M₁ and M₃ muscarinic receptors in human pulmonary arteries

Abstract

1 Acetylcholine (ACh) and the M, agonists (McN-A-343 or PD142505) relaxed human isolated pulmonary arteries which were pre-contracted with noradrenaline (10 ,gM). 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 N0-nitro-L-arginine (L-NOARG: 0.1 mM) and indomethacin (1.7 giM). 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 /M: 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 gM) but not with pirenzepine (1 gM). In addition, the ACh relaxation was present when preparations were treated with either pFHHSiD (2 gM) or pirenzepine (1 gM), 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 M, receptors are involved in the endothelium-dependent ACh-induced relaxation.

Prostacyclin release and receptor activation: differential control of human pulmonary venous and arterial tone

“…These observations are supported by the different physiological results obtained with L-NOARG on the relaxations induced by ACh in human pulmonary veins when compared with arteries. The effect of L-NOARG in the arterial preparations only unmasked the contractile activity of ACh (Norel et al, 1996). In the veins since there is no contraction induced by ACh (Walch et al, 1997), the reduced ACh relaxation observed in the presence of L-NOARG was entirely associated with the reduced production of NO.…”

“…Previous reports have shown that EDHF is not involved in the AChinduced relaxations of human pulmonary arterial preparations, since treatment of tissues with a combination of NO-synthase (NOS) and cyclooxygenase (COX) inhibitors completely abolished these effects (Norel et al, 1996;Lawrence et al, 1998). In several species, the relaxant effect of ACh in pulmonary arteries and veins has been reported to be different, since veins are insensitive to this relaxant agonist (De Mey & Vanhoutte, 1982;Gruetter & Lemke, 1986;Ignarro et al, 1987;Kemp et al, 1997;Shi et al, 1997).…”

Vascular function in arteries of intertidal fish Girella laevifrons(Kyphosidae)

“…Furthermore, pharmacological studies support the presence of functional muscarinic receptors type 1 and 3 (Norel et al, 1996). Additionally, studies performed in human pulmonary arteries suggest the presence of muscarinic receptor type 3 in smooth muscle mediating the Ach-induced contraction, and muscarinic receptors type 1 are involved in the endothelium-dependent Achinduced relaxation (Norel et al, 1996). In fish, Ach induced contraction in all the species studied so far (Small et al, 1990;Olson and Villa, 1991;Miller and Vanhoutte,1992; Evans and Gunderson, 1998a).…”

“…Molecular approach has demonstrated the presence of muscarinic receptors type 1-3 in arterial vessels (See review, Kawashima and Fujii, 2008). Furthermore, pharmacological studies support the presence of functional muscarinic receptors type 1 and 3 (Norel et al, 1996). Additionally, studies performed in human pulmonary arteries suggest the presence of muscarinic receptor type 3 in smooth muscle mediating the Ach-induced contraction, and muscarinic receptors type 1 are involved in the endothelium-dependent Achinduced relaxation (Norel et al, 1996).…”

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

“…62 Hypertension is likely due to the blockade of M 1 or M 3 receptors on the arterial endothelium and the blockade of NO release because muscarinic stimulation can relax pulmonary arteries that are pre-contracted with noradrenaline. 63 Therefore, in general the cardiovascular side effects associated with anticholinergic medications at doses that are clinically effective for LUTS are minor and they are rarely, if ever, a reason for discontinuing the medication.…”