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

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 E(Amax) 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, E(Amax) = 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 Nomega-nitro-L-arginine (L-NNA; 10(-5) mol/L) elicited a gradual constriction (approximately 20%) of the arterioles, indicating the presence of constitutive NO release in these vessels. Nomega-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.

Cerebral Blood Flow Regulation by Nitric Oxide: Recent Advances

“…L-NA elicited a gradual constriction in isolated, perfused bovine and human intracortical penetrating arterioles, indicating the presence of constitutive NO release (Elhusseiny and Hamel, 2000). In isolated rat middle cerebral arteries, blocking the basal release of NO by L-NA or guanylyl cyclase inhibition by ODQ induced vasomotion, which was enhanced and became irregular after UTP administration; the thromboxane receptor antagonist ICI 192,605 attenuated the vasomotion induced by L-NA and UTP, suggesting that the lack of NO in cerebral vessels provokes vulnerability to chaotic vasomotion that is mediated by activation of thromboxane receptors (Lacza et al, 2001).…”

Specific Subtypes of Cortical GABA Interneurons Contribute to the Neurovascular Coupling Response to Basal Forebrain Stimulation

“…Together with the c-Fos studies, these pharmacologic findings pointed to blockade of ACh receptor-mediated activation of cholinoceptive GABA interneurons contributing to the decreased neurovascular coupling response. This is notwithstanding additional blocking effects of scopolamine on mAChR-activated pyramidal cells (McCormick and Prince, 1986), m5AChR-mediated dilatation of cortical microvessels (Elhusseiny and Hamel, 2000), or astroglial cell responses to cholinergic activation (Seigneur et al, 2006).…”

Cortical GABA Interneurons in Neurovascular Coupling: Relays for Subcortical Vasoactive Pathways

“…Additionally, basal forebrain-induced increase in cortical blood flow is not only sensitive to muscarinic and nicotinic blockade but also to NO synthase inhibition (for review, see Hamel, 2004). NOS interneurons, via muscarinic activation (Moro et al, 1995), may modulate perivascular release of NO, which then either directly dilates microvessels or assists in the relaxing effect of ACh on cortical microarterioles (Elhusseiny and Hamel, 2000;Hamel, 2004). Similarly, the changes in cortical perfusion elicited by dorsal raphe stimulation could involve 5-HT3 receptor-mediated activation of VIP interneurons (Ferezou et al, 2002) as well as other serotonin-responsive interneurons (Foehring et al, 2002) equally contacted by 5-HT terminals (Paspalas and Papadopoulos, 2001; our study).…”