13 research outputs found

    Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced nitric oxide production and vasorelaxation in rabbit mesenteric arteries.

    Get PDF
    Stimulation of calcium-sensing receptors (CaSR) by increasing the external calcium concentration (Ca(2+)]o) induces endothelium-dependent vasorelaxation through nitric oxide (NO) production and activation of intermediate Ca(2+)-activated K(+) currents (IKCa) channels in rabbit mesenteric arteries. The present study investigates the potential role of heteromeric TRPV4-TRPC1 channels in mediating these CaSR-induced vascular responses. Immunocytochemical and proximity ligation assays showed that TRPV4 and TRPC1 proteins were expressed and co-localised at the plasma membrane of freshly isolated endothelial cells (ECs). In wire myography studies, increasing [Ca(2+)]o between 1 and 6mM induced concentration-dependent relaxations of methoxamine (MO)-induced pre-contracted tone, which were inhibited by the TRPV4 antagonists RN1734 and HC067047, and the externally-acting TRPC1 blocking antibody T1E3. In addition, CaSR-evoked NO production in ECs measured using the fluorescent NO indicator DAF-FM was reduced by RN1734 and T1E3. In contrast, [Ca(2+)]o-evoked perforated-patch IKCa currents in ECs were unaffected by RN1734 and T1E3. The TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent relaxation of MO-evoked pre-contracted tone and increased NO production, which were inhibited by the NO synthase inhibitor L-NAME, RN1734 and T1E3. GSK activated 6pS cation channel activity in cell-attached patches from ECs which was blocked by RN1734 and T1E3. These findings indicate that heteromeric TRPV4-TRPC1 channels mediate CaSR-induced vasorelaxation through NO production but not IKCa channel activation in rabbit mesenteric arteries. This further implicates CaSR-induced pathways and heteromeric TRPV4-TRPC1 channels in regulating vascular tone

    Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1−/- mice

    Get PDF
    We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit mesenteric arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in mesenteric arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone

    Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

    Get PDF
    Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P < 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement

    Safety of hospital discharge before return of bowel function after elective colorectal surgery

    Get PDF
    Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P < 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

    Safety of hospital discharge before return of bowel function after elective colorectal surgery

    No full text
    Background Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system. Results A total of 3288 patients were included in the analysis, of whom 301 (9 center dot 2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0 center dot 001). There were no significant differences in rates of readmission between these groups (6 center dot 6 versus 8 center dot 0 per cent; P = 0 center dot 499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0 center dot 90, 95 per cent c.i. 0 center dot 55 to 1 center dot 46; P = 0 center dot 659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34 center dot 7 versus 39 center dot 5 per cent; major 3 center dot 3 versus 3 center dot 4 per cent; P = 0 center dot 110). Conclusion Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

    Safety of hospital discharge before return of bowel function after elective colorectal surgery

    No full text
    Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.Results: A total of 3288 patients were included in the analysis, of whom 301 (9.2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0.001). There were no significant differences in rates of readmission between these groups (6.6 versus 8.0 per cent; P = 0.499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0.90, 95 per cent c.i. 0.55 to 1.46; P = 0.659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34.7 versus 39.5 per cent; major 3.3 versus 3.4 per cent; P = 0.110).Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

    Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

    No full text
    Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56\u20131.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion

    Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

    No full text
    Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56–1.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion

    Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

    No full text
    Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P < 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement

    Electron Microscopic in Cellular and Molecular Biology

    No full text
    corecore