Muscarinic—but Not Nicotinic—Acetylcholine Receptors Mediate a Nitric Oxide-Dependent Dilation in Brain Cortical Arterioles: A Possible Role for the M5 Receptor Subtype

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Abstract
Increases in cortical cerebral blood flow are induced by stimulation of basal forebrain cholinergic neurons. This response is mediated in part by nitric oxide (NO) and reportedly involves both nicotinic and muscarinic receptors, some of which are possibly located in the vessel wall. In the present study, the vasomotor response(s) elicited by acetylcholine (ACh) on isolated and pressurized bovine and/or human intracortical penetrating arterioles were investigated, and pharmacological characterization of the receptor involved in this response was carried out. Acetylcholine (10−11 to 10−4 mol/L) dose dependently dilated bovine and human intracortical arterioles at spontaneous tone (respective pD2 values of 6.4 ± 0.3 and 7.2 ± 0.3 and EAmax of 65.0 ± 26.8 and 43.2 ± 30.1% of the maximal dilation obtained with papaverine) and bovine arterioles after preconstriction with serotonin (pD2 = 6.3 ± 0.1, EAmax = 80.0 ± 17.9% of induced tone). In contrast, nicotine (10−8 to 10−4 mol/L) failed to induce any vasomotor response in bovine vessels whether at spontaneous or at pharmacologically induced tone. Application of the nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine (L-NNA; 10−5 mol/L) elicited a gradual constriction (∼20%) of the arterioles, indicating the presence of constitutive NO release in these vessels. Nω-Nitro-L-argigine (10−5 to 10−4 mol/L) also significantly blocked the dilation induced by ACh. The muscarinic ACh receptor (mAChR) antagonists pirenzepine, 4-DAMP, and AF-DX 384 dose dependently inhibited the dilatation induced by ACh (10−5 mol/L) with the following rank order of potency: 4-DAMP (pIC50 = 9.2 ± 0.3) ≫ pirenzepine (pIC50 = 6.7 ± 0.4) > AF-DX 384 (pIC50 = 5.9 ± 0.2). These results suggest that ACh can induce a potent, dose-dependent, and NO-mediated dilation of bovine and/or human intracortical arterioles via interaction with an mAChR that best corresponds to the M5 subtype.