptation to morphine are proposed, including sequential sympathetic and parasympathetic compensations.
Napier
L D
LD
Department of Integrative Physiology and The Cardiovascular Research Institute University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
Roerig
S C
SC
Yoshishige
D A
DA
Barron
B A
BA
Caffrey
J L
JL
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D016275:Atrial Function; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009020:Morphine / Q000097:blood / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D016276:Ventricular Function
D011976:Receptors, Muscarinic; D005576:Colforsin; D009020:Morphine; D002217:Carbachol; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine; D004837:Epinephrine