M1 and M3 muscarinic receptors in human pulmonary arteries

1. Acetylcholine (ACh) and the M1 agonists (McN-A-343 or PD142505) relaxed human isolated pulmonary arteries which were pre-contracted with noradrenaline (10 microM). In preparations where the endothelium had been removed ACh induced a contractile response whereas the M1 agonists (McN-A-343 or PD142505) had no effect. 2. ACh- and McN-A-343-induced relaxations were abolished after treatment of endothelium-intact preparations with the drug combination NG-nitro-L-arginine (L-NOARG: 0.1 mM) and indomethacin (1.7 microM). 3. The affinity (pKB value) for pirenzepine was higher in human pulmonary arteries when tissues were relaxed with McN-A-343 as compared with ACh (pKB values, 7.71 +/- 0.30 (n = 4) and 6.68 +/- 0.15 (n = 8), respectively). In addition, the affinity for pFHHSiD against McN-A-343- and ACh-induced relaxations was 6.86 +/- 0.13 (n = 3) and 7.35 +/- 0.11 (n = 9) respectively. 4. The low affinities for methoctramine in human isolated pulmonary arteries with the endothelium either intact or removed, suggested the lack of involvement of M2 and M4 receptors in the Ach responses. 5. Phenoxybenzamine (3 microM: 30 min) abolished both ACh contraction and relaxation in human pulmonary artery. The ACh contraction was present when the phenoxybenzamine treatment was preceded by incubation with pFHHSiD (2 microM) but not with pirenzepine (1 microM). In addition, the ACh relaxation was present when preparations were treated with either pFHHSiD (2 microM) or pirenzepine (1 microM), before exposure to phenoxybenzamine. 6. These results in human isolated pulmonary arteries support the notion that only M3 receptors, on smooth muscle, mediate the ACh-induced contraction whereas M3 and M1 receptors are involved in the endothelium-dependent ACh-induced relaxation.