Role of Ca<sup>2+</sup>-Activated K<sup>+</sup>Channels And Connexin40 In Response To Transient Ischemia In Isolated Rat Hearts
Bibliographic record
Abstract
Background: Ischemic heart disease (IHD) is a leading cause of death worldwide. Once an ischemic attack occurs, primary myocardial reperfusion remains the gold standard treatment; however, ischemia-reperfusion (IR) injury contributes to myocardial damage and subsequent heart failure. Thus, there is a clinical need to further understand the mechanisms underlying the response of the heart to ischemia that leads to IR injury and to identify novel therapeutic targets. In this study, we have tested two hypotheses in isolated perfused rat heart: 1. Pharmacological activation of cardiac mitochondrial small (SK Ca ) and intermediate conductance (IK Ca ) Ca 2+ -activated K + channels may prevent I/R injury. 2. Loss of Connexin40 (Cx40), which is associated with impaired cardiac electrical coupling, may exacerbate I/R injury. Methods: Male Sprague Dawley rats, and male and female Cx40 knockout rats (Wistar background) were euthanized using sodium pentobarbitol anesthesia followed by decapitation. Hearts were rapidly excised, cannulated via the ascending aorta and perfused in Langendorff mode with warmed Krebs buffer at a constant flow rate. Left ventricular pressure and heart rate were recorded and left ventricular developed pressure (LVDP) was calculated as the difference between left ventricular systolic pressure (LVSP) and LVEDP. Hearts were perfused under normoxic conditions for 30 minutes before global no-flow ischemia was induced by clamping the aortic inflow line and switching off the pump for 15 minutes. The pump was restarted, and the clamp reopened, and the hearts perfused aerobically for a further 45 minutes. Activators of SK Ca and IK Ca channels were added to the perfusate 10 minutes prior to induction of ischemia. Data were analyzed using a two-way ANOVA was performed separately for pre- and post-ischemia. Results: Together, CyPPA and SKA-31 (both 10 microM), activators of SK Ca and IK Ca channels respectively, enhanced recovery following ischemia in isolated Sprague-Dawley rat hearts increasing post-ischemic LVDP from 5.9 +/- 1.7 to 72.6 +/- 2.3 mmHg (p<0.01; n=6). This effect was partially reduced by inhibitors of SK Ca and IK Ca channels but post-ischemic LVDP was still significantly greater than control at 43.9 =/- 3.6 mmHg (p<0.01; n=6). In isolated hearts from both male and female rats lacking Cx40, post-ischemic functional recovery was significantly impaired compared to controls: 1.4 +/- 1.9 and 15.7 +/- 3.4 compared to 24 +/- 1.6 and 34.6 +/- 4.2 mmHg, respectively, (n=5-15). Conclusions: We have shown that small molecule activators of SK Ca and IK Ca channels may protect against IR injury in isolated perfused hearts whereas loss of Cx 40, a protein which mediates cellular electrical coupling, exacerbates IR damage. This study provides new insights into the role of K Ca channels and opens the possibility that they may be therapeutic targets to protect against IR injury in the heart. Heart & Stroke Foundation Canada. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".