Functional acetylcholine and serotonin receptors in brain microcirculation : importance of subtype and cellular localization in the determination of function
Bibliographic record
Abstract
The brain intraparenchymal microcirculation is regulated by various brain neuronal pathways, including the cholinergic and serotonergic systems. In this study, we determined the molecular identity, second messenger coupling, cellular distribution and/or vasomotor functions of the receptors for these two neurovascular systems in human and/or bovine brain microvasculature. Using reverse transcriptase-polymerase chain reaction (RT-PCR), we first identified heterogeneous muscarinic acetylcholine receptors (mAChRs) in microvessel and capillary fractions isolated from human cerebral cortex. Using a combination of RT-PCR and second messenger assays on human cerebromicrovascular cell cultures, we then identified functional M2 and M5 mAChRs in endothelial cells, the M1, M3 and possibly M5 in smooth muscle cells, and all five mAChRs in astrocytes. In order to identify the vasomotor function(s) mediated by these receptors, we developed a technique to test the effect of vasoactive neurotransmitters on isolated and pressurized human and/or bovine intracortical penetrating arterioles (diameter ∼47mum), known to be innervated by brain neurovascular pathways. ACh dose-dependently dilated human and bovine intracortical arterioles at spontaneous tone or following pre-constriction with serotonin (5-HT). In contrast, nicotine failed to significantly affect the diameters of the arterioles under similar conditions. Application of L-NNA (10-5 M), an inhibitor of nitric oxide synthase (NOS), elicited a gradual constriction (∼40%) of the arterioles, indicating the presence of constitutive NO release in these vessels. It also significantly blocked the dilation induced by ACh in both human and bovine arterioles. The mAChR antagonists pirenzepine, 4-DAMP, and AF-DX 384 dose-dependently inhibited the dilation elicited by 10 -5M ACh with the following order of potency: 4-DAMP (pIC 50 = 9.2 +/- 0.1) >> pirenzepine (pIC50 = 6.7 +/- 0.2) > AF-DX 384 (pIC50 = 5.9 +/- 0.1), which best corr
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".