Chronic administration of an endothelial KCa channel activator (SKA‐31) improves agonist evoked vasodilation in mesenteric arteries of aged rats
Bibliographic record
Abstract
Endothelial dysfunction occurs in healthy ageing, and may contribute to the development of cardiovascular complications (e.g. hypertension, atherosclerosis) that are more prevalent in aged individuals. One cause of age‐related endothelial dysfunction is an imbalance in the generation and/or release of vasodilatory and constrictor agents by the vascular endothelium (e.g. reduced NO bioavailability). Ageing may also impact the expression of endothelial proteins involved with vasoactive signaling to the surrounding smooth muscle. The goal of our study was to assess the effects of long term, in vivo administration of SKA‐31, a small molecule activator of KCa 2.x and KCa 3.1 channels, on the functional reactivity of mesenteric arteries in healthy aged rats. Young (225–250 g, 12 weeks of age) and aged (600–700 g, 18 months of age) male Sprague Dawley (SD) rats were treated daily with either vehicle or 10 mg/kg SKA‐31 for 8 weeks, after which mesenteric arteries (i.e. 200–400 μm internal diameter) were isolated and cannulated in an arterial pressure myography chamber. Experimentally, arteries were pressurized to 70 mmHg, preconstricted with 1 μM phenylephrine (PE) and superfused at 6–7 ml/min with Krebs' solution at ~36°C using a peristaltic pump. Vasoactive agents were added directly to the superfusate. The PE‐induced decrease in the intraluminal diameter of pressurized mesenteric arteries (i.e. % change of maximal passive diameter) was significantly greater in aged (44.3 ± 2.7%, n=8) vs. young animals (38.1 ± 3.6%, n=12), whereas chronic SKA‐31 treatment of aged rats reduced the level of vasoconstriction to 36.5 ± 4.0% (n=8). Aged mesenteric arteries dilated less in response to 0.3 μM acetylcholine (ACh), 0.3 μM bradykinin (BK) and 10 μM sodium nitroprusside (SNP) (i.e. inhibition of active tone = 37.0 ± 1.9%, 44.6 ± 4.5%, 55.5 ± 4.8%, respectively; n=4) compared with young arteries (48.3 ± 6.8%, 62.0 ± 7.1%, 68.0 ± 7.9%, respectively, n=4). Chronic treatment of aged SD rats with SKA‐31 improved vasodilation evoked by ACh, BK and SNP (58.5 ± 5.5%, 64.3 ± 5.5%, 76.7 ± 4.4%, respectively; n=4), however, SKA‐31 treatment had no effect on the dilations evoked by either 10 μM adenosine or 5 μM pinacidil. Molecular analysis confirmed that expression of KCa 2.3 and KCa 3.1 channels was significantly decreased in aged mesenteric arteries compared with young vessels. Chronic SKA‐31 administration significantly increased the expression of these channels relative to vehicle‐treated animals (n=3). Collectively, these data demonstrate that chronic SKA‐31 treatment can improve evoked vasodilation in the aged mesenteric microcirculation, in part by enhancing the expression of endothelial KCa 2.3 and KCa 3.1 channels. Support or Funding Information Supported by research funding to APB from the Canadian Institutes of Health Research. RKM is a recipient of a postdoctoral scholarship from the Libin Cardiovascular Institute and Cumming School of Medicine, Univ. of Calgary. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.002 | 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".