Muscarinic-but not nicotinic-acetylcholine receptors mediate a nitric oxide-dependent dilation in brain cortical arterioles: A possible role for the M5 receptor subtype

Increases in cortical cerebral blood flow are induced by stimulation of bas al forebrain cholinergic neurons. This response is mediated in part by nitr ic oxide (NO) and reportedly involves both nicotinic and muscarinic recepto rs, some of which are possibly located in the vessel wall. In the present s tudy, the vasomotor response(s) elicited by acetylcholine (ACh) on isolated and pressurized bovine and/or human intracortical penetrating arterioles w ere investigated, and pharmacological characterization of the receptor invo lved in this response was carried out. Acetylcholine (10(-11) to 10(-4) mol /L) dose dependently dilated bovine and human intracortical arterioles at s pontaneous tone (respective pD(2) values of 6.4 +/- 0.3 and 7.2 +/- 0.3 and E-Amax of 65.0 +/- 26.8 and 43.2 +/- 30.1% of the maximal dilation obtaine d with papaverine) and bovine arterioles after preconstriction with seroton in (pD(2) = 6.3 +/- 0.1, E-Amax = 80.0 +/- 17.9% of induced tone). rn contr ast, nicotine (10(-8) to 10(-4) mol/L) failed to induce any vasomotor respo nse in bovine vessels whether at spontaneous or at pharmacologically induce d tone. Application of the nitric oxide synthase (NOS) inhibitor N-omega ni tro-L-arginine (L-NNA, 10(-5) mol/L) elicited a gradual constriction (simil ar to 20%) of the arterioles, indicating the presence of constitutive NO Ic lease in these vessels. N-omega-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, I-DAMP, and AF-DX 384 close depen dently inhibited the dilatation induced by ACh (10(-5) mol/L) with the foll owing rank order of potency: I-DAMP (pIC(50) = 9.2 +/- 0.3) >> pirenzepine (pIC(50) = 6.7 +/- 0.4) > AF-DX 384 (pIC(50) = 5.9 +/- 0.2). These results suggest that ACh can induce a potent, dose-dependent, and NO-mediated dilat ion of bovine and/or human intracortical arterioles via interaction with an mAChR that best corresponds to the M5 subtype.