The effect of asymmetry in abdominal aortic aneurysms under physiologically realistic pulsatile flow conditions

In the abdominal segment of the human aorta under a patient's average resting conditions, pulsatile blood flow exhibits complex laminar patterns with secondary flows induced by adjacent branches and irregular vessel geometries. The flow dynamics becomes more complex when there is a pathological condition that causes changes in the normal structural composition of the vessel wall, for example, in the presence of an aneurysm. This work examines the hemodynamics of pulsatile blood flow in hypothetical three-dimensional models of abdominal aortic aneurysms (AAAs). Numerical predictions of blood flow patterns and hemodynamic stresses in AAAs are performed in single-aneurysm, asymmetric, rigid wall models using the finite element method. We characterize pulsatile flow dynamics in AAAs for average resting conditions by means of identifying regions of disturbed flow and quantifying the disturbance by evaluating flow-induced stresses at the aneurysm wall, specifically wall pressure and wall shear stress. Physiologically realistic abdominal aortic blood flow is simulated under pulsatile conditions for the range of time-average Reynolds numbers 50 < or = Rem < or = 300, corresponding to a range of peak Reynolds numbers 262.5 < or = Repeak < or = 1575. The vortex dynamics induced by pulsatile flow in AAAs is depicted by a sequence of four different flow phases in one period of the cardiac pulse. Peak wall shear stress and peak wall pressure are reported as a function of the time-average Reynolds number and aneurysm asymmetry. The effect of asymmetry in hypothetically shaped AAAs is to increase the maximum wall shear stress at peak flow and to induce the appearance of secondary flows in late diastole.     

Viscous energy dissipation in a model of the human bronchial tree

The viscous energy dissipation in a two generation model of the human bronchial tree is determined from inspiratory velocity and static pressure data obtained for large Reynolds numbers (10⁴ < Re < 10⁵). This dissipation is found to be an increasing function of both Re and distance downstream from the inlet of the model. The ratio of the dissipation in the model to the energy dissipation in an equivalent straight pipe system is determined. This ratio, Z^*, for the model is compared to values in the literature for lower (laminar) Re. There is more dissipation in the branched model than in a straight pipe (Z^* > 1) and turbulence keeps Z^* at roughly a fixed value for large Reynolds numbers (10⁴ < Re < 10⁵). Z^* values for curved pipes are also compared to the branching system values. It is found that the energy dissipation for the branched model behaves similarly to that in curved pipes.     

Hydrogen bonding in nucleosides and nucleotides

An analysis of the hydrogen bonding in 76 nucleoside and 11 nucleotide crystal structures shows that the hydrogen bond lengths fall into well-defined categories according to the nature of the donor or acceptor groups. The shortest bonds are those involving P---OH or O=P groups. For donor groups, the sequence in bond lengths is

P—OH<C—OH< N−H<O_w(H)—H<N(H)—H<C−H

There are ten examples of two centre

H—H…O

bonds, which are comparable in length with P---OH …O bonds. The acceptor seqeunce is

O=P<OH₂<OH₂<O=CO(H)C<N N(H₂)C<Cl^…<O<S=C

The number of three-centre bonds, about 24%, is comparable to that observed in the carbohydrates and the amino acids. Most hydrogen bonds are involved in short finite chains. Only in the nucleotides are cyclic hydrogen bonding schemes observed.     

Velocity field studies at surgically imposed arterial stenoses on the abdominal aorta in pigs

In order to describe velocity profiles and the size of deterministic and non-deterministic velocity disturbances at arterial stenoses, symmetrical and asymmetrical stenoses with intended area reductions of 50% (‘moderate’) and 85% (‘severe’) were applied on the abdominal aorta in six pigs. Blood velocities were registered by hot-film anemometry in 21 measuring points distributed across the vessel cross-sectional area in one pre-stenotic and three post-stenotic positions. Signal analysis included ensemble averaging, the high-pass filtering technique, and three-dimensional visualization. None of the stenoses affected the pre-stenotic velocity field. Downstream moderate stenoses flow separation and vortex formation were present. Moderate asymmetric stenoses induced turbulence in the post-stenotic velocity field. Immediately downstream of severe stenoses a prominent post-stenotic jet was present. Farther downstream, a multitude of coherent vortices and turbulence dominated the flow field. The transverse distribution of turbulence intensity parallelled with the peak systolic velocity profile, whereas transverse profiles of the relative turbulence intensity (turbulence intensity/mean velocity) revealed peak values in flow field locations with high velocity gradients. Velocity parameters for symmetric and asymmetric severe stenoses were highly comparable. However, the exact degree of stenosis was significantly higher for symmetrical (85%) than for asymmetrical (76%) stenoses. Therefore, recalling that stenosis severity strongly influences the development of velocity disturbances, this indicates that asymmetry of a stenosis is a predictor for blood velocity disturbances.     

Long term stabilization of expanding aortic aneurysms by a short course of cyclosporine A through transforming growth factor-beta induction

Abdominal aortic aneurysms (AAAs) expand as a consequence of extracellular matrix destruction, and vascular smooth muscle cell (VSMC) depletion. Transforming growth factor (TGF)-beta 1 overexpression stabilizes expanding AAAs in rat. Cyclosporine A (CsA) promotes tissue accumulation and induces TGF -beta1 and, could thereby exert beneficial effects on AAA remodelling and expansion. In this study, we assessed whether a short administration of CsA could durably stabilize AAAs through TGF-beta induction. We showed that CsA induced TGF-beta1 and decreased MMP-9 expression dose-dependently in fragments of human AAAs in vitro, and in animal models of AAA in vivo. CsA prevented AAA formation at 14 days in the rat elastase (diameter increase: CsA: 131.9±44.2%; vehicle: 225.9±57.0%, P = 0.003) and calcium chloride mouse models (diameters: CsA: 0.72±0.14 mm; vehicle: 1.10±0.11 mm, P = .008), preserved elastic fiber network and VSMC content, and decreased inflammation. A seven day administration of CsA stabilized formed AAAs in rats seven weeks after drug withdrawal (diameter increase: CsA: 14.2±15.1%; vehicle: 45.2±13.7%, P = .017), down-regulated wall inflammation, and increased αSMA-positive cell content. Co-administration of a blocking anti-TGF-beta antibody abrogated CsA impact on inflammation, αSMA-positive cell accumulation and diameter control in expanding AAAs. Our study demonstrates that pharmacological induction of TGF-beta1 by a short course of CsA administration represents a new approach to induce aneurysm stabilization by shifting the degradation/repair balance towards healing.     

Flow-induced wall shear stress in abdominal aortic aneurysms: Part I--steady flow hemodynamics

Numerical predictions of blood flow patterns and hemodynamic stresses in Abdominal Aortic Aneurysms (AAAs) are performed in a two-aneurysm, axisymmetric, rigid wall model using the spectral element method. Homogeneous, Newtonian blood flow is simulated under steady conditions for the range of Reynolds numbers 10 < or =Re < or =2265. Flow hemodynamics are quantified by calculating the distributions of wall pressure (p(w)), wall shear stress (tau(w)), Wall Shear Stress Gradient (WSSG). A correlation between maximum values of hemodynamic stresses and Reynolds number is established, and the spatial distribution of WSSG is considered as a hemodynamic force that may cause damage to the arterial wall at an intermediate stage of AAA growth. The temporal distribution of hemodynamic stresses in pulsatile flow and their physical implications in AAA rupture are discussed in Part II of this paper.     

Efficacy and Mechanism of Angiotensin II Receptor Blocker Treatment in Experimental Abdominal Aortic Aneurysms

Background

Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease.

Methodology/Principal Findings

AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE^−/− mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE^−/− mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion.

Conclusion/Significance

Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.     

Numerical identification of the rupture locations in patient-specific abdominal aortic aneurysmsusing hemodynamic parameters

The rupture of an abdominal aortic aneurysm (AAA) is generally an unexpected event. Up to now, there is no agreement on an accurate criteria to predict the rupture risk of AAAs. This paper aims to numerically investigate the hemodynamics of three ruptured and one non-ruptured patient-specific AAA models to correlate local hemodynamic parameters with the rupture sites, and for the first time, this study introduced helicity as a potential index for the rupture potential of AAAs.3D reconstructions from CT scans were done. The simulation revealed that all the rupture sites were in regions of stagnation with near zero wall shear stress (WSS) but large WSS gradient (WSSG), which may explain the observation by the former researchers that the rupture site in the ruptured AAA has the lowest recorded wall thickness compared to other non-ruptured regions. Moreover, all the ruptures occurred at regions of zero helicity which represents a purely axial or circumferential flow. In addition, this study revealed that the double low region for the non-ruptured AAA was present with a thick layer of plaques, it suggests that the AAA rupture and the formation of atherosclerotic plaques may share a lot common physiological features. However, the fact that there are no plaques present in the walls of three RAAAs also indicates that AAA is not always a result of atherosclerosis. The current computational study may complement the maximum diameter, peak wall stress and other clinically relevant factors in AAA ruptures to identify the rupture sites of AAAs.     

Hemodynamics of the mouse abdominal aortic aneurysm

The abdominal aortic aneurysm (AAA) is a significant cause of death and disability in the Western world and is the subject of many clinical and pathological studies. One of the most commonly used surrogates of the human AAA is the angiotensin II (Ang II) induced model used in mice. Despite the widespread use of this model, there is a lack of knowledge concerning its hemodynamics; this study was motivated by the desire to understand the fluid dynamic environment of the mouse AAA. Numerical simulations were performed using three subject-specific mouse models in flow conditions typical of the mouse. The numerical results from one model showed a shed vortex that correlated with measurements observed in vivo by Doppler ultrasound. The other models had smaller aneurysmal volumes and did not show vortex shedding, although a recirculation zone was formed in the aneurysm, in which a vortex could be observed, that elongated and remained attached to the wall throughout the systolic portion of the cardiac cycle. To link the hemodynamics with aneurysm progression, the remodeling that occurred between week one and week two of the Ang II infusion was quantified and compared with the hemodynamic wall parameters. The strongest correlation was found between the remodeled distance and the oscillatory shear index, which had a correlation coefficient greater than 0.7 for all three models. These results demonstrate that the hemodynamics of the mouse AAA are driven by a strong shear layer, which causes the formation of a recirculation zone in the aneurysm cavity during the systolic portion of the cardiac waveform. The recirculation zone results in areas of quiescent flow, which are correlated with the locations of the aneurysm remodeling.     

Analysis of biomechanical factors affecting stent-graft migration in an abdominal aortic aneurysm model

Focusing on a representative abdominal aortic aneurysm (AAA) with a bifurcating stent-graft (SG), a fluid-structure interaction (FSI) solver with user-supplied programs has been employed to solve for blood flow, AAA/SG deformation, sac pressure and wall stresses, as well as the downward forces acting on the SG. Simulation results indicate that implanting a SG can significantly reduce sac pressure, mechanical stress, pulsatile wall motion, and maximum diameter change in AAAs; hence, it may restore normal blood flow and prevent AAA rupture effectively. The transient SG drag force is similar in trend as the cardiac pressure. Its magnitude depends on multi-factors including blood flow conditions, as well as SG and aneurysm geometries. Specifically, AAA neck angle, iliac bifurcation angle, neck aorta-to-iliac diameter ratio, SG size, and blood waveform play important roles in generating a fluid flow force potentially leading to SG migration. It was found that the drag force can exceed 5N for an AAA with a large neck or iliac angle, wide aortic neck and narrow iliac arteries, large SG size, and/or abnormal blood waveform. Thus, the fixation of self-expandable or balloon-expandable SG contact may be inadequate to withstand the forces of blood flowing through the implant and hence means of extra fixation should be considered. A comprehensive FSI analysis of the coupled SG-AAA dynamics provides physical insight for evaluating the luminal hemodynamics, and maximum AAA-stresses as well as biomechanical factors leading potentially to SG migration.     

The efficacy of pharmacotherapy for decreasing the expansion rate of abdominal aortic aneurysms: a systematic review and meta-analysis

Background

Pharmacotherapy may represent a potential means to limit the expansion rate of abdominal aortic aneurysms (AAAs). Studies evaluating the efficacy of different pharmacological agents to slow down human AAA-expansion rates have been performed, but they have never been systematically reviewed or summarized.

Methods and Findings

Two independent reviewers identified studies and selected randomized trials and prospective cohort studies comparing the growth rate of AAA in patients with pharmacotherapy vs. no pharmacotherapy. We extracted information on study interventions, baseline characteristics, methodological quality, and AAA growth rate differences (in mm/year). Fourteen prospective studies met eligibility criteria. Five cohort studies raised the possibility of benefit of beta-blockers [pooled growth rate difference: −0.62 mm/year, (95%CI, −1.00 to −0.24)], but this was not confirmed in three beta-blocker RCTs [pooled RCT growth rate difference: −0.05 mm/year (−0.16 to 0.05)]. Statins have been evaluated in two cohort studies that yield a pooled growth rate difference of −2.97 (−5.83 to −0.11). Doxycycline and roxithromycin have been evaluated in two RCTs that suggest possible benefit [pooled RCT growth rate difference: −1.32 mm/year (−2.89 to 0.25)]. Studies assessing NSAIDs, diuretics, calcium channel blockers and ACE inhibitors, meanwhile, did not find statistically significant differences.

Conclusions

Beta-blockers do not appear to significantly reduce the growth rate of AAAs. Statins and other anti-inflammatory agents appear to hold promise for decreasing the expansion rate of AAA, but need further evaluation before definitive recommendations can be made.     

Ammonia emissions during the initial phase of microbial degradation of solid and liquid cattle manure

The maximum specific ammonia emissions from liquid manure (LM) and solid manure containing 2.5 kg straw/livestock unit (LU)/day (SM 2.5) or 15 kg straw/LU/day (SM 15) increased in the sequence LM < SM 2.5 < SM 15 (662.6 < 3163.7 < 6299.8 μg NH₃–N/h/kg). These emission levels were attained soon after the maximum temperatures (22.9°C < 34.3°C < 69.5°C) induced by microbial self-heating had been reached. After that, NH₄⁺ was microbially re-bound in amounts that increased with a higher C content and a widening C:N ratio, i.e. also in the sequence LM < SM 2.5 < SM 15. Over a period of 15 to 16 days, 6.0% (LM), 10.8% (SM 2.5) and 5.9% (SM 15) of the N_total was emitted. When the accumulated ammonia emissions were extrapolated beyond this period of investigation, it was concluded that, over longer storage periods, solid manure offers better biological conditions for low ammonia emissions than liquid manure.     

An MCD spectroscopic study of the molybdenum active site in sulfite oxidase: insight into the role of coordinated cysteine

Temperature-dependent magnetic circular dichroism (MCD) spectroscopy has been used for the first time to probe the electronic structure of the Mo active site in sulfite oxidase (SO). The enzyme was poised in the catalytically relevant [Mo(V):Fe(II)] state by anaerobic reduction of the enzyme with the natural substrate, sulfite, in the absence of the physiological oxidant cytochrome c. The [Mo(V):Fe(II)] state is of particular importance, as it is proposed to be a catalytic intermediate in the oxidative half reaction, where SO is reoxidized to the resting [Mo(VI):Fe(III)] state by two sequential one-electron transfers to cytochrome c. The MCD spectrum of the enzyme shows no charge transfer transitions below 17 000 cm⁻¹. This has been interpreted to result from (1) a severe reduction in ene-1,2-dithiolate sulfur in-plane and out-of-plane p orbital mixing, (2) a decrease in the dithiolate sulfur out-of-plane p-Mo d_xy orbital overlap, and (3) an orthogonal orientation between the vertical cysteine sulfur p (perpendicular to the Mo–S_cys σ-bond) and Mo d_xy orbitals. The spectroscopically determined cysteine sulfur p-Mo d_xy bonding scheme in the [Mo(V):Fe(II)] state is consistent with the crystallographically determined O–Mo–S_cys–C dihedral angle of 90° and precludes a covalent interaction between the vertical cysteine sulfur p orbital and Mo d_xy, effectively decoupling the cysteine from an effective through-bond electron transfer pathway. We have tentatively assigned a 22 250 cm⁻¹ positive C-term feature in the MCD as the cysteine S(σ)→Mo d_xy charge transfer that becomes allowed by a combination of configuration interaction and low-symmetry; however, the orbital overlap is anticipated to be quite small due to the near orthogonality of these orbitals. Therefore, we propose that the primary role of the coordinated cysteine is to decrease the effective nuclear charge on Mo by charge donation to the metal, statically poising the active site at more negative reduction potentials during electron transfer (ET) regeneration. Finally, the results of this study are consistent with the pyranopterin ene-1,2-dithiolate acting to couple the Mo site into efficient superexchange pathways for ET regeneration following oxygen atom transfer to the substrate.     

Evaluation of the surface-averaged load exerted on a blood element by the Reynolds shear stress field provided by artificial cardiovascular devices

Implantable prosthetic devices can often affect the recipient's hemostasis, with possible hemolysis and thrombus formation. Since such devices can produce turbulent flow, it is important to characterize it as accurately as possible, by means of the Reynolds stress tensor. Some parameters related to the latter have been often used to provide a quantity related to the possible damage to blood constituents: the TSS_max, for instance, has been associated with hemolysis. It can be expressed as TSS_max=(σ₁−σ₃)/2, σ₁ and σ₃ being the highest and lowest principal normal stresses (PNSs) in each point of the flow.

In the present work, the average value of the shear stress over a spherical surface, representative of a blood component, is derived. All three PNSs (σ₁, σ₂ and σ₃) are found to have an equal role in the determination of this parameter, since the relative formula shows a marked symmetry with respect to the PNSs. The average shear stress level, for a given (σ₁, σ₃) pair (hence, for a given TSS_max), has a minimum and maximum value, depending on the particular σ₂ value yielded by the local structure of the turbulent flow field. A numerical investigation on more complex geometries shows similar results. The role of the intermediate PNS is thus shown for the first time to have a physical relevance. The presented results can be useful whenever a spatial averaging of the shear field is important to be assessed, such as in the case of platelet activation. A new parameter is thus proposed, which can be correlated with prosthetic devices complications.     

Mechanical stresses in abdominal aortic aneurysms: influence of diameter, asymmetry, and material anisotropy

Biomechanical studies suggest that one determinant of abdominal aortic aneurysm (AAA) rupture is related to the stress in the wall. In this regard, a reliable and accurate stress analysis of an in vivo AAA requires a suitable 3D constitutive model. To date, stress analysis conducted on AAA is mainly driven by isotropic tissue models. However, recent biaxial tensile tests performed on AAA tissue samples demonstrate the anisotropic nature of this tissue. The purpose of this work is to study the influence of geometry and material anisotropy on the magnitude and distribution of the peak wall stress in AAAs. Three-dimensional computer models of symmetric and asymmetric AAAs were generated in which the maximum diameter and length of the aneurysm were individually controlled. A five parameter exponential type structural strain-energy function was used to model the anisotropic behavior of the AAA tissue. The anisotropy is determined by the orientation of the collagen fibers (one parameter of the model). The results suggest that shorter aneurysms are more critical when asymmetries are present. They show a strong influence of the material anisotropy on the magnitude and distribution of the peak stress. Results confirm that the relative aneurysm length and the degree of aneurysmal asymmetry should be considered in a rupture risk decision criterion for AAAs.     

The radiosensitivity of spermatogonial stem cells in C3H/101 F1 hybrid mice

The radiosensitivity of spermatogonial stem cells of C3H/HeH × 101/H F₁ hybrid mice was determined by counting undifferentiated spermatogonia at 10 days after X-irradiation. During the spermatogenic cycle, differences in radiosensitivity were found, which were correlated with the proliferative activity of the spermatogonial stem cells. In stage VIII_irr, during quiescence, the spermatogonial stem cells were most radiosensitive with a D₀ of 1.4 Gy. In stages XI_irr−V_irr, when the cells were proliferatively active, the D₀ was about 2.6 Gy. Based on the D₀ values for sensitive and resistant spermatogonia and on the D₀ for the total population, a ratio of 45:55% of sensitive to resistant spermatogonial stem cells was estimated for cell killing.

When the present data were compared with data on translocation induction obtained in mice of the same genotype, a close fit was obtained when the translocation yield (Y; in % abnormal cells) after a radiation dose D was described by Y = e^τD, with τ = 1 for the sensitive and τ = 0.1 for the resistant spermatogonial stem cells, with a maximal e^τD of 100.     

Pulsatile flow in fusiform models of abdoiminal aortic aneurysms: flow fields, velocity patterns and flow-induced wall stresses

As one important step in the investigation of the mechanical factors that lead to rupture of abdominal aortic aneurysms, flow fields and flow-induced wall stress distributions have been investigated in model aneurysms under pulsatile flow conditions simulating the in vivo aorta at rest. Vortex pattern emergence and evolution were evaluated, and conditions for flow stability were delineated. Systolic flow was found to be forward-directed throughout the bulge in all the models, regardless of size. Vortices appeared in the bulge initially during deceleration from systole, then expanded during the retrograde flow phase. The complexity of the vortex field depended strongly on bulge diameter In every model, the maximum shear stress occurred at peak systole at the distal bulge end, with the greatest shear stress developing in a model corresponding to a 4.3 cm AAA in vivo. Although the smallest models exhibited stable flow throughout the cycle, flow in the larger models became increasingly unstable as bulge size increased, with strong amplification of instability in the distal half of the bulge. These data suggest that larger aneurysms in vivo may be subject to more frequent and intense turbulence than smaller aneurysms. Concomitantly, increased turbulence may contribute significantly to wall stress magnitude and thereby to risk of rupture.     

A novel series of complexones with bis- or biazole structure as mixed ligands of paramagnetic contrast agents for MRI

We describe the syntheses, physicochemical properties and biological evaluation of a novel series of complexones containing bis- or biazoles moieties and two iminodiacetic acid units as novel ligands for paramagnetic lanthanides. The complexones were prepared by reaction of the corresponding 1,1′-bishaloethylbi- or bispyrazoles with methyl iminodiacetate and subsequent NaOH hydrolysis. 1,1′-Bisbromoethyl precursors were obtained by direct alkylation with an excess of 1,2-dibromoethane, or by heating the corresponding alcohol in HCl. Sigmoidal binding isotherms and MO calculations supported as most stable structures in solution, those containing two Gd(III) atoms bound per molecule of complexone with half saturation values S_0.5 (M⁻¹, 22 °C, pH 7.2) in the range 6.5 10⁻⁶0.5<36.1 10⁻⁶. Relaxivity properties [r₁, r₂, s⁻¹ mM⁻¹ Gd(III)] determined at 1.5 Tesla gave values (12.0<r₁<17.7, 12.2<r₂<20), improving significantly the relaxivities of reference compounds such as Gd(III)EDTA (5.2, 5.6) or Gd(III)DTPA (4.30, 4.30). These improvements involve mainly increased hydration and slower rotational motions. In vitro toxicity experiments are reported.     

Influence of intravenously administered leptin on nitric oxide production, renal hemodynamics and renal function in the rat

We investigated the effect of leptin on systemic nitric oxide (NO) production, arterial pressure, renal hemodynamics and renal excretory function in the rat. Leptin (1 mg/kg) was injected intravenously and mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF) and renal cortical blood flow (RCBF), were measured for 210 min after injection. Urine was collected for seven consecutive 30-min periods and blood samples were withdrawn at 15, 45, 75, 105, 135, 165 and 195 min after leptin administration. Leptin had no effect on MAP, HR, RBF, RCBF and creatinine clearance, but increased urine output by 37.8% (0–30 min), 32.4% (31–60 min) and 27.0% (61–90 min), as well as urinary sodium excretion by 175.8% (0–30 min), 136.4% (31–60 min) and 124.2% (61–90 min). In contrast, leptin had no effect on potassium and phosphate excretion. Plasma concentration of NO metabolites, nitrites+nitrates (NO_x), increased following leptin injection at 15, 45, 75 and 105 min by 27.7%, 178.1%, 156.4% and 58.7%, respectively. Leptin increased urinary NO_x excretion by 241.6% (0–30 min), 552.6% (31–60 min), 430.7% (61–90 min) and 88.9% (91–120 min). This was accompanied by increase in plasma and urinary cyclic GMP. These data indicate that leptin stimulates systemic NO production but has no effect on arterial pressure and renal hemodynamics.     

Doxycycline Does Not Influence Established Abdominal Aortic Aneurysms in Angiotensin II-Infused Mice

Background

There is no proven medical approach to attenuating expansion and rupture of abdominal aortic aneurysms (AAAs). One approach that is currently being investigated is the use of doxycycline. Despite being primarily used as an antimicrobial drug, doxycycline has been proposed to function in reducing AAA expansion. Doxycycline is effective in reducing the formation in the most commonly used mouse models of AAAs when administered prior to the initiation of the disease. The purpose of the current study was to determine the effects of doxycycline on established AAAs when it was administered at a dose that produces therapeutic serum concentrations.

Methods and Results

LDL receptor −/− male mice fed a saturated-fat supplemented diet were infused with AngII (1,000 ng/kg/min) via mini-osmotic pumps for 28 days. Upon verification of AAA formation by noninvasive high frequency ultrasonography, mice were stratified based on aortic lumen diameters, and continuously infused with AngII while also administered either vehicle or doxycycline (100 mg/kg/day) in drinking water for 56 days. Administration of doxycycline led to serum drug concentrations of 2.3±0.6 µg/ml. Doxycycline administration had no effect on serum cholesterol concentrations and systolic blood pressures. Doxycycline administration did not prevent progressive aortic dilation as determined by temporal measurements of lumen dimensions using high frequency ultrasound. This lack of effect on AAA regression and progression was confirmed at the termination of the study by ex vivo measurements of maximal width of suprarenal aortas and AAA volumes. Also, doxycycline did not reduce AAA rupture. Medial and adventitial remodeling was not overtly changed by doxycycline as determined by immunostaining and histological staining.

Conclusions

Doxycycline administration did not influence AngII-induced AAA progression and aortic rupture when administered to mice with established AAAs.