152 research outputs found
Local renin-angiotensin systems
The aim of this thesis was twofold. First, the regional metabolism and
production of angiotensin I and angiotensin U were quantified in vivo in man
and in anesthetized pigs. This was done by giving constant infusions of
radiolabelect J25J-angiotensin I into either a peripheral vein (man) or into the
left cardiac ventricle (pig). Blood samples were taken under steady state
conditions from various arterial and venous sampling sites. By measuring in
each sample the levels of intact radiolabelect angiotensin I and angiotensin U
and of endogenous angiotensin I and angiotensin II one can calculate both the
degree of regional metabolism of angiotensin I and angiotensin II and the amount of angiotensin I and angiotensin II that is generated in a certain
vascular bed. Additional measurements of plasma renin activity (PRA) and
calculations of the regional conversion of 125I-angiotensin I to 125I-angiotensin
TI make it possible to calculate the amount of locally generated angiotensin I
that can be attributed to the action of circulating renin on circulating renin
substrate and the amount of locally generated angiotensin U that can be
accounted for by regional conversion of arterially delivered angiotensin I. Our
data show clearly that part of angiotensin I in plasma is produced locally,
probably in vascular tissue, and not in circulating plasma by PRA, and that
most of the renin responsible for this local production is kidney-derived. Part
of circulating angiotensin U also appeared to be produced locally, independent
of plasma angiotensin I.
The second aim of this thesis was to in
The use of angiotensin II for the treatment of post-cardiopulmonary bypass vasoplegia
Purpose Vasoplegia is a common complication after cardiac surgery and is related to the use of cardiopulmonary bypass (CPB). Despite its association with increased morbidity and mortality, no consensus exists in terms of its treatment. In December 2017, angiotensin II (AII) was approved by the Food and Drug Administration (FDA) for use in vasodilatory shock; however, except for the ATHOS-3 trial, its use in vasoplegic patients that underwent cardiac surgery on CPB has mainly been reported in case reports. Thus, the aim of this review is to collect all the clinically relevant data and describe the pharmacologic mechanism, efficacy, and safety of this novel pharmacologic agent for the treatment of refractory vasoplegia in this population. Methods Two independent reviewers performed a systematic search in PubMed, Embase, Web of Science, and Cochrane Library using relevant MeSH terms (Angiotensin II, Vasoplegia, Cardiopulmonary Bypass, Cardiac Surgical Procedures). Results The literature search yielded 820 unique articles. In total, 9 studies were included. Of those, 2 were randomized clinical trials (RCTs) and 6 were case reports and 1 was a retrospective cohort study. Conclusions AII appears to be a promising means of treatment for patients with post-operative vasoplegia. It is demonstrated to be effective in raising blood pressure, while no major adverse events have been reported. It remains uncertain whether this agent will be broadly available and whether it will be more advantageous in the clinical management of vasoplegia compared to other available vasopressors. For that reason, we should contain our eagerness and enthusiasm regarding its use until supplementary knowledge becomes available.Thoracic Surger
Megalin: a Novel Determinant of Renin-Angiotensin System Activity in the Kidney?
Purpose of Review: Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine. Recent Findings: Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Summary: Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin
From ARB to ARNI in Cardiovascular Control
Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition (‘ARNI’) with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria w
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
Drug mechanisms to help in managing resistant hypertension in obesity
Obesity is a major risk factor for the development of hypertension. Because the prevalence of obesity is increasing worldwide, the prevalence of obesity hypertension is also increasing. Importantly, hypertension in obesity is commonly complicated by dyslipidemia and type 2 diabetes mellitus and hence imposes a high cardiovascular disease risk. Furthermore, obesity is strongly associated with resistant hypertension. Activation of the sympathetic nervous system and the renin-angiotensin system, leading to renal sodium and water retention, links obesity with hypertension. There is also evidence for the release of factors by visceral adipose tissue promoting excessive aldosterone production, and a more central role of aldosterone in obesity hypertension is emerging. Randomized studies evaluating the effect of different classes of antihypertensive agents in obesity hypertension are scarce, short-lasting, and small. Considering the emerging role of aldosterone in the pathogenesis of obesity hypertension, mineralocorticoid receptor antagonism may play a more central role in the pharmacologic treatment of obesity hypertension in the near future
Functional importance of angiotensin-converting enzyme-dependent in situ angiotensin II generation in the human forearm
To assess the importance for vasoconstriction of in situ angiotensin (Ang)
II generation, as opposed to Ang II delivery via the circulation, we
determined forearm vasoconstriction in response to Ang I (0.1 to 10 ng.
kg(-1). min(-1)) and Ang II (0.1 to 5 ng. kg(-1). min(-1)) in 14
normotensive male volunteers (age 18 to 67 years). Changes in forearm
blood flow (FBF) were registered with venous occlusion plethysmography.
Arterial and venous blood samples were collected under steady-state
conditions to quantify forearm fractional Ang I-to-II conversion. Ang I
and II exerted the same maximal effect (mean+/-SEM 71+/-4% and 75+/-4%
decrease in FBF, respectively), with similar potencies (mean EC(50)
[range] 5.6 [0.30 to 12.0] nmol/L for Ang I and 3.6 [0.37 to 7.1] nmol/L
for Ang II). Forearm fractional Ang I-to-II conversion was 36% (range 18%
to 57%). The angiotensin-converting enzyme (ACE) inhibitor enalaprilat (80
ng. kg(-1). min(-1)) inhibited the contra
Revisiting the Brain Renin-Angiotensin SystemFocus on Novel Therapies
Purpose of Review Although an independent brain renin-angiotensin system is often assumed to exist, evidence for this concept
is weak. Most importantly, renin is lacking in the brain, and both brain angiotensinogen and angiotensin (Ang) II levels are
exceptionally low. In fact, brain Ang II levels may well represent uptake of circulating Ang II via Ang II type 1 (AT1) receptors.
Recent Findings Nevertheless, novel drugs are now aimed at the brain RAS, i.e., aminopeptidase A inhibitors should block Ang
III formation from Ang II, and hence diminish AT1 receptor stimulation by Ang III, while AT2 and Mas receptor agonists are
reported to induce neuroprotection after stroke. The endogenous agonists of these receptors and their origin remain unknown.
Summary This review addresses the questions whether independent angiotensin generation truly occurs in the brain, what its
relationship with the kidney is, and how centrally acting RAS blockers/agonists might work
Localization and production of angiotensin II in the isolated perfused rat heart
We used a modification of the isolated perfused rat heart, in which
coronary effluent and interstitial transudate were separately collected,
to investigate the localization and production of angiotensin II (Ang II)
in the heart. During combined renin (0.7 to 1.5 pmol Ang I/mL per minute)
and angiotensinogen (6 to 12 pmol/mL) perfusion (4 to 8 mL/min) for 60
minutes (n=3), the steady-state levels of Ang II in interstitial
transudate in two consecutive 10-minute periods were 4.3+/-1.5 and
3.6+/-1.5 fmol/mL compared with 1.1+/-0.4 and 1.1+/-0.6 fmol/mL in
coronary effluent (mean+/-half range). During perfusion with Ang II (n=5),
steady-state Ang II in interstitial transudate was 32+/-19% of arterial
Ang II compared with 65+/-16% in coronary effluent (mean+/-SD, P<.02)
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