p-Aminobenzamidine attenuates cardiovascular dysfunctions in spontaneously hypertensive rats.

AIMS: Diminazene aceturate, a putative ACE2 activator, is susceptible to cleavage resulting in the formation of p-aminobenzamidine (PAB). This study aimed to investigate the effects of PAB in addressing cardiovascular dysfunctions in spontaneously hypertensive rats (SHR). MAIN METHODS: Acute effects of PAB on mean arterial pressure (MAP), heart rate (HR), and aortic (AVC) and mesenteric vascular conductance (MVC) were evaluated in anesthetized SHR. Isolated aortic rings and the Langendorff technique were used to investigate the acute and chronic effects of PAB in the artery and heart. Chronic treatment with PAB (1 mg/kg, gavage) was carried out for 60 days. During this period, systolic blood pressure (SBP) and HR were measured by tail-cuff plethysmography. After the treatment, the left ventricle was collected for histology analyses, western blotting, and ACE2 activity. KEY FINDINGS: Bolus infusion of PAB acutely reduced MAP and increased both AVC and MVC in SHR. Additionally, PAB induced coronary and aorta vasodilation in isolated organs from Wistar and SHR in an endothelial-dependent manner. The chronic PAB treatment in SHR significantly attenuated the increase of SBP and improved the aorta vasorelaxation induced by acetylcholine and bradykinin-induced coronary vasodilation. In addition, chronic treatment with PAB attenuated the cardiomyocyte hypertrophy and extracellular matrix deposition in hearts from SHR. PAB did not alter the protein expression of the AT1, AT2, Mas, ACE, ACE2, or ACE2 activity. SIGNIFICANCE: PAB induced beneficial effects on cardiovascular dysfunctions induced by hypertension, suggesting that this molecule could be used in the development of new drugs for the treatment of cardiovascular diseases.

Assessment of Stiffness of Large to Small Arteries in Multistage Renal Disease Model: A Numerical Study.

Arterial stiffness (AS), as assessed via pulse wave velocity (PWV), is a major biomarker for cardiovascular risk assessment in patients with chronic kidney disease (CKD). However, the mechanisms responsible for the changes in PWV in the presence of kidney disease are not yet fully elucidated. In the present study, we aimed to investigate the direct effects attributable to biomechanical changes in the arterial tree caused by staged renal removal, independent of any biochemical or compensatory effects. Particularly, we simulated arterial pressure and flow using a previously validated one-dimensional (1-D) model of the cardiovascular system with different kidney configurations: two kidneys (2KDN), one single kidney (1KDN), no kidneys (0KDN), and a transplanted kidney (TX) attached to the external iliac artery. We evaluated the respective variations in blood pressure (BP), as well as AS of large-, medium-, and small-sized arteries via carotid-femoral PWV (cfPWV), carotid-radial PWV (crPWV), and radial-digital PWV (rdPWV), respectively. Our results showed that BP was increased in 1KDN and 0KDN, and that systolic BP values were restored in the TX configuration. Furthermore, a rise was reported in all PWVs for all tested configurations. The relative difference in stiffness from 2KDN to 0KDN was higher in the case of crPWV (15%) in comparison with the increase observed for cfPWV (11%). In TX, we observed a restoration of the PWVs to values close to 1KDN. Globally, it was demonstrated that alterations of the outflow boundaries to the renal arteries with staged kidney removal led to changes in BP and central and peripheral PWV in line with previously reported clinical data. Our findings suggest that the PWV variations observed in clinical practice with different stages of kidney disease may be partially attributed to biomechanical alterations of the arterial tree and their effect on BP.

eyeWatch™ System Combined with Non-plated Intraorbital Tube Insertion for the Management of Refractory Glaucoma: A Case Series.

INTRODUCTION: The eyeWatch™ is a novel device in glaucoma surgery aiming at the control of aqueous flow through the use of an external magnetic control unit. We propose the modification of this approach through the use of an injectable perforated tube rather than a plated valve. MATERIALS AND METHODS: Procedures were performed at the Department of Ophthalmology of the University of Crete. Three blind painful eyes of three patients were included. All patients were operated under topical anesthesia. A purpose designed blunt-ended injector was used to insert intraorbitally a perforated 4 cm-long silicone tube. The tube was then connected to an eyeWatch™ device which was placed in a standard fashion along the superior-temporal quadrant of the eyeball. The procedure was uneventful in cases I and II, whereas in case III the tube had to be trimmed by 1.5 cm because of cicatricial changes in the orbit. The eyeWatch™ was left closed (position VI) at the conclusion of surgeries. Patients were examined on the 1-day, 1-week, 2-week, 1-month, 3-month, and 6-month intervals and in one case on the 12-month interval. RESULTS: No major complications were observed. The intraocular pressure (IOP) remained under 15 mm Hg without anti-glaucomatous medications in all postoperative intervals in cases I and 2 with readjustment of eyeWatch™ at position IV. In case III, despite the change of the eyeWatch™ to the open position, the IOP remained high (40 mm Hg). DISCUSSION: The combination of the eyeWatch™ with an insertable perforated tube instead of a standard non-valved plate may prove a valid minimally invasive option. Modifications of the technique, such as an increased number and diameter of tube perforations, increased inserted tube length, perhaps aided by a sharp-ended injector, and selection of the insertion quadrant, may increase the effectiveness of the method. CLINICAL SIGNIFICANCE: eyeWatch™ combined with a single tube instead of a plated valve is a feasible, quick, and minimally invasive technique that can be used in glaucoma surgery. HOW TO CITE THIS ARTICLE: Detorakis ET, Villamarin A, Roy S, et al. eyeWatch™ System Combined with Non-plated Intraorbital Tube Insertion for the Management of Refractory Glaucoma: A Case Series. J Curr Glaucoma Pract 2020;14(2):64-67.

Performance and safety of treatment options for erectile dysfunction in patients with spinal cord injury: A review of the literature.

BACKGROUND: For a large proportion of patients with spinal cord injury, sexuality and reproduction are important issues. However, sparse data exist regarding available treatment options for this patient population. OBJECTIVES: We sought to review performance and safety rates of all currently available treatment options for erectile dysfunction in spinal cord injury men. MATERIALS AND METHODS: A systematic literature review without time restrictions was performed using PubMed/EMBASE database for English-, Italian-, German-, and Spanish-language articles. Articles' selection was performed according to the PRISMA guidelines. Relevant papers on erectile dysfunction in spinal cord injury patients were included in the final analyses. RESULTS AND DISCUSSION: Overall, 47 studies were eligible for inclusion in this review. Of these, most evidence dealt with phosphodiesterase 5-inhibitors and intracavernous drug injection. Both treatment options are associated with high levels of performance and with patients/partners' satisfaction; side effects are acceptable. Overall, penile prostheses and vacuum erection devices are in general less approved by spinal cord injury patients and are correlated with increased rates of complications in comparison with phosphodiesterase 5-inhibitors and intracavernous drug injection. Sacral neuromodulation, transcutaneous electrical nerve stimulation, and intraurethral suppositories have been poorly studied, but preliminary studies did not show convincing results. CONCLUSION: The best treatment options for erectile dysfunction in spinal cord injury patients emerged to be phosphodiesterase 5-inhibitors and intracavernous drug injection. The choice of erectile dysfunction treatment should be based on several aspects, including residual erectile function, spinal cord injury location, and patients' comorbidities. Future studies assessing the applicability of less well-studied treatments, as well as evaluating innovative options, are needed in this specific population.

Co-localization of microstructural damage and excessive mechanical strain at aortic branches in angiotensin-II-infused mice.

Animal models of aortic aneurysm and dissection can enhance our limited understanding of the etiology of these lethal conditions particularly because early-stage longitudinal data are scant in humans. Yet, the pathogenesis of often-studied mouse models and the potential contribution of aortic biomechanics therein remain elusive. In this work, we combined micro-CT and synchrotron-based imaging with computational biomechanics to estimate in vivo aortic strains in the abdominal aorta of angiotensin-II-infused ApoE-deficient mice, which were compared with mouse-specific aortic microstructural damage inferred from histopathology. Targeted histology showed that the 3D distribution of micro-CT contrast agent that had been injected in vivo co-localized with precursor vascular damage in the aortic wall at 3 days of hypertension, with damage predominantly near the ostia of the celiac and superior mesenteric arteries. Computations similarly revealed higher mechanical strain in branching relative to non-branching regions, thus resulting in a positive correlation between high strain and vascular damage in branching segments that included the celiac, superior mesenteric, and right renal arteries. These results suggest a mechanically driven initiation of damage at these locations, which was supported by 3D synchrotron imaging of load-induced ex vivo delaminations of angiotensin-II-infused suprarenal abdominal aortas. That is, the major intramural delamination plane in the ex vivo tested aortas was also near side branches and specifically around the celiac artery. Our findings thus support the hypothesis of an early mechanically mediated formation of microstructural defects at aortic branching sites that subsequently propagate into a macroscopic medial tear, giving rise to aortic dissection in angiotensin-II-infused mice.

Correction: A 1D computer model of the arterial circulation in horses: An important resource for studying global interactions between heart and vessels under normal and pathological conditions.

[This corrects the article DOI: 10.1371/journal.pone.0221425.].

A 1D computer model of the arterial circulation in horses: An important resource for studying global interactions between heart and vessels under normal and pathological conditions.

Arterial rupture in horses has been observed during exercise, after phenylephrine administration or during parturition (uterine artery). In human pathophysiological research, the use of computer models for studying arterial hemodynamics and understanding normal and abnormal characteristics of arterial pressure and flow waveforms is very common. The objective of this research was to develop a computer model of the equine arterial circulation, in order to study local intra-arterial pressures and flow dynamics in horses. Morphologically, large differences exist between human and equine aortic arch and arterial branching patterns. Development of the present model was based on post-mortem obtained anatomical data of the arterial tree (arterial lengths, diameters and branching angles); in vivo collected ultrasonographic flow profiles from the common carotid artery, external iliac artery, median artery and aorta; and invasively collected pressure curves from carotid artery and aorta. These data were used as input for a previously validated (in humans) 1D arterial network model. Data on terminal resistance and arterial compliance parameters were tuned to equine physiology. Given the large arterial diameters, Womersley theory was used to compute friction coefficients, and the input into the arterial system was provided via a scaled time-varying elastance model of the left heart. Outcomes showed plausible predictions of pressure and flow waveforms throughout the considered arterial tree. Simulated flow waveform morphology was in line with measured flow profiles. Consideration of gravity further improved model based predicted waveforms. Derived flow waveform patterns could be explained using wave power analysis. The model offers possibilities as a research tool to predict changes in flow profiles and local pressures as a result of strenuous exercise or altered arterial wall properties related to age, breed or gender.

Mapping the site-specific accuracy of loop-based local pulse wave velocity estimation and reflection magnitude: a 1D arterial network model analysis.

OBJECTIVE: Local pulse wave velocity (PWV) can be estimated from the waterhammer equation and is an essential component of wave separation analysis. However, previous studies have demonstrated inaccuracies in the estimations of local PWV due to the presence of reflections. In this study we compared the estimates of local PWV from the PU-loop, ln(D)U-loop, QA-loop and ln(D)P-loop methods along the complete human arterial tree, and analyzed the impact of the estimations on subsequent wave separation analysis. APPROACH: Estimated values were derived from the numerical outputs (pressure, flow, flow velocity, area and diameter waveforms) of a 1D model of the human circulation, and compared against a reference PWV obtained from the Bramwell-Hill equation in a reference configuration, and in a configuration with lower distensibility representing ageing. MAIN RESULTS: When including all nodes, the overall performance of the methods was poor (correlations and mean differences of R 2 < 0.4 and 3.0 ± 4.1 m s-1 for the PU-loop, R 2 < 0.07 and -0.7 ± 2.3 m s-1 for the ln(D)U-loop, and R 2 < 0.06 and -0.4 ± 2.3 m s-1 for the QA-loop). Focusing on specific sites, the ln(D)U- and QA-loop methods yielded acceptable results in the thoracic aorta and iliac arteries, while the PU-loop method was acceptable at the aortic arch. The reflection-insensitive ln(D)P-loop method performed well over the complete network (R 2 = 0.9 and 0.3 ± 0.3 m s-1), as did a previously proposed reflection-correction method for most vascular sites. Large errors in PWV estimation are attenuated in subsequent wave separation analysis, but the errors are site-dependent. SIGNIFICANCE: We conclude that the performances of the PU-loop, ln(D)U-loop and QA-loop methods are highly site-specific. The results should be interpreted with caution at all times.

Modulation of nNOSser852 phosphorylation and translocation by PKA/PP1 pathway in endothelial cells.

Neuronal nitric oxide synthase (nNOS) is now considered an important player in vascular function. It has a protective role in atherosclerosis and hypertension. However, despite its importance, little is known about the mechanisms that regulate its activity in vascular cells. Here we explore the mechanisms by which nNOS is activated in endothelium. We evaluated aorta relaxation response and phosphorylation of nNOS during protein phosphatases 1 and 2 (PP1 and PP2) inhibition, in eNOS silenced mice. PP1 translocation and interaction between the nuclear inhibitor of PP1 (NIPP1) and PP1 was evaluated in endothelial EA.hy926 cells. We demonstrate here that acetylcholine (Ach)-induced relaxation is completely abolished by nNOS inhibition in eNOS silenced mice aorta which also decreased NO and H2O2 concentrations. ACh induced dephosphorylation of nNOSser852 in aorta after 20 min stimulation. Endothelial cells also showed a decrease in nNOSser852 phosphorylation during 20 min of ACh stimulation. PP2 inhibition had no effect on Ach-induced nNOSSer852 dephosphorylation in endothelial cells and did not modify Ach-induced vasodilation in aorta from eNOS silenced mice. Non-selective PP1/PP2 inhibition prevented nNOSSer852 dephosphorylation in endothelial cells and prevented Ach-induced vasodilation in eNOS silenced mice. ACh induced time-dependent PP1 and NIPP1 dissociation and PP1 translocation to cytoplasm. Protein kinase A (PKA) inhibition abolished PP1 translocation and further nNOSser852 dephosphorylation. In addition, 8-Br-cAMP reduced NIPP1/PP1 interaction, stimulated PP1 translocation and nNOSser852 dephosphorylation. Moreover, PKA Inhibition led to a decreased nNOS translocation to perinuclear region. Taken together, our results elucidate a mechanism whereby PP1 is activated by a cAMP/PKA-dependent pathway, leading to dephosphorylation of nNOSser852 and subsequent NO and possible H2O2 production resulting in endothelium-dependent vascular relaxation.

Numerical assessment and comparison of pulse wave velocity methods aiming at measuring aortic stiffness.

Pulse waveform analyses have become established components of cardiovascular research. Recently several methods have been proposed as tools to measure aortic pulse wave velocity (aPWV). The carotid-femoral pulse wave velocity (cf-PWV), the current clinical gold standard method for the noninvasive assessment of aPWV, uses the carotid-to-femoral pulse transit time difference (cf-PTT) and an estimated path length to derive cf-PWV. OBJECTIVE: The heart-ankle PWV (ha-PWV), brachial-ankle PWV (ba-PWV) and finger-toe (ft-PWV) are also methods presuming to approximate aPWV based on time delays between physiological cardiovascular signals at two locations (~heart-ankle PTT, ha-PTT; ~brachial-ankle PTT, ba-PTT; ~finger-toe PTT, ft-PTT) and a path length typically derived from the subject's height. To test the validity of these methods, we used a detailed 1D arterial network model (143 arterial segments) including the foot and hand circulation. APPROACH: The arterial tree dimensions and properties were taken from the literature and completed with data from patient scans. We calculated PTTs with all the methods mentioned above. The calculated PTTs were compared with the aortic PTT (aPTT), which is considered as the absolute reference method in this study. MAIN RESULTS: The correlation between methods and aPTT was good and significant, cf-PTT (R 2 = 0.97; P < 0.001; mean difference 5 ± 2 ms), ha-PTT (R 2 = 0.96; P < 0.001; 150 ± 23 ms), ba-PTT (R 2 = 0.96; P < 0.001; 70 ± 13 ms) and ft-PTT (R 2 = 0.95; P < 0.001; 14 ± 10 ms). Consequently, good correlation was also observed for the PWV values derived with the tested methods, but absolute values differed because of the different path lengths used. SIGNIFICANCE: In conclusion, our computer model-based analyses demonstrate that for PWV methods based on peripheral signals, pulse transit time differences closely correlate with the aortic transit time, supporting the use of these methods in clinical practice.

Hemodynamic Impact of the C-Pulse Cardiac Support Device: A One-Dimensional Arterial Model Study.

The C-Pulse is a novel extra-aortic counter-pulsation device to unload the heart in patients with heart failure. Its impact on overall hemodynamics, however, is not fully understood. In this study, the function of the C-Pulse heart assist system is implemented in a one-dimensional (1-D) model of the arterial tree, and central and peripheral pressure and flow waveforms with the C-Pulse turned on and off were simulated. The results were studied using wave intensity analysis and compared with in vivo data measured non-invasively in three patients with heart failure and with invasive data measured in a large animal (pig). In all cases the activation of the C-Pulse was discernible by the presence of a diastolic augmentation in the pressure and flow waveforms. Activation of the device initiates a forward traveling compression wave, whereas a forward traveling expansion wave is associated to the device relaxation, with waves exerting an action in the coronary and the carotid vascular beds. We also found that the stiffness of the arterial tree is an important determinant of action of the device. In settings with reduced arterial compliance, the same level of aortic compression demands higher values of external pressure, leading to stronger hemodynamic effects and enhanced perfusion. We conclude that the 1-D model may be used as an efficient tool for predicting the hemodynamic impact of the C-Pulse system in the entire arterial tree, complementing in vivo observations.

Role of ERK1/2 activation and nNOS uncoupling on endothelial dysfunction induced by lysophosphatidylcholine.

BACKGROUND AND AIMS: Lysophosphatidylcholine (LPC) - a main component of oxidized LDL - is involved in endothelial dysfunction that precedes atherosclerosis, with an increased superoxide anions and a reduced NO production via endothelial NO synthase (eNOS) uncoupling. However, there is no evidence about the mechanisms involved in neuronal NOS (nNOS) uncoupling. Extracellular signal-regulated kinase (ERK) is related to the control of NO production and inflammatory gene transcription activation in atherosclerosis. Our aim was to investigate the role of nNOS/ERK1/2 pathway on endothelial dysfunction induced by LPC, in mouse aorta and human endothelial cells. METHODS: Thoracic aorta from wild type mice was used to perform vascular reactivity studies in the presence or absence of LPC. Human endothelial cells were used to investigate the effect of LPC on expression of nNOS and his products NO and H2O2. RESULTS: LPC reduced acetylcholine (ACh)-induced vasodilation in mouse aorta (EmaxCT/LPC = âˆ¼95 ± 2/62 ± 3%, p = 0.0004) and increased phenylephrine-induced vasoconstriction (EmaxCT/LPC = âˆ¼4 ± 0,1/6 ± 0,1 mN/mm, p = 0.0002), with a reduction in NO (fluorescence intensityCT/LPC = 91 ± 3/62±2 × 103, p = 0.0002) and H2O2 (fluorescence intensityCT/LPC = âˆ¼16 ± 0,8/10 ± 0,7 × 103, p = 0.0041) production evocated by ACh. An inhibition of nNOS by TRIM (EmaxCT/CT+TRIM = âˆ¼93 ± 1/43 ± 3%, p = 0,0048; EmaxLPC/LPC+TRIM = âˆ¼62 ± 3/65 ± 3%) or H2O2 degradation by catalase (EmaxCT/CT+cat = âˆ¼93 ± 1/46 ± 2%, p < 0,001; EmaxLPC/LPC+cat = âˆ¼62,8 ± 3,2/60,5 ± 4,7%) reduced the relaxation in the control but not in LPC group. PD98059, an ERK1/2 inhibitor, abolished the increase in vasoconstriction in LPC-treated vessels (EmaxLPC/LPC+PD = âˆ¼6 ± 0,1/3 ± 0,1 mN/mm, p = 0.0001). LPC also reduced the dimer/monomer proportion and increased nNOSser852 phosphorylation. CONCLUSIONS: LPC induced nNOS uncoupling and nNOSSer852 phosphorylation, reduced NO and H2O2 production and improved superoxide production by modulating ERK1/2 activity in human and murine endothelial cells.

Contribution of the Arterial System and the Heart to Blood Pressure during Normal Aging - A Simulation Study.

During aging, systolic blood pressure continuously increases over time, whereas diastolic pressure first increases and then slightly decreases after middle age. These pressure changes are usually explained by changes of the arterial system alone (increase in arterial stiffness and vascular resistance). However, we hypothesise that the heart contributes to the age-related blood pressure progression as well. In the present study we quantified the blood pressure changes in normal aging by using a Windkessel model for the arterial system and the time-varying elastance model for the heart, and compared the simulation results with data from the Framingham Heart Study. Parameters representing arterial changes (resistance and stiffness) during aging were based on literature values, whereas parameters representing cardiac changes were computed through physiological rules (compensated hypertrophy and preservation of end-diastolic volume). When taking into account arterial changes only, the systolic and diastolic pressure did not agree well with the population data. Between 20 and 80 years, systolic pressure increased from 100 to 122 mmHg, and diastolic pressure decreased from 76 to 55 mmHg. When taking cardiac adaptations into account as well, systolic and diastolic pressure increased from 100 to 151 mmHg and decreased from 76 to 69 mmHg, respectively. Our results show that not only the arterial system, but also the heart, contributes to the changes in blood pressure during aging. The changes in arterial properties initiate a systolic pressure increase, which in turn initiates a cardiac remodelling process that further augments systolic pressure and mitigates the decrease in diastolic pressure.

In vivo testing of a novel adjustable glaucoma drainage device.

PURPOSE: We report on the in vivo testing of a novel noninvasively adjustable glaucoma drainage device (AGDD), which features an adjustable outflow resistance, and assess the safety and efficiency of this implant. METHODS: Under general anesthesia, the AGDD was implanted on seven white New Zealand rabbits for a duration of 4 months under a scleral flap in a way analogous to the Ex-PRESS device and set in an operationally closed position. The IOP was measured on a regular basis on the operated and control eyes using a rebound tonometer. Once a month the AGDD was adjusted noninvasively from its fully closed to its fully open position and the resulting pressure drop was measured. The contralateral eye was not operated and served as control. After euthanization, the eyes were collected for histology evaluation. RESULTS: The mean preoperative IOP was 11.1 ± 2.4 mm Hg. The IOP was significantly lower for the operated eye (6.8 ± 2 mm Hg) compared to the nonoperated eye (13.1 ± 1.6 mm Hg) during the first 8 days after surgery. When opening the AGDD from its fully closed to fully open position, the IOP dropped significantly from 11.2 ± 2.9 to 4.8 ± 0.9 mm Hg (P < 0.05). CONCLUSIONS: Implanting the AGDD is a safe and uncomplicated surgical procedure. The fluidic resistance was noninvasively adjustable during the postoperative period with the AGDD between its fully closed and fully open positions.

A new adjustable glaucoma drainage device.

PURPOSE: This work is focused on the testing of a new experimental noninvasively adjustable glaucoma drainage device (AGDD) that allows for the control of its outflow resistance to modulate intraocular pressure (IOP) in a customized fashion. METHODS: Six AGDDs were directly connected to a pressure transducer and a perfusion system continuously delivering saline solution at rate of 2 µL/min. The steady-state pressure was measured and reported as a function of the angular position of the AGDD disk. Ex vivo experiments were conducted on six freshly enucleated rabbit eyes. The IOP was measured, and the flow rate was increased with a syringe pump to simulate elevated IOP associated with glaucoma. After insertion of the implant in the anterior chamber, the position of the disk was sequentially adjusted. RESULTS: The relation between the pressure drop and the angular position of the AGDD disk is nonlinear. The functional range lies between 80° and 130°, which allows for four or five different reproducible adjustment positions. Above 130° the implant is considered to be closed (no outflow), and below 80° it is considered to be open (minimum resistance to flow). CONCLUSIONS: The resistance to outflow of the experimental AGDD can be adjusted to keep IOP in the desired physiological range. This feature could be useful for addressing the risk of hypotony in the early postoperative stages and could provide a means to achieve optimal IOP under a wide range of postoperative conditions.

Effects of isoflurane anesthesia on aortic compliance and systemic hemodynamics in compliant and noncompliant aortas.

OBJECTIVES: To investigate the effect of general anesthesia on aortic compliance and other cardiovascular hemodynamics in chronically instrumented pigs with compliant and noncompliant (stiff) aortas. DESIGN: Experimental study. SETTING: University animal laboratory. PARTICIPANTS: Twelve adult Yucatan miniature pigs. INTERVENTIONS: Chronic instrumentation of a compliant (control; n = 7) and noncompliant (n = 5) group to measure pressure and flow in the ascending aorta. A Teflon prosthesis was wrapped around the aorta (noncompliant group) to limit wall compliance. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were recorded on the 15th postoperative day, both awake and after general anesthesia. Banding the aorta caused a significant decrease in arterial compliance (-49%, p<0.001) and increases in systolic blood pressure (SBP: +38%, p = 0.001) and pulse pressure (+107%, p< 0.01). Induction of anesthesia in the control group produced a 15% increase in arterial compliance (p<0.05), resulting in a subtle decrease in SBP (-12%), diastolic blood pressure (DBP; -13%) and mean blood pressure (MBP; -12%). Induction of anesthesia in the noncompliant group also caused a significant increase in arterial compliance (17%, p<0.001), but caused significant decreases in SBP (21%, p<0.01), DBP (23%, p<0.01) and MBP (22%, p<0.01) as compared with controls. CONCLUSIONS: Induction of general anesthesia caused a similar increase in total arterial compliance and was associated with a decrease in SBP that was more pronounced in animals with noncompliant aortas. These results indicated that anesthesia caused a greater hemodynamic effect on noncompliant (stiff) aortas and may explain the extensive hemodynamic fluctuation and instability often observed in atherosclerotic, elderly patients with stiff aortas.

Pathophysiological role of the renin-angiotensin system on erectile dysfunction.

BACKGROUND: The renin-angiotensin system (RAS) has been shown to play an active role within the erectile tissues. The aim of this narrative review is to summarize the literature addressing the pathophysiological role of RAS on erectile function. Additionally, we update evidence on recent findings on the role of the Ang-(1-7) and Mas receptor on the erectile function and its therapeutic potential for treating erectile dysfunction (ED). MATERIALS AND METHODS: This narrative review is based on the material searched and obtained via MEDLINE and PubMed up to November 2012. The search terms we used are 'angiotensin, erectile dysfunction, renin, Mas receptor' in combination with 'pathophysiology, fibrosis, pathways'. RESULTS: The levels of angiotensin (Ang) II, the main component of this system, are increased in the corpus cavernosum as compared to those found in the systemic circulation. Moreover, emerging evidence indicates that an increased activity of Ang II via AT1 receptor might contribute to the development of ED, whereas the pharmacological blockage of Ang II/AT1 actions has beneficial effects on the erection. On the other hand, the heptapeptide Ang-(1-7), known as a major endogenous counter-regulator of Ang II actions, favours penile erection via the activation of Mas receptor. CONCLUSIONS: Ang-(1-7) and Mas receptor pathway might be considered as a promising therapeutic target for the treatment of ED.

Arginase inhibition prevents the low shear stress-induced development of vulnerable atherosclerotic plaques in ApoE-/- mice.

AIMS: Wall shear stress differentially regulates the arginase pathway in carotid arteries perfused ex vivo. Specific patterns of wall shear stress can locally determine atherosclerotic plaque size and composition in vivo. The present work investigates the effects of arginase inhibition on shear stress induced plaque composition. METHODS AND RESULTS: Carotid arteries of apolipoprotein E deficient mice were exposed to high (HSS), low (LSS) and oscillatory (OSS) shear stress conditions by the placement of a local shear stress modifier device for 9 weeks with or without the administration of the arginase inhibitor N-ω-Hydroxy-nor-L-arginine (nor-Noha) (10 mg/kg, i.p., 5 days/week). Carotid arginase activity was measured by colorimetric determination of urea. Atherosclerotic plaque size and composition, arginase expression and cellular localization were assessed by immunohistochemistry. Arginase activity was significantly increased in both LSS and OSS regions as compared to HSS. In the lesions, arginase II isoform co-localized preferentially with EC. Inhibition of arginase by nor-Noha decreased arginase activity and reduced plaque size in both LSS and OSS regions. Arginase inhibition affected mainly the composition of plaques developed in LSS regions by decreasing the total vascular ROS, the number of macrophages, apoptosis rate, lipid and collagen contents. CONCLUSIONS: Arginase activity is modulated by patterns of wall shear stress in vivo. Chronic inhibition of vascular arginase decreased the size of atherosclerotic lesions in both OSS and LSS regions, whereas changes on plaque composition were more pronounced in plaques induced by LSS. We identified wall shear stress as a key biomechanical regulator of arginase during plaque formation and stability.