Computational assessment of model-based wave separation using a database of virtual subjects

The quantification of arterial wave reflection is an important area of interest in arterial pulse wave analysis. It can be achieved by wave separation analysis (WSA) if both the aortic pressure waveform and the aortic flow waveform are known. For better applicability, several mathematical models have been established to estimate aortic flow solely based on pressure waveforms. The aim of this study is to investigate and verify the model-based wave separation of the ARCSolver method on virtual pulse wave measurements.The study is based on an open access virtual database generated via simulations. Seven cardiac and arterial parameters were varied within physiological healthy ranges, leading to a total of 3325 virtual healthy subjects. For assessing the model-based ARCSolver method computationally, this method was used to perform WSA based on the aortic root pressure waveforms of the virtual patients. As a reference, the values of WSA using both the pressure and flow waveforms provided by the virtual database were taken.The investigated parameters showed a good overall agreement between the model-based method and the reference. Mean differences and standard deviations were −0.05 ± 0.02 AU for characteristic impedance, −3.93 ± 1.79 mmHg for forward pressure amplitude, 1.37 ± 1.56 mmHg for backward pressure amplitude and 12.42 ± 4.88% for reflection magnitude.The results indicate that the mathematical blood flow model of the ARCSolver method is a feasible surrogate for a measured flow waveform and provides a reasonable way to assess arterial wave reflection non-invasively in healthy subjects.     

Effect of dietary nitrate on blood pressure,endothelial function,and insulin sensitivity in type 2 diabetes

Diets rich in green, leafy vegetables have been shown to lower blood pressure (BP) and reduce the risk of cardiovascular disease. Green, leafy vegetables and beetroot are particularly rich in inorganic nitrate. Dietary nitrate supplementation, via sequential reduction to nitrite and NO, has previously been shown to lower BP and improve endothelial function in healthy humans. We sought to determine if supplementing dietary nitrate with beetroot juice, a rich source of nitrate, will lower BP and improve endothelial function and insulin sensitivity in individuals with type 2 diabetes (T2DM). Twenty-seven patients, age 67.2±4.9 years (18 male), were recruited for a double-blind, randomized, placebo-controlled crossover trial. Participants were randomized to begin, in either order, a 2-week period of supplementation with 250 ml beetroot juice daily (active) or 250 ml nitrate-depleted beetroot juice (placebo). At the conclusion of each intervention period 24-h ambulatory blood pressure monitoring, tests of macro- and microvascular endothelial function, and a hyperinsulinemic isoglycemic clamp were performed. After 2 weeks administration of beetroot juice mean ambulatory systolic BP was unchanged: 134.6±8.4 mm Hg versus 135.1±7.8 mm Hg (mean±SD), placebo vs active—mean difference of −0.5 mm Hg (placebo–active), p=0.737 (95% CI −3.9 to 2.8). There were no changes in macrovascular or microvascular endothelial function or insulin sensitivity. Supplementation of the diet with 7.5 mmol of nitrate per day for 2 weeks caused an increase in plasma nitrite and nitrate concentration, but did not lower BP, improve endothelial function, or improve insulin sensitivity in individuals with T2DM.     

Noninvasive pressure pulse waveform analysis of flow-mediated vasodilation evoked by post-occlusive reactive hyperemia maneuver

Post-occlusive reactive hyperemia (PORH) assesses flow-mediated vasodilation at microvascular level due to bioactivity of endothelial-derived factors. Ordinary augmentation index that quantifies endothelial response is based on an ensemble-averaged waveform that limits its short-time application. This study proposes a mathematical model and two corresponding indices to evaluate arterial pressure response after blood flow restoration. Radial pressure pulse waveforms were acquired by a 12 bits acquisition board at a sampling rate of 1.0 kHz using a piezoelectric transducer. Signals were stored during 30 s at baseline condition and 60 s after 5-min occlusion using an arm-cuff placed over the brachial artery. In both conditions, the pressure pulse waveform presents systolic and diastolic phases with progressive and regressive pulse waveforms, respectively. Changes in pulse wave morphology were also observed and comprised attenuation of the pulse pressure amplitude (markedly first and second systolic peaks). This characteristic of the pulse pressure was described by the time-domain summation of two pairs of Gaussian-like waveforms (representing independent progressive and regressive components) with parameters related to amplitude, time lag, and duration for each component. A steepest descent optimization routine was used to fit the model parameters to experimental data of normotensive and subjects with hypertension. The optimized parameters were used to calculate two indices, RIx_1,2 (second-to-first systolic peak ratio) and RIx_1,3 (first diastolic-to-first systolic ratio). The observed responses between groups suggest that RIx_1,2 is related to an endothelial response to the ischemic process and could be used as a clinical tool to assess endothelial function in hypertension.     

Myoglobin functions in the heart

The physiological role of myoglobin (Mb) within the heart depends on its oxygenation state. The myocardium exhibits a broad oxygen partial pressure (pO₂) spectrum with a transmural gradient from the epicardial to the subendocardial layer, ranging from arterial values to an average of 19.3 mm Hg down to 0 mm Hg. The function of Mb as an O₂ storage depot is well appreciated, especially during systolic compression. In addition, Mb controls myocardial nitric oxide (NO) homeostasis and thus modulates mitochondrial respiration under physiological and pathological conditions. We recently discovered the role of Mb as a myocardial O₂ sensor; in its oxygenated state Mb scavenges NO, protecting the heart from the deleterious effects of excessive NO. Under hypoxia, however, deoxygenated Mb changes its role from an NO scavenger to an NO producer. The NO produced protects the cell from short phases of hypoxia and from myocardial ischemia/reperfusion injury. In this review we summarize the traditional and novel aspects of Mb and its (patho)physiological role in the heart.     

Capteur SAW implantable dédié à la télémesure de la température et de la pression artérielle : le projet ANR-TECSAN CIMPA

The CIMPA Project (2007-2008), led under the ANR-TECSAN Call, was coordinated by SENSeOR, in partnership with the LEAT and the FEMTO. The aim of the project was to develop a surface acoustic wave sensor demonstrator, passive implantable to monitoring the blood pressure and the temperature. This sensor uses the surface acoustic wave technology (SAW) and is composed of three resonators using quartz as piezoelectric substrate. One resonator for temperature measurement (T), a second resonator for the blood pressure measurement (P) and a third resonator, which is used as reference (R). This sensor is compatible with size requirements inherent to an implantation in an artery, since the size of the resonator with its antennas in its most compact configuration is of the order of 5.2 mm × 3.7 mm × 0.85 mm. It requires no embarked sources of energy and being able to be interrogated by a radiofréquence (RF) connection thanks to a transceiver, which emits a signal in the band industrial, scientific and medical (ISM). The sensor (connected to an integrated antenna on quartz of very small dimension) requested by the signal of interrogation emits in its turn a signal, which carries information of pressure and temperature. The transceiver then collects apart from its transmitting phase the signal emitted by the sensor and extracts by an appropriate signal processing method information of pressure and temperature. The targeted range for pressure measurement extends from 1 bar to 1.35 bar with an accuracy of about 2% FS.     

A possible correlation between the correction of endothelial dysfunction and normalization of high blood pressure levels by 1,3,4-oxadiazole derivative,an L-type Ca2+ channel blocker in deoxycorticosterone acetate and NG-nitro-l-arginine hypertensive rats

We have previously demonstrated the vasorelaxant activity of 1,3,4-oxadiazole derivative (NOX-1) through L-type Ca²⁺ channel blockage. In the present study, we investigated whether the correction of endothelial dysfunction is dependent on the normalization of high blood pressure levels by 1,3,4-oxadiazole derivative (NOX-1) in deoxycorticosterone acetate (DOCA-salt) and N^G-nitro-l-arginine (L-NNA) hypertensive rats. In DOCA-salt and L-NNA hypertensive rats, the mean systolic blood pressure (MSBB) was 185.3 ± 4.7 and 170.2 ± 4.1 mmHg, whereas after administration of NOX-1 to hypertensive rats, MSBB was 127.8 ± 4.5 and 120.2 ± 5.1 mmHg, respectively. To study the endothelial dysfunction, concentration–response curves of norepinephrine (NE) and acetylcholine (Ach) were constructed in rat aortic rings isolated from normotensive, hypertensive (DOCA and L-NNA) and NOX-1 treated rats. NE-induced contractions and Ach-induced relaxations were significantly (p < 0.05) decreased and increased, respectively in the aorta of NOX-1 treated rats. Vasorelaxant activity of NOX-1 was not abolished by pretreatment of aortic rings with L-NNA, 1H-[1,2,4] oxadiazolo [4,3-A] quinoxalin-1-one (ODQ), indomethacin or glibenclamide. The results suggest that the endothelial dysfunction can be corrected by the L-type Ca²⁺ channel blocker with endothelium-independent action and that is dependent on the normalization of high blood pressure levels. The antihypertensive and vasorelaxant effects of NOX-1 are mainly endothelial-independent and it can be used to treat hypertension, a state associated with endothelial dysfunction.     

Structural analysis of the natural aortic valve in dynamics: From unpressurized to physiologically loaded

A novel finite element model of the natural aortic valve was developed implementing anisotropic hyperelastic material properties for the leaflets and aortic tissues, and starting from the unpressurized geometry. Static pressurization of the aortic root, silicone rubber moulds and published data helped to establish the model parameters, while high-speed video recording of the leaflet motion in a left-heart simulator allowed for comparisons with simulations. The model was discretized with brick elements and loaded with time-varying pressure using an explicit commercial solver. The aortic valve model produced a competent valve whose dynamic behavior (geometric orifice area vs. time) closely matched that observed in the experiment. In both cases, the aortic valve took approximately 30 ms to open to an 800 mm² orifice and remained completely or more than half open for almost 200 ms, after which it closed within 30–50 ms. The highest values of stress were along the leaflet attachment line and near the commissure during diastole. Von Mises stress in the leaflet belly reached 600–750 kPa from early to mid-diastole. While the model using the unpressurized geometry as initial configuration was specially designed to satisfy the requirements of continuum mechanics for large deformations of hyperelastic materials, it also clearly demonstrated that dry models can be adequate to analyze valve dynamics. Although improvements are still needed, the advanced modeling and validation techniques used herein contribute toward improved and quantified accuracy over earlier simplified models.     

The role of the angiotensin AT2 receptor on the diurnal variations of nociception and motor coordination in rats

Phasic pain demonstrates significant diurnal variation in rats. Angiotensin II modulates pain transmission and the diurnal variation in nociception in several rodent pain models. The participation of AT2 receptors in the diurnal regulation of nociception is not yet elucidated. In the present study we investigated the effects of selective peptide AT2 agonist CGP 42112A and the nonpeptide AT2 receptor antagonist PD 123319 on the nociception, motor coordination and arterial blood pressure. Male Wistar 12 weeks old rats were used. CGP 42112A was injected at single doses of 1 and 5 μg/rat intracerebroventricularly (ICV) and infused chronically ICV at a dose of 12 μg/rat/day during 14 days by osmotic minipumps. PD123319 was injected at single doses of 1 and 5 μg/rat, ICV and chronically subcutaneously at a dose of 10 mg/kg/day/14 days. Nociception was assessed by an analgesimeter, arterial blood pressure (ABP) was measured by tail cuff method, and motor coordination by Rota-rod method. Single doses of CGP 42112A (1 and 5 μg/rat) provoked a short lasting antinociception. Unlike acute injection, chronic CGP 42112A infusion increased nociception at the beginning and the end of light phase thus attenuating the diurnal variations observed in the controls. Moreover, it produced an increase of ABP and improved motor coordination. Both acute (1 μg/rat) and chronic PD 123319 treatment resulted in a decrease of pain threshold and chronic treatment attenuated its diurnal fluctuation. Our data support a role for Ang II type 2 receptors in the control of diurnal variations of nociception in rats.     

Asociación de la fuerza muscular con marcadores tempranos de riesgo cardiovascular en adultos sedentarios

ObjectiveTo assess the association between muscle strength and early cardiovascular risk (CVR) markers in sedentary adults.Materials and methodsA total of 176 sedentary subjects aged 18-30 years were enrolled. Body mass index and fat percentage were calculated, and waist circumference, grip strength by dynamometry, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and maximal oxygen uptake by VO_2max were measured as CVR markers. A multivariate logistic regression analysis was used to assess associations between muscle strength and CVR markers.ResultsInverse correlations were found between muscle strength and adiposity (r = -.317; P = .001), waist circumference (r = -.309; P = .001), systolic blood pressure (r = -.401; P = .001), and mean arterial pressure (r = -.256; P = .001). Subjects with lower levels of muscle strength had a 5.79-fold (95% CI 1.57 to 9.34; P = .008) risk of having higher adiposity levels (≥ 25%) and a 9.67-fold (95% CI = 3.86 to 19.22; P < .001) risk of having lower physical capacity values for VO_2max (≤ 31.5 mL/kg/min^-1).ConclusionsIn sedentary adults, muscle strength is associated to early manifestations of CVR. It is suggested that muscle strength testing is added to routine measurement of VO_2max and traditional risk factors for prevention and treatment of cardiovascular risk.     

Antioxidant treatment reduces matrix metalloproteinase-2-induced vascular changes in renovascular hypertension

Mounting evidence indicates that structural and functional vascular changes associated with two-kidney, one-clip (2K-1C) hypertension result, at least in part, from altered activity of matrix metalloproteinases (MMPs). Because MMPs are upregulated by increased formation of reactive oxygen species (ROS), we hypothesized that antioxidant approaches could attenuate the increases in MMP-2 expression/activity and the vascular dysfunction and remodeling associated with 2K-1C hypertension. Sham-operated or 2K-1C hypertensive rats were treated with tempol 18 mg/kg/day or apocyanin 25 mg/kg/day (or vehicle). Systolic blood pressure was monitored weekly. After 8 weeks of treatment, aortic rings were isolated to assess endothelium-dependent and -independent relaxation. Quantitative morphometry of structural changes in the aortic wall was studied in hematoxylin/eosin sections. Aortic and systemic ROS levels were measured using dihydroethidine and thiobarbituric acid-reactive substances, respectively. Aortic MMP-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry, and immunohistochemistry. Tempol and apocyanin attenuated 2K-1C hypertension (181 ± 20.8 and 192 ± 17.6 mm Hg, respectively, versus 213 ± 18 mm Hg in hypertensive controls; both p < 0.05) and prevented the reduction in endothelium-dependent vasorelaxation found in 2K-1C rats. Tempol, but not apocyanin (p > 0.05), prevented the vascular remodeling found in 2K-1C rats (all p < 0.01). Tempol was more effective than apocyanin in attenuating hypertension-induced increases in oxidative stress (both p < 0.05), MMP-2 levels, and MMP-2 activity in hypertensive rats (all p < 0.05). Our results suggest that antioxidant approaches decrease MMP-2 upregulation and attenuate the vascular dysfunction and remodeling during 2K-1C hypertension.     

Effect of eicosapentaenoic acid on central systolic blood pressure

Central systolic blood pressure (C-SBP) has been shown to be a better predictor of cardiovascular risk than brachial SBP. In this study, the effects of eicosapentaenoic acid (EPA) on C-SBP were compared with pravastatin. Twenty-four patients with hyperlipidemia were assigned 13 to receive 1800 mg/day EPA (EPA group) and 11 to receive 10 mg/day pravastatin (pravastatin group) for 3 months. In the EPA group, there were no changes in the LDL–cholesterol level. However, the radial augmentation index (AI) and C-SBP decreased after treatment by 5.7% (p<0.01) and 8.7% (p<0.001), respectively. Moreover, systolic and diastolic brachial BPs decreased by 7.1% and 8.0%, respectively (p<0.01 for both). In the pravastatin group, the LDL–cholesterol level decreased by 29.5% (p<0.001). However, there were no significant changes in brachial BP, AI and C-SBP between. These results suggested that EPA but not pravastatin may reduce cardiac afterload by reducing vascular reflected waves and lowering C-SBP.     

Effects of cilnidipine on sympathetic outflow and sympathetic arterial pressure and heart rate regulations in rats

AimsCilnidipine is a unique Ca^2 + channel blocker that inhibits both L-type and N-type Ca^2 + channels. The present study aimed to assess the effects of intravenous cilnidipine on sympathetic outflow and sympathetic arterial pressure (AP) and heart rate (HR) regulations.Main methodsCarotid sinus baroreceptor regions were isolated from the systemic circulation in anesthetized and vagotomized Wistar Kyoto rats. Changes in efferent sympathetic nerve activity (SNA), AP and HR in response to a stepwise input of carotid sinus pressure were examined before and during intravenous cilnidipine administration (30 μg/kg bolus + 100 μg kg^? 1 h^? 1 infusion, n = 6).Key findingsCilnidipine significantly reduced the AP response range (from 68.0 ± 10.2 to 34.6 ± 4.1 mmHg, P = 0.007) but did not affect the SNA response range (from 90.4 ± 10.3 to 84.7 ± 9.5%, P = 0.297) or the HR response range (from 50.4 ± 10.1 to 48.1 ± 6.2 beats/min, P = 0.719).SignificanceCilnidipine, at a depressor dose used in the present study, does not acutely suppress sympathetic outflow from the central nervous system. Also, it spared the sympathetic HR response, suggesting that N-type Ca^2 + channel blocking action at the cardiac sympathetic nerve endings may be a modest one.     

A high-speed C++/MEX solution for long-duration arterial blood pressure characteristic locations detection

The major concentration of this study is to describe the structure of a C++/MEX solution for robust detection and delineation of arterial blood pressure (ABP) signal events. Toward this objective, the original ABP signal was pre-processed by application of à trous discrete wavelet transform (DWT) to extract several dyadic scales. Then, a sliding window with fixed length was moved on the appropriately selected scale. In each slid, mean, variance, Skewness and Kurtosis values of the excerpted segment were superimposed to generate a newly defined multiple higher order moments (MHOM) metric to be used as the detection decision statistic (DS). Then, after application of an adaptive-nonlinear transformation for making the DS baseline static, the histogram parameters of the enhanced DS were used for regulation of the α-level Neyman–Pearson classifier aimed for false alarm probability (FAP)-bounded delineation of the ABP events. The proposed method was applied to all 18 subjects of the MIT-BIH Polysomnographic Database (359,000 beats). The end-systolic and end-diastolic locations of the ABP signal as well as the dicrotic notch pressure were extracted and values of sensitivity Se = 99.86% and positive predictivity P+ = 99.95% were obtained for the detection of all ABP events. This paper proves the proposed MHOM-based ABP events detection–delineation algorithm as an improvement because of its merits such as: high robustness against measurement noises, acceptable detection–delineation accuracy of the ABP events in the presence of severe heart valvular, arrhythmic dysfunctions within a tolerable computational burden (processing time) and having no parameters dependency on the acquisition sampling frequency.     

Models of hemorrhagic shock: Differences in the physiological and inflammatory response

IntroductionThe hemorrhagic shock (HS) model is commonly used to initiate a systemic post-traumatic inflammatory response. Numerous experimental protocols exist and it is unclear how differences in these models affect the immune response making it difficult to compare results between studies. The aim of this study was to compare the inflammatory response of different established protocols for volume-controlled shock in a murine model.MethodsMale C57/BL6 mice 6–10 weeks and weighing 20–25 g were subjected to volume-controlled or pressure-controlled hemorrhagic shock. In the volume-controlled group 300 μl, 500 μl, or 700 μl blood was collected over 15 min and mean arterial pressure was continuously monitored during the period of shock. In the pressure-controlled hemorrhagic shock group, blood volume was depleted with a goal mean arterial pressure of 35 mmHg for 90 min. Following hemorrhage, mice from all groups were resuscitated with the extracted blood and an equal volume of lactated ringer solution. Six hours from the initiation of hemorrhagic shock, serum IL-6, KC, MCP-1 and MPO activity within the lung and liver tissue were assessed.ResultsIn the volume-controlled group, the mice were able to compensate the initial blood loss within 30 min. Approximately 800 μl of blood volume was removed to achieve a MAP of 35 mmHg (p < 0.001). No difference in the pro-inflammatory cytokine (IL-6 and KC) profile was measured between the volume-controlled groups (300 μl, 500 μl, or 700 μl). The pressure-controlled group demonstrated significantly higher cytokine levels (IL-6 and KC) than all volume-controlled groups. Pulmonary MPO activity increased with the severity of the HS (p < 0.05). This relationship could not be observed in the liver.ConclusionVolume-controlled hemorrhagic shock performed following current literature recommendations may be insufficient to produce a profound post-traumatic inflammatory response. A decrease in the MAP following blood withdrawal (300 μl, 500 μl or 700 μl) was usually compensated within 30 min. Pressure-controlled hemorrhagic shock is a more reliable for induction of a systemic inflammatory response.     

Modélisation des flux cérébraux par une analogie électrique : validation par vélocimétrie IRM

The cine Phase-Contrast Magnetic Resonance (PCMR) sequence is the only noninvasive technique for the study of cerebrospinal fluid (CSF) oscillations. It can provide CSF and blood flow measurements throughout the cardiac cycle. To study cerebral hydro-hemodynamic, models have been developed; nevertheless the majority of these models did not take into account the CSF oscillations. The objective of this study was to establish reference values for cerebral hydro-hemodynamic and propose a new electrical model of the brain dynamics.Material and methodsCSF and blood flows were measured in 19 control subjects by PCMR imaging. Dynamic flow images were analyzed on dedicated software to reconstruct the flow curves during the cardiac cycle. An electrical analogue was realized. The inputs of the model were fed by PCMR arterial and venous flows to simulate CSF oscillations. The simulated CSF oscillations were compared to the measured CSF oscillations to validate the model.ResultsThe key parameters of the CSF and blood flow curves were obtained, e.g. total cerebral blood flow was 688 ± 115 mL/min, ventricular CSF oscillatory volume was 0.05 ± 0.02 mL/cardiac cycle, and the subarachnoid CSF oscillatory volume was 0.55 ± 0.15 mL/cardiac cycle. A close agreement was found between measured and simulated cerebral CSF oscillations.ConclusionThis study established the main values characterizing cerebral hydrodynamics in a control population. It provided a better understanding of the mechanisms of intracranial volumes regulation during the cardiac cycle. Our results are now used in clinical practice and the model proposed is effective to study cerebral hydro-hemodynamic.     

Biomechanics of invasive growth by Armillaria rhizomorphs

Rhizomorphs of wood-decay basidiomycetes are root-like structures produced by the coordinated growth of thousands of hyphae. Very little is known about their development nor the way that they penetrate soils and rotting wood. In this study, we applied techniques used in previous studies on hyphae to explore the mechanics of the invasive growth process in Armillaria gallica. Growth rate measurements were made in media with different gel strengths. The osmolyte composition of rhizomorph sap was determined spectroscopically and the forces exerted by growing tips were measured using a force transducer. Cultured rhizomorphs extended at much faster rates than unbundled hyphae (3.5 mm d⁻¹ versus 1.5 mm d⁻¹) and their growth accelerated in response to increased medium gel strength (to 7.4 mm d⁻¹). Measurements of rhizomorph osmolality provided a turgor pressure estimate of 760 kPa (7.5 atm.), and spectroscopic analysis showed that this pressure was generated by the accumulation of erythritol, mannitol, and KCl. Forces exerted by growing tips ranged from 1 to 6 mN, corresponding to pressures of 40–300 kPa (0.4–3.0 atm.). Pressures exerted by extending rhizomorphs are comparable to those produced by individual vegetative hyphae. This suggests that the mechanical behavior of hyphae is similar whether they grow as unbundled cells or aggregate to form macroscopic rhizomorphs.     

Endothelial permeability in vitro and in vivo: Protective actions of ANP and omapatrilat in experimental atherosclerosis

Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I¹²⁵ albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n = 13) or placebo (n = 13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system.     

Low-dose chronic lead exposure increases systolic arterial pressure and vascular reactivity of rat aortas

Chronic lead exposure induces hypertension affecting endothelial function. We investigated whether low-concentration lead exposure alters blood pressure and vascular reactivity, focusing on the roles of NO, oxidative stress, cyclooxygenase-derived vasoconstrictor prostanoids, and the local angiotensin–renin system. Aortic rings from 3-month-old Wistar rats were treated daily with lead acetate (first dose 4 mg/100 g, subsequent doses 0.05 mg/100 g, im) or vehicle for 30 days. Treatment increased lead blood levels (12 μg/dl), blood pressure, and aortic ring contractile response to phenylephrine (1 nM–100 mM). Contractile response after L-NAME administration increased in both groups but was higher after lead treatment. Lead effects on R_max decreased more after apocynin and superoxide dismutase administration compared to control. Indomethacin reduced phenylephrine response more after lead treatment than in controls. The selective COX-2 inhibitor NS398, thromboxane A₂/prostaglandin H2 receptor antagonist SQ 29,548, TXA₂ synthase inhibitor furegrelate, EP₁ receptor antagonist SC 19220, and ACE inhibitor and AT₁ receptor antagonist losartan reduced phenylephrine responses only in vessels from lead-treated rats. Basal and stimulated NO release was reduced and local O₂⁻ liberation increased in the lead-treated group compared to controls. eNOS, iNOS, and AT₁ receptor protein expression increased with lead exposure, but COX-2 protein expression decreased. This is the first demonstration that blood Pb²⁺ (12 µg/dl) concentrations below the WHO-established values increased systolic blood pressure and vascular phenylephrine reactivity. This effect was associated with reduced NO bioavailability, increased reactive oxygen species production, increased participation of COX-derived contractile prostanoids, and increased renin–angiotensin system activity.     

Effects of praeruptorin C on blood pressure and expression of phospholamban in spontaneously hypertensive rats

BackgroundThe traditional Chinese medicine Praeruptorin c (Pra-c) has many physiological and pharmacological effects, including antagonistic effects on blood pressure and calcium levels, maintenance of cellular calcium homeostasis, and improved cardiac systolic and diastolic function. It is potentially a novel and versatile drug for the treatment and prevention of cardiovascular diseases.ObjectiveTo explore the possible impact of Pra-c on blood pressure in SHR and its mechanism of action.Materials and methodsTwenty SHR were randomly divided into a Pra-c group [Pra-c was administered intragastrically, 20 mg kg⁻¹ d⁻¹, n = 10] or an untreated control group (n = 10), containing 10 age-matched SD rats. Each group of rats was followed for 8 weeks. Before and during the treatment, tail artery systolic blood pressure was measured using a tail-cuff every 2 weeks. After 8 weeks, the rats were sacrificed and RNA was extracted from homogenates of cardiac tissue. Tissue from the left ventricle was fixed, sectioned and H&E stained to assess possible changes in myocardial cell structure and morphology. Semi-quantitative RT-PCR was used to assess changes in phospholamban gene expression in treated and untreated rats.ResultsSHR treated with Pra-c for 8 weeks had a lower systolic pressure than untreated SHR (p < 0.05), two measures of cardiac damage, the heart mass index and left ventricle mass index (HMI and LVMI, respectively) were improved, and the level of PLB mRNA expression was lower in the untreated SHR group (p < 0.05).Discussion and conclusionWith continuous hypertension, SHR gradually formed or developed cardiac hypertrophy and fibrosis. Pra-c had a clear effect on blood pressure in SHR, and reversed SHR ventricular remodeling by upregulating the gene expression of sarcoplasmic reticulum PLB.     

The protective efficacy of magnolol in hind limb ischemia-reperfusion injury

We investigated the protective effects of magnolol, an active antioxidant and free radical scavenger extracted from Magnolia officinalis, in a hind limb ischemic-reperfusion animal model. Adult male Spraque-Dawley rats were subjected to hind limb ischemic insult for 2 hours and were intravenously treated with magnolol at 0.01 mg/kg (n=8), 0.3 mg/kg (n=8) mg/kg or 1 mg/kg (n=8) mg/kg, or vehicle (n=8). At 24 h post-insult, the levels of nitrite/nitrate (NOX), malondialdehyde (MDA) and myeloperoxidase (MPO), as well as the degree of muscle damage, were assessed. Relative to controls, animals treated with magnolol (0.3 and 1 mg/kg) had attenuated muscular inflammation, edema and damage. Magnolol (0.3–1 mg/kg) also effectively reduced postischemic rises in the MDA, NOx and MPO levels (p<0.05, respectively). Magnolol administrated at 0.01 mg/kg, however, failed to protect against the ischemic-perfusion limb injury. In addition, magnolol (0.01–1 mg/kg) did not affect local muscular blood reperfusion or other physiological parameters, including hematocrit, glucose, arterial blood gases and mean arterial blood pressure. Thus, intravenous administration with magnolol at 0.3–1 mg/kg protects against ischemic limb damage in rats. This cytoprotection may be attributed to its antioxidant, anti-nitrosative and anti-inflammatory actions.