Pharmacological characterization of muscarinic acetylcholine binding sites in human and bovine cerebral microvessels

Linville, Donald G.; Hamel, Edith

doi:10.1007/bf00176772

Cited by 26 publications

(17 citation statements)

References 42 publications

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“…The exclusive mRNA expression of the m2 subtype and the ability of the mAChR antagonist AF-DX 384 (Dorje et aI.,199 1) to block the inhibitory effect of car bachol on cAMP production (the downstream effect of m2 activation) unequivocally indicated the existence of functional endothelial m2 mAChR. The apparent dis-crepancy between the present results and the inability of previous radioligand binding studies to detect m2 mAChR in isolated human cerebral microvasculature (Linville and Hamel, 1995) could possibly be explained by the fact that radioligand binding studies, unlike PCR, require that a sizable amount of the receptor protein be present to be detectable. In fact, from the present results, m2 receptors are located in the endothelial but not in the muscular compartment (see below) of the intraparenchy mal vascular tissue.…”

Section: Discussioncontrasting

confidence: 46%

“…Al though more than one population of mAChR were later suggested (Garda-Villalon et al, 199 1; Linville and Hamel, 1995), there was disagreement as to which mAChR SUbtypes were present in the brain microvascu lature. Garda-Villalon and colleagues exclusively iden tified a pharmacologic m4 mAChR in bovine microvas cular fractions, but others concluded on the basis of phar macologic characterization and correlation analyses with the cloned mAChR that the ml, m3, and possibly the m5 receptors were most likely the cerebromicrovascular re ceptors present, not only in bovine, but also in human cerebromicrovascular fractions (Linville and Hamel, 1995). In the present study, the high sensitivity and se lectivity of the RT-PCR approach, together with the demonstration of functional second messenger signaling pathways in the cell cultures, provided unequivocal sup port for the presence of cerebromicrovascular m 1, m3, and m5 mAChR, and further allowed us to identify en dothelial m2 mAChR.…”

Section: Discussionmentioning

confidence: 99%

“…Human brains (n = 6; average postmortem delay, 16.2 ± 2.2 hours; 4 men, 2 women) were obtained at autopsy from subjects sue (see Linville and Hamel, 1995).…”

Section: Isolated MV and Capmentioning

confidence: 99%

“…Inter estingly, cholinergic-mediated increases in local CBF have been observed in the frontal and parietal subdivi sions of the cerebral cortex on stimulation of basal fore brain cholinergic neurons and muscarinic ACh receptors (mAChR), some of which, presumably associated with the local microcirculation, have been implicated in this response (for review see Sato and Sato, 1995). Cerebro microvascular mAChR binding sites have indeed been reported (Estrada et aI., 1983), and more recently, mul tiple mAChR subtypes have been identified in intracor tical microvessels and capillaries, including in man (Gar cia-Villal6n et aI., 1991;Linville and Hamel, 1995). However, the absence of highly selective sUbtype specific ligands for all mAChR made it difficult to con clusively identify the exact receptor SUbtype involved.…”

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confidence: 99%

“…However, the absence of highly selective sUbtype specific ligands for all mAChR made it difficult to con clusively identify the exact receptor SUbtype involved. Furthermore, these radioligand binding studies in tissue homogenates could not localize mAChR to a specific cellular compartment of the isolated microvascular frac tions (Linville and Hamel, 1995;Moro et aI., 1995).…”

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confidence: 99%

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Functional Acetylcholine Muscarinic Receptor Subtypes in Human Brain Microcirculation: Identification and Cellular Localization

Elhusseiny¹,

Cohen²,

Olivier

et al. 1999

J Cereb Blood Flow Metab

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126

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Summary: Acetylcholine is an important regulator of local cerebral blood flow. There is, however, limited information available on the possible sites of action of this neurotransmitter on brain intraparenchymal microvessels. In this study, a com bination of molecular and functional approaches was used to identify which of the five muscarinic acetylcholine receptors (mAChR) are present in human brain microvessels and their intimately associated astroglial cells. Microvessel and capillary fractions isolate<;i from human cerebral cortex were found by reverse transcriptase-polymerase chain reaction to express m2, m3, and, occasionally, ml and m5 receptor subtypes. To local ize these receptors to a specific cellular compartment of the vessel wall, cultures of human brain microvascular endothelial and smooth muscle cells were used, together with cultured human brain astrocytes. Endothelial cells invariably expressed m2 and m5 receptors, and occasionally the ml receptor; smooth muscle cells exhibited messages for all except the m4 mAChR subtypes, whereas messages for all five muscarinic receptors Acetylcholine (ACh) is an important regulator of CBF in man and in many other species (for review see Sato and Sato, 1995;Dauphin and MacKenzie, 1995). Intra cortical and basalocortical cholinergic nerve fibers have been shown to intimately associate with microarterioles and capillaries in the rat (Vaucher and Hamel, 1995)

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Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

“…Human brains (n = 6; average postmortem delay, 16.2 ± 2.2 hours; 4 men, 2 women) were obtained at autopsy from subjects sue (see Linville and Hamel, 1995).…”

Section: Isolated MV and Capmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Functional Acetylcholine Muscarinic Receptor Subtypes in Human Brain Microcirculation: Identification and Cellular Localization

Elhusseiny¹,

Cohen²,

Olivier

et al. 1999

J Cereb Blood Flow Metab

Self Cite

126

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Heterogeneous control of blood flow amongst different vascular beds

2000

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The control and maintenance of vascular tone is due to a balance between vasoconstrictor and vasodilator pathways. Vasomotor responses to neural, metabolic and physical factors vary between vessels in different vascular beds, as well as along the same bed, particularly as vessels become smaller. These differences result from variation in the composition of neurotransmitters released by perivascular nerves, variation in the array and activation of receptor subtypes expressed in different vascular beds and variation in the signal transduction pathways activated in either the vascular smooth muscle or endothelial cells. As the study of vasomotor responses often requires pre‐existing tone, some of the reported heterogeneity in the relative contributions of different vasodilator mechanisms may be compounded by different experimental conditions. Biochemical variations, such as the expression of ion channels, connexin subtypes and other important components of second messenger cascades, have been documented in the smooth muscle and endothelial cells in different parts of the body. Anatomical variations, in the presence and prevalence of gap junctions between smooth muscle cells, between endothelial cells and at myoendothelial gap junctions, between the two cell layers, have also been described. These factors will contribute further to the heterogeneity in local and conducted responses. © 2000 John Wiley & Sons, Inc. Med Res Rev, 21, No. 1, 1–60, 2001

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Heterogeneous control of blood flow amongst different vascular beds

Hill¹,

Phillips²,

Sandow³

2001

Med. Res. Rev.

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The control and maintenance of vascular tone is due to a balance between vasoconstrictor and vasodilator pathways. Vasomotor responses to neural, metabolic and physical factors vary between vessels in different vascular beds, as well as along the same bed, particularly as vessels become smaller. These differences result from variation in the composition of neurotransmitters released by perivascular nerves, variation in the array and activation of receptor subtypes expressed in different vascular beds and variation in the signal transduction pathways activated in either the vascular smooth muscle or endothelial cells. As the study of vasomotor responses often requires pre-existing tone, some of the reported heterogeneity in the relative contributions of different vasodilator mechanisms may be compounded by different experimental conditions. Biochemical variations, such as the expression of ion channels, connexin subtypes and other important components of second messenger cascades, have been documented in the smooth muscle and endothelial cells in different parts of the body. Anatomical variations, in the presence and prevalence of gap junctions between smooth muscle cells, between endothelial cells and at myoendothelial gap junctions, between the two cell layers, have also been described. These factors will contribute further to the heterogeneity in local and conducted responses.ß

show abstract

Pharmacological characterization of muscarinic acetylcholine binding sites in human and bovine cerebral microvessels

Cited by 26 publications

References 42 publications

Functional Acetylcholine Muscarinic Receptor Subtypes in Human Brain Microcirculation: Identification and Cellular Localization

Functional Acetylcholine Muscarinic Receptor Subtypes in Human Brain Microcirculation: Identification and Cellular Localization

Heterogeneous control of blood flow amongst different vascular beds

Heterogeneous control of blood flow amongst different vascular beds

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