Stimulation of opioid mu-receptors potentiates beta adrenoceptor-mediated relaxation of canine airway smooth muscle.
To elucidate the effect of an opioid on airway smooth muscle relaxant responses and its mechanism of action, we studied canine bronchial segments under isometric conditions in vitro. Addition of the opioid mu-receptor-specific agonist DAMGO (10(-5) M) or Tyr-D-Arg-phe-Lys-NH2 (10(-5) M) did not alter the resting tension or the contractile responses to Ach but augmented the relaxation induced by isoproterenol: the concentrations of isoproterenol required to produce a half-maximal effect were decreased from 1.9 +/- 0.6 x 10(-6) to 3.1 +/- 1.0 x 10(-7) M (P < .01) by DAMGO and from 2.1 +/- 0.4 x 10(-6) M to 4.3 +/- 0.7 x 10(-7) M (P < .01), by Tyr-D-Arg-phe-Lys-NH2. This effect of DAMGO was concentration-dependent and was abolished by naloxone or Cys2, Tyr3, Orn5, Pen7-amide, a mu-receptor antagonist. DAMGO likewise caused a leftward displacement of concentration-response curves for forskolin but was without effect on those for 3-isobutyl-3-methylxanthine and 8-bromo-cAMP. Also, DAMGO did not affect the relaxant responses to verapamil, nitroprusside or 8-bromo-cGMP. Incubation of bronchial smooth muscle with DAMGO (10(-5) M) potentiated the intracellular accumulation of cAMP induced by isoproterenol (10(-6) M) from 258 +/- 22 pmol/g tissue wt. to 420 +/- 27 pmol/g tissue wt. (P < .01), an effect that was abolished by naloxone. These results suggest that stimulation of opioid mu-receptors specifically augments beta adrenoceptor-mediated bronchodilation probably by acting at the site proximal to adenylate cyclase in the cAMP-dependent pathway.
Tagaya
E
E
First Department of Medicine, Tokyo Women's Medical College, Japan.
Tamaoki
J
J
Chiyotani
A
A
Konno
K
K
D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D008297:Male; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000502:physiology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
D004745:Enkephalins; D009842:Oligopeptides; D011943:Receptors, Adrenergic, beta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide; D000242:Cyclic AMP