24 research outputs found
New Aspects of Ace Inhibition: Importance of ACE co-localization with angiotensin and bradykinin receptors
The beneficial effect of angiotensin-converting enzyme (ACE) inhibitors in
hypertension and heart failure may relate, at least in part, to their capacity to interfere
with bradykinin metabolism. In addition, recent studies have provided evidence for
bradykinin-potentiating effects of ACE inhibitors that are independent of bradykinin
hydrolysis, i.e., ACE-bradykinin type 2 (B2) receptor ‘crosstalk’, resulting in B2
receptor upregulation and/or more efficient activation of signal transduction pathways,
as well as direct activation of bradykinin type 1 (B1) receptors by ACE inhibitors. This
review critically reviews the current evidence for hydrolysis-independent bradykinin
potentiation by ACE inhibitors, evaluating not only the many studies that have been
performed with ACE-resistant bradykinin analogues, but also paying attention to
angiotensin-(1-7) (Ang-(1-7)), a metabolite of both angiotensin (Ang) I and II, that
could act as an endogenous ACE inhibitor. The levels of Ang-(1-7) are increased
during ACE inhibition, and most studies suggest that its hypotensive effects are
mediated in a bradykinin-dependent manner
Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade
ACE inhibitors block B(2) receptor desensitization, thereby potentiating
bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also
acts as an ACE inhibitor and, in addition, may stimulate bradykinin
release via angiotensin II type 2 receptors. In this study we compared the
bradykinin-potentiating effects of Ang-(1-7), quinaprilat, and captopril.
Porcine coronary arteries, obtained from 32 pigs, were mounted in organ
baths, preconstricted with prostaglandin F(2alpha), and exposed to
quinaprilat, captopril, Ang-(1-7), and/or bradykinin. Bradykinin induced
complete relaxation (pEC(50)=8.11+/-0.07, mean+/-SEM), whereas
quinaprilat, captopril, and Ang-(1-7) alone were without effect.
Quinaprilat shifted the bradykinin curve to the left in a biphasic manner:
a 5-fold shift at concentrations that specifically block the C-domain (0.1
to 1 nmol/L) and a 10-fold shift at concentrations that block both
domains. Captopril and Ang-(1-7) monophasically shifted the bradykinin
curve to the left, by a factor of 10 and 5, respectively. A 5-fold shift
was also observed when Ang-(1-7) was combined with 0.1 nmol/L quinaprilat.
Repeated exposure of porcine coronary arteries to 0.1 micromol/L
bradykinin induced B(2) receptor desensitization. The addition of 10
micromol/L quinaprilat or Ang-(1-7) to the bath, at a time when bradykinin
alone was no longer able to induce relaxation, fully restored the relaxant
effects of bradykinin. Angiotensin II type 1 or 2 receptor blockade did
not affect any of the observed effects of Ang-(1-7). In conclusion,
Ang-(1-7), like quinaprilat and captopril, po
ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?
OBJECTIVE: The objective of this study was to investigate ACE- and
chymase-dependent angiotensin I-to-II conversion in human coronary
arteries (HCAs). METHODS AND RESULTS: HCA rings were mounted in organ
baths, and concentration-response curves to angiotensin II, angiotensin I,
and the chymase-specific substrate Pro(11)-D-Ala(12)-angiotensin I
(PA-angiotensin I) were constructed. All angiotensins displayed similar
efficacy. For a given vasoconstriction, bath (but not interstitial)
angiotensin II during angiotensin I and PA-angiotensin I was lower than
during angiotensin II, indicating that interstitial (and not bath)
angiotensin II determines vasoconstriction. PA-angiotensin I increased
interstitial angiotensin II less efficiently than angiotensin I. Separate
inhibition of ACE (with captopril) and chymase (with C41 or chymostatin)
shifted the angiotensin I concentration-response curve approximately
5-fold to the right, whereas a 10-fold shift occurred during combined ACE
and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced
bath angiotensin II and abolished PA-Ang I-induced vasoconstriction.
Perfused HCA segments, exposed luminally or adventitially to angiotensin
I, released angiotensin II into the luminal and adventitial fluid,
respectively, and this release was blocked by chymostatin. CONCLUSIONS:
Both ACE and chymase contribute to the generation of functionally active
angiotensin II in HCAs. However, because angiotensin II loss in the organ
bath is chymase-dependent, ACE-mediated conversion occurs more efficiently
(ie, closer to AT(1) receptors) than chymase-mediated conversion
Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries
Abstract
Background
Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres.
Methods
This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries.
Results
In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia.
Conclusion
This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries