Bibliographic record
Abstract
Particulate (GC-A) and soluble (sGC) guanylyl cyclases are two important cGMP synthesizing enzymes. Both of these genes have been proposed as candidate genes of hypertension. They both map to the rat chromosome 2, within a blood pressure QTL identified in several rat genetic models of hypertension and defects of both sGC and GC-A activity have been found to be associated with impaired vasodilation and salt-sensitive hypertension in rodents. Here, we investigated the two guanylyl cylcase pathways in aortic smooth muscle cells (ASMC) from normotensive (BN) and hypertensive (SHR) rats. We used RIA to measure cGMP levels in cell culture medium, as a determinant of guanylyl cyclase activity. Cells were studied under basal conditions or after a 90 min stimulation with 100 nM ANP, the biological ligand of GC-A, or 100μM SNP, a NO donor, ligand of sGC, in presence of 30 μM L-NMMA or 10 μM ODQ, a sGC inhibitor. We also performed semi-quantitative RT-PCR in order to assess mRNA levels of sGC. We observed a significant increase in guanylyl cyclase activity in SHR compared to BN rats for both basal and in response to SNP (basal cGMP levels, SHR: 119.61±31.21 versus BN: 3.76±0.76, p<0.005; and SHR: 5800±700 versus BN: 300 ±50, p<0.005 after SNP activation). This result was associated with a swich in the expression of sGC subunits (from alpha2 to alpha1) in ASMC from hypertensive rats, whereas beta1 subunit expression did not differ from normotensive rats. We then tested the activity of sGC in SHR rats by using inhibitors of its pathway. We did not observe any significant effect of L-NMMA on basal cGMP levels, whereas a 400% increase in cGMP levels was detected in presence of ODQ. These results were confirmed after guanylyl cyclase stimulation: SNP induced a significantly higher cGMP increase in presence of L-NMMA, whereas ODQ abolished its effect. Interestingly, ANP enhanced cGMP levels in presence of ODQ, not L-NMMA. Since alpha1/beta1sGC heterodimer is more effective than alpha2/beta1, our results suggest that the change in sGC alpha1 subunit expression could explain the increased sGC activity observed in ASMC of SHR rats. Furthermore, our study strongly suggests a crosstalk between sGC and GC-A, sGC seems to be involved in the negative regulation of GC-A activity. Supported by CIHR and FRSQ-INSERM.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".