Atypical Adrenoceptor-mediated Relaxation of Canine Pulmonary Artery Through a Cyclic Adenosine Monophosphate–dependent Pathway

Abstract.

To determine whether functional atypical β-adrenoceptors (β₃-adrenoceptors) are present in pulmonary vascular smooth muscle, we studied isolated canine pulmonary arterial rings under isometric conditions in vitro. Addition of β-adrenoceptor agonists produced a concentration-dependent relaxation of noradrenaline-precontracted tissues, a rank order potency being isoproterenol (1) > salbutamol (0.95) > selective β₃-adrenoceptor agonists, CL 316243 (0.85), and BRL 37344 (0.83). A marked desensitization to salbutamol occurred by pretreatment with salbutamol but not with CL 316243. When β₁-adrenoceptors had been blocked, the relaxant responses to salbutamol were competitively antagonized by the β₂-adrenoceptor antagonist ICI 118551 with a pA₂ value of 7.67 ± 0.21 (mean ± S.E.), but the response to CL 316243 was weekly antagonized by ICI 118551 only at a high concentration of 10⁻⁵ M, where an apparent pA₂ value was 5.24. In contrast, cyanopindolol, a nonselective β-adrenoceptor antagonist, antagonized CL 316243–induced relaxation in a competitive manner with a pA₂ of 6.10 ± 0.11. This pA₂ value was lower than that when salbutamol was used as an agonist (6.69 ± 0.14, p < 0.01). Intracellular 3′,5′-cyclic adenosine monophosphate (cAMP) levels were increased by CL 316243 in a concentration-dependent fashion, an effect that was not altered by ICI 118551. These results suggest that β₃-adrenoceptors may exist in canine pulmonary artery smooth muscle and that stimulation of this atypical receptor causes vasodilation through a cAMP-dependent pathway.