Short-Lived Active Prorenin: Precursor of So-Called Native Prorenin.

The enzymatic activity of the aspartic protease, renin, is critical for its function in blood pressure regulation and sodium homeostasis. Incubation of so-called native prorenin at low pH leads to its activation. After binding to transition-state mimicking renin inhibitors at neutral pH, prorenin attains the active conformation, as indicated by immunosorbent assay using monoclonal antibodies specific for epitopes of the prosegment or the renin body.

New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin.

Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC50 and t1/2, and a much higher bioavailability.

How does the angiotensin II type 1 receptor 'trump' the type 2 receptor in blood pressure control?

Background: A kinetic model for the binding of angiotensin II (Ang II) to AT1 receptors (AT1Rs) in arterioles did suggest a novel mechanism of association rate amplification and facilitated Ang II diffusion in vivo.

Aim Of Study: To examine how this mechanism, acting on AT1R, will affect the stimulation of AT2R.

Method: The model distinguishes between the diffusion of plasma Ang II across the endothelium layer (thickness 10(-4) - 5 × 10(-4) cm) into the vascular smooth muscle (VSM) layer (5 × 10(-4) cm), and the diffusion of tissue Ang II from perivascular interstitium (thickness of micromilieu fluid layer at abluminal VSM surface 10(-6) - 10(-5) cm, i.

Facilitated diffusion of angiotensin II from perivascular interstitium to AT1 receptors of the arteriole. A regulating step in vasoconstriction.

Background: A kinetic model for the binding of angiotensin (Ang) II to AT1 receptors (AT1R) in arterioles in vivo did suggest a novel mechanism of stimulus amplification.

Objective: To further clarify the role of this mechanism in the functioning of the local renin-angiotensin systems, as opposed to circulating Ang II.

Methods And Results: The model was refined in order to account for geometric characteristics of the vascular smooth muscle (VSM) cells in arterioles with a single VSM cell layer.

Newly developed renin and prorenin assays and the clinical evaluation of renin inhibitors.

Background: The last decade has seen the introduction of renin inhibitors and new plasma renin and prorenin assays, which has led to a better understanding of the tissue renin-angiotensin system.

Aim Of The Study: To clarify the consequences of these developments for the methodology and interpretation of measurements of renin and prorenin.

Methods: The principles and application of the newly developed immunosorbent assays (ISAs) are surveyed and the results are compared with those of enzyme-kinetic assays (EKAs).

A local pre-receptor mechanism of hormone stimulus amplification: focus on angiotensin II in resistance blood vessels.

Background: The in-vivo correlation between vascular tone and the concentration of free angiotensin (Ang) II at the level of the arterioles, under (patho)physiological conditions, is not known.

Objective: To examine the in-vivo kinetics of binding of Ang II to Ang II type 1 (AT1) receptors in vascular tissue.

Methods And Results: A plane vascular smooth muscle (VSM) sheet containing a single layer of cells, at one side exposed to Ang II, was the starting point for designing a mathematical model based on local receptor density and geometric considerations and on kinetic parameters of Ang II diffusion and Ang II-AT1 receptor complex formation and internalization.

Angiotensin II production and distribution in the kidney: I. A kinetic model.

Information on the levels of angiotensin II (Ang II) and its receptors in the various renal tissue compartments is still incomplete. A model is presented describing the kinetics of Ang II production, distribution, and disposal in the renal cortex. Basic features are: (1) the model is designed to derive, from Ang II measurements in blood and in whole tissue, estimates of the local densities of the Ang II type 1 (AT(1)) and type 2 (AT(2)) receptors, and to calculate the concentrations of endocrine and paracrine Ang II they actually 'see'; (2) glomerular and peritubular tissue are conceived as separate regions (glomerular region (Glom), peritubular region (Pt)); (3) in Glom and in Pt, Ang II is homogeneously distributed in capillary blood and in interstitial fluid; (4) the model allows for local Ang II concentration gradients between interstitium and blood; (5) Ang II from the circulation diffuses into the interstitium of Glom after convective transcapillary transport; (6) Ang II produced in tubules or Pt enters the microcirculation through diffusive overflow from interstitium; (7) the presence of cell-surface-bound Ang II depends on the reaction with AT(1) and AT(2) receptors, and the presence of intracellular Ang II depends on the internalization of Ang II - AT(1) receptor complex; and (8) the model provides for glomerular filtration, vasopeptidase-mediated degradation, and intracellular degradation as mechanisms of elimination.

Angiotensin II production and distribution in the kidney--II. Model-based analysis of experimental data.

Information on the regional concentrations of angiotensin (Ang) II and its type-1 and -2 receptors (AT(1)R, AT(2)R) in the kidney is still incomplete. Published data on the levels of arterially delivered Ang I and II (Ang Ia, Ang IIa) and intrarenally produced Ang I and II (Ang Ii, Ang IIi) in the renal vein and in whole tissue were analyzed by using a kinetic model of Ang production and distribution in the glomerular and peritubular cortical tissue regions (Glom, Pt). (1) 90% of Ang II is cell-associated, due to its binding to AT(1)R and AT(2)R; (2) most Ang II in the renal cortex is Ang IIi; (3) Ang IIa is mainly localized in Glom; (4) Ang Ii rather than Ang Ia is a substrate of renal angiotensin-converting enzyme; (5) Ang IIi is localized in Pt and its concentration in interstitial fluid is 5-15 times the Ang II concentration in arterial plasma; and (6) in Glom the interstitial concentration of cell surface-bound AT(1)R is above 200K(d), and in Pt the AT(1)R and AT(2)R concentrations are above 10K(d).

Arterial stiffness as the candidate underlying mechanism for postural blood pressure changes and orthostatic hypotension in older adults: the Rotterdam Study.

Objective: To investigate whether arterial stiffening, one of the characteristics of the aging vascular system, is associated with orthostatic hypotension.

Design: Cross-sectional data of a cohort study in elderly men and women.

Participants: We investigated the relationship between arterial stiffness and orthostatic hypotension within the framework of the Rotterdam Study, a population-based study in individuals aged 55 and older.

Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study.

Background: Arterial stiffness has been associated with the risk of cardiovascular disease in selected groups of patients. We evaluated whether arterial stiffness is a predictor of coronary heart disease and stroke in a population-based study among apparently healthy subjects.

Methods And Results: The present study included 2835 subjects participating in the third examination phase of the Rotterdam Study.

Moderate alcohol consumption is associated with reduced arterial stiffness in older adults: the Rotterdam study.

Background: Light-to-moderate alcohol consumption has been associated with a lower risk of cardiovascular disease. The protective effect of alcohol could involve arterial properties as arterial stiffness and distensibility.

Methods: The relationship between alcohol and arterial stiffness was studied within the framework of the Rotterdam Study, a population-based study in individuals aged 55 and older.

Adrenal angiotensin: origin and site of generation.

Background: Circulating angiotensin (Ang) II accumulates in adrenal tissue via binding to Ang II type 1 (AT1) receptors, reaching levels that are 15 to 20 times higher than in blood. Adrenal tissue contains a second renin transcript that gives rise to a truncated prorenin representing a cytosolic form of renin. Here we investigated what percentage of adrenal Ang II originates at adrenal tissue sites, and whether intracellular renin contributes to adrenal angiotensin production.

Blood pressure components and cardiovascular events in older adults: the Rotterdam study.

Objectives: To compare the strength of the relative risks of systolic (SBP) diastolic blood pressure (DBP) and pulse pressure (PP) as predictors of myocardial infarction and stroke in older adults.

Design: Prospective cohort study.

Setting: The Rotterdam Study, a Dutch population-based study.

C-reactive protein and arterial stiffness in older adults: the Rotterdam Study.

Arterial stiffness is one of the characteristics of vascular aging. Increases in pulse pressure, which reflect an increase in the stiffness of the large arteries, are associated with elevated C-reactive protein (CRP) levels. This may suggest a role of inflammation in the development of arterial stiffness.

Angiotensin-converting enzyme gene polymorphism and common carotid stiffness. The Rotterdam study.

The insertion/deletion (I/D) polymorphism of the ACE gene may be involved in structural arterial changes. Aim of the present study was to assess the relationship between the ACE I/D gene and vessel wall stiffness among older adults. The study was conducted within the Rotterdam study, a population-based cohort study including subjects aged 55 years and older.

Intima-media thickness of the common carotid arteries is related to coronary atherosclerosis and left ventricular hypertrophy in older adults.

Increased intima-media thickness (IMT) of the common carotid arteries is related to generalized atherosclerosis and increased risk of future myocardial infarction and cerebrovascular disease. An association between IMT and the presence of coronary artery disease (CAD) has been documented, but controversial data have been found about the relation between increased IMT and the extent of CAD. An association between carotid atherosclerosis and cardiac remodeling has also been reported.

Functional effects of renal artery stent placement on treated and contralateral kidneys.

Background: This study examined the effects of stent placement for renal artery stenosis on the function of treated and contralateral kidneys.

Methods: Eighteen patients who underwent stent placement for unilateral renal artery stenosis presenting with hypertension and/or renal failure were studied before angiography and stent placement and at their one-year follow-up. Renal vein blood samples were taken at both sides, at each side simultaneously with a sample from the aorta, to measure the plasma renin concentration and the concentrations of 131I-hippuran and 125I-thalamate during constant systemic infusion of these radiochemicals.

Prorenin-induced myocyte proliferation: no role for intracellular angiotensin II.

Cardiomyocytes bind, internalize, and activate prorenin, the inactive precursor of renin, via a mannose 6-phosphate receptor (M6PR)--dependent mechanism. M6PRs couple directly to G-proteins. To investigate whether prorenin binding to cardiomyocytes elicits a response, and if so, whether this response depends on angiotensin (Ang) II, we incubated neonatal rat cardiomyocytes with 2 nmol/L prorenin and/or 150 nmol/L angiotensinogen, with or without 10 mmol/L M6P, 1 micromol/L eprosartan, or 1 micromol/L PD123319 to block M6P and AT(1) and AT(2) receptors, respectively.

Vasoconstriction is determined by interstitial rather than circulating angiotensin II.

1. We investigated why angiotensin (Ang) I and II induce vasoconstriction with similar potencies, although Ang I-II conversion is limited. 2.

Intrarenal angiotensin II: interstitial and cellular levels and site of production.

Background: Both local production and angiotensin II subtype 1 (AT1) receptor-mediated uptake from the circulation contribute to the high levels of angiotensin (Ang) II in the kidney. It is largely unknown where Ang II is produced in the kidney and how much of it originates from the circulation.

Methods: The concentrations of endogenous and 125I-labeled Ang I and II were measured in renal tissue and in blood from pigs receiving systemic infusions of 125I-Ang I.

Resistance to antihypertensive medication as predictor of renal artery stenosis: comparison of two drug regimens.

Background: Renal artery stenosis is among the most common curable causes of hypertension. The definitive diagnosis is made by renal angiography, an invasive and costly procedure. The prevalence of renal artery stenosis is less than 1% in non-selected hypertensive patients but is higher when hypertension is resistant to drugs.

Prorenin accumulation and activation in human endothelial cells: importance of mannose 6-phosphate receptors.

ACE inhibitors improve endothelial dysfunction, possibly by blocking endothelial angiotensin production. Prorenin, through its binding and activation by endothelial mannose 6-phosphate (M6P) receptors, may contribute to this production. Here, we investigated this possibility as well as prorenin activation kinetics, the nature of the prorenin-activating enzyme, and M6P receptor-independent prorenin binding.

Angiotensin converting enzyme is the main contributor to angiotensin I-II conversion in the interstitium of the isolated perfused rat heart.

Objectives: Recent studies in homogenized hearts suggest that chymase rather than angiotensin converting enzyme (ACE) is responsible for cardiac angiotensin I to angiotensin II conversion. We investigated in intact rat hearts whether (i) enzymes other than ACE contribute to angiotensin I to angiotensin II conversion and (ii) the localization (endothelial/extra-endothelial) of converting enzymes.

Design And Methods: We used a modified version of the rat Langendorff heart, allowing separate collection of coronary effluent and interstitial fluid.

Subcellular localization of angiotensin II in kidney and adrenal.

Objectives: To investigate whether tissue angiotensin II generation occurs intra- or extracellularly, we studied the subcellular localization of angiotensin II in kidney and adrenal, two organs with high endogenous angiotensin II concentrations.

Design And Methods: Tissues were obtained, following a 1 h infusion of 125I-angiotensin I or 125I-angiotensin II to simultaneously determine the localization of plasma-derived angiotensin II, from five control pigs and four pigs that had been pretreated with the AT1 receptor antagonist eprosartan. Subcellular organelles, prepared by differential centrifugation from homogenized tissue, were characterized using organelle-specific markers.