Role of Ca2+- and swelling-activated Cl− channels in α1-adrenoceptor-mediated tone in pressurized rabbit mesenteric arterioles
Bibliographic record
Abstract
BACKGROUND: Ca2+-activated (I(Cl(Ca))) and swelling-induced (I(Cl(swell))) Cl- channels have, respectively, been postulated to participate in the membrane depolarization and contraction mediated by activation of alpha1-adrenoceptors and vascular wall distension during pressurization. Their respective function in generating active force in pressurized arterioles during alpha1-adrenoceptor stimulation remains unsettled. OBJECTIVES: Experimental protocols were designed to: (1) assess the relative contribution of I(Cl(Ca)) to the pressure-dependence of lumen diameter of mesenteric arterioles at different states of activation of the alpha1-adrenoceptor, and (2) investigate the potential role of I(Cl(swell)) in spontaneous and agonist-mediated myogenic reactivity. METHODS: Segments of endothelium-denuded rabbit mesenteric arterioles with a lumen diameter of approximately 70 microm were cannulated at both ends and studied under isobaric conditions at 36 degrees C. Steady-state lumen diameter at each pressure step investigated (0-100 mmHg, in 20-mmHg increments) was measured by a video-microscopy edge-detection technique. RESULTS: Under control conditions, 23% of the arterioles developed nifedipine-sensitive spontaneous myogenic tone. In the presence of 1 mM tetraethylammonium chloride (TEA) to inhibit Ca2+-dependent K+ channels, the alpha1-agonist phenylephrine (PE) contracted the vessels in a concentration-dependent manner (0.1-10 microM) and potentiated myogenic reactivity. The contraction mediated by 1 microM PE/TEA was abolished by 1 microM nifedipine, indicating that Ca2+ entry through voltage-gated Ca2+ channels was a necessary step in the cascade leading to contraction. Niflumic acid (NfA, 100 microM), a relatively selective inhibitor of I(Cl(Ca)), had no effect on myogenic tone but reversed the PE-induced contraction, varying with the concentration of PE and transmural pressure. For PE concentrations between 0.1 and 1 microM, but not for 10 microM PE, the relaxing efficacy of NfA decreased as applied pressure was raised from 0 to 100 mmHg. At all pressure steps, the NfA-induced relaxation was inversely related to the concentration of PE. DIDS (200 microM), another Cl- channel blocker, inhibited spontaneous myogenic tone, and partially suppressed a component of contraction at elevated transmural pressures in arterioles incubated in 1 microM PE/1 mM TEA/100 microM NfA. CONCLUSIONS: Our data indicate that under low to moderate stimulation of the alpha1-adrenoceptor signaling pathway, I(Cl(Ca)) channels play an important role in the sustained contraction produced. Their declining contribution to contraction with increasing transmural pressure may be explained, at least in part, by a progressive enhancement of stretch-induced ionic conductances, possibly volume-sensitive Cl- channels.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".