Regional Hemodynamics Research Articles

Evaluation of the effectiveness of diabetic nephropathy stage III in patients with type 2 diabetes mellitus therapy with sulodexide

Introduction. Diabetes mellitus (DM) - takes the main place in the structure of endocrine diseases, and the third after cardiovascular and cancer pathology. In Ukraine 1.2 million of people suffer from diabetes and type 2 diabetes occurs in 85-90% of them. In 2004, 3.4 million of people died from diabetes complications. Diabetic nephropathy (DN) is a serious chronic complication of diabetes that leads to the formation of nodular or diffuse glomerulosclerosis. It is the most frequent cause of terminal chronic renal failure (CRF) in the world, accounting for over 25% of all cases of CRF. The generally accepted classification is Moggensen`s classification (1983, WHO), according to which five stages of diabetic nephropathy are identified, the first two stages of them are preclinical. Leading role in the pathogenesis of DN takes hyperglycemia, which is implemented by the phenomenon of glucosetoxicity. A lot of facts underscore the importance of inflammatory mechanisms triggered by cytokines. There's immune and non-immune theory of DN. The basis of non-immune theory is a violation of the synthesis of glycosaminoglycans (GAGs) that are a major component of the glomerular basement membrane (GMB). GAGs create its negative charge, which prevents the passage through the renal filter small negatively charged molecules, including albumin. In hemodynamic regulation leading role belongs to the renin-angiotensin-aldosterone system (RAAS). The blockade of the RAAS system with ACE inhibitors is the basis of a treatment strategy of DN. All mentioned above became a reason for study of the possibility of a new direction in the treatment of DN using the drug sulodexid, which is a natural mixture of GAGs.Objective of the research. Evaluating the effectiveness of sulodexide therapy of DN stage III in patients with type 2 diabetes.Materials and methods. The patients were divided into 2 groups. Group I consisted of 24 patients aged 40 to 68 years. 5 of them were women and 19 were men. In 20 patients from the group alimentary-constitutional obesity was noted. II group consisted of 11 people: 4 women and 7 men, aged 48 to 68 years, 6 of which were suffering from alimentary-constitutional obesity. Patients received standard treatment of type 2 diabetes and hypertension. In group I, sulodexide (600 LPL units intramuscularly 1 time per day for 10 days) was further included. The research of microalbuminuria (MAU) was conducted on admission and on the 10th day of treatment.Results. The initial values of MAU in 1st group were 92,7 ± 25,2 mcg/min. In the dynamics of monitoring rates decreased to 44,4 ± 9,6 mcg/min. The degree of decrease was 47% (p <0.05). In 2nd Group MAU initial values were 46,7 ± 23,4 mcg/min. In the dynamics of monitoring MAU decreased to 29,5 ± 12,6 mcg/min. Degree of decrease was 27% (p <0.05)Conclusions. 1) In patients with stage III DN with diabetes type 2 by including in the basic therapy of sulodexide level MAU was reliable decreased on 47%, which is on 20% lower than in the comparison group (p <0.05).2) During the research reliable direct dependence of decreased MAU rates with its initial values and degree of obesity was found. It indicates the increase in the effectiveness of the drug at a higher initial level of MAU in people with overweight.

The RIP1-Kinase Inhibitor Necrostatin-1 Prevents Osmotic Nephrosis and Contrast-Induced AKI in Mice

The pathophysiology of contrast-induced AKI (CIAKI) is incompletely understood due to the lack of an appropriate in vivo model that demonstrates reduced kidney function before administration of radiocontrast media (RCM). Here, we examine the effects of CIAKI in vitro and introduce a murine ischemia/reperfusion injury (IRI)-based approach that allows induction of CIAKI by a single intravenous application of standard RCM after injury for in vivo studies. Whereas murine renal tubular cells and freshly isolated renal tubules rapidly absorbed RCM, plasma membrane integrity and cell viability remained preserved in vitro and ex vivo, indicating that RCM do not induce apoptosis or regulated necrosis of renal tubular cells. In vivo, the IRI-based CIAKI model exhibited typical features of clinical CIAKI, including RCM-induced osmotic nephrosis and increased serum levels of urea and creatinine that were not altered by inhibition of apoptosis. Direct evaluation of renal morphology by intravital microscopy revealed dilation of renal tubules and peritubular capillaries within 20 minutes of RCM application in uninjured mice and similar, but less dramatic, responses after IRI pretreatment. Necrostatin-1 (Nec-1), a specific inhibitor of the receptor-interacting protein 1 (RIP1) kinase domain, prevented osmotic nephrosis and CIAKI, whereas an inactive Nec-1 derivate (Nec-1i) or the pan-caspase inhibitor zVAD did not. In addition, Nec-1 prevented RCM-induced dilation of peritubular capillaries, suggesting a novel role unrelated to cell death for the RIP1 kinase domain in the regulation of microvascular hemodynamics and pathophysiology of CIAKI.

Effects of Pretreatment Hypothermia During Resuscitated Porcine Hemorrhagic Shock

Accidental hypothermia increases mortality and morbidity after hemorrhage, but controversial data are available on the effects of therapeutic hypothermia. Therefore, we tested the hypothesis whether moderate pretreatment hypothermia would beneficially influence organ dysfunction during long-term, porcine hemorrhage and resuscitation. Prospective, controlled, randomized study. University animal research laboratory. Twenty domestic pigs of either gender. Using an extracorporeal heat exchanger, anesthetized and instrumented animals were maintained at 38°C, 35°C, or 32°C core temperature and underwent 4 hours of hemorrhage (removal of 40% of the blood volume and subsequent blood removal/retransfusion to maintain mean arterial pressure at 30 mm Hg). Resuscitation comprised of hydroxyethyl starch and norepinephrine infusion titrated to maintain mean arterial pressure at preshock values. Before, immediately at the end of, and 12 and 22 hours after hemorrhage, we measured systemic and regional hemodynamics (portal vein, hepatic and right kidney artery ultrasound flow probes) and oxygen transport, and nitric oxide and cytokine production. Hemostasis was assessed by rotation thromboelastometry. Postmortem biopsies were analyzed for histomorphology (hematoxylin and eosin staining) and markers of apoptosis (kidney Bcl-xL and caspase-3 expression). Hypothermia at 32°C attenuated the shock-related lactic acidosis but caused metabolic acidosis, most likely resulting from reduced carbohydrate oxidation. Although hypothermia did not further aggravate shock-related coagulopathy, it caused a transitory attenuation of kidney and liver dysfunction, which was ultimately associated with reduced histological damage and more pronounced apoptosis. During long-term porcine hemorrhage and resuscitation, moderate pretreatment hypothermia was associated with a transitory attenuation of organ dysfunction and less severe histological tissue damage despite more pronounced metabolic acidosis. This effect is possibly due to a switch from necrotic to apoptotic cell death, ultimately resulting from reduced tissue energy deprivation during the shock phase.

Renal effects of NO-inhibition in patients with cirrhosis vs. healthy controls: a randomized placebo-controlled crossover study

Nitric oxide (NO) is an important regulator of renal hemodynamics and sodium excretion. Systemic and splanchnic NO-synthesis is increased in liver cirrhosis contributing to the characteristic hyperdynamic circulation. The significance of renal NO in human cirrhosis is not clear. In order to clarify the role of NO in the regulation of renal hemodynamics and sodium excretion in human cirrhosis, we studied the effects of N(G)-monomethyl-L-arginine (L-NMMA) - a nonselective NO-inhibitor - on blood pressure (MAP), heart rate (HR), GFR, RPF, UNa × V, FENa, FELi and plasma levels of renin, angII, aldo, ANP, BNP and cGMP in 13 patients with cirrhosis (Child gr.A: 8; Child gr.B+C: 5) and 13 healthy controls. The study was randomized and placebo-controlled. Renal hemodynamics were assessed by measuring renal clearance of (51) Cr-EDTA and (125) I-Hippuran for GFR and RPF, respectively. L-NMMA induced a similar, significant increase in MAP in both groups and a more pronounced relative decrease in HR in the CIR group (P = 0.0209, anova). L-NMMA did not change GFR in any group, but RPF decreased significantly in both groups, but most pronouncedly in CIR (P = 0.0478, anova). FENa decreased significantly in both groups after l-NMMA, but the response was again most pronounced in the CIR group (P = 0.0270, anova). All parameters remained stable after placebo. No significant differences were observed between the effects of L-NMMA in Child gr.A vs. Child gr. B+C patients. The data supports the hypothesis that renal NO is enhanced in human cirrhosis.

Abstract 73: Atrial Fibrillation-induced Changes in Left Atrial Hemodynamics Directly Impact the Thrombotic Potential of Human Primary Endothelial Cell Cultures

Thrombus formation in the left atrial appendage (LAA) of the heart is a source of stroke risk in patients with atrial fibrillation (Afib). Strategies to prevent thromboembolism from the LAA via restoration of normal rhythm or prevention of clot formation are limited by lack of adequate human surrogate systems that recapitulate the biology ex vivo. Endothelial cell phenotype and function in blood vessels and chambers of the heart are regulated in part by regional hemodynamics. Blood flow shear forces in the LAA are substantially altered during Afib. Thus, we hypothesized that Afib-induced alterations in hemodynamics directly impacts the thrombotic potential of the endothelium in the LAA. To test this, human primary aortic endothelial cell cultures were primed under hemodynamic shear forces simulating the human LAA during normal sinus rhythm for 24 hrs and continued under sinus rhythm or switched to simulate Afib for an additional 24 hrs. Compared to sustained sinus rhythm, Afib hemodynamics suppressed genes (qRTPCR) that define a healthy/quiescent endothelial cell phenotype (e.g. KLF2 and NOS3/eNOS) while inducing the pro-thrombotic gene F3 (tissue factor) and suppressing ADAMSTS13, MMP14 and TIMP2. To determine whether the observed molecular response produced a functional prothrombotic phenotype, hemodynamic primed aortic endothelial cells were exposed to dilute (~27% final concentration) human platelet-free plasma supplemented with Alexa488-labeled human fibrinogen, corn trypsin inhibitor and calcium. Cleavage of fibrinogen to fibrin and concomitant deposition on the endothelium was measured by quantitative confocal microscopy. When exposed to Afib hemodynamics, endothelial cells supported significant fibrin deposition that extended to greater depth (i.e., thicker) on the endothelium compared to sinus rhythm hemodynamics. In conclusion, we show for the first time a direct mechanistic link between changes in LAA hemodynamics associated with development of Afib and functional alterations in the thrombotic potential of the endothelium. This study produced a novel insight enabled by studying potential triggers of thrombosis in a context that more closely mimics the normal and pathological human in vivo environment.

Abstract 133: Hemodynamic Environment-dependent Effects of Human HDL and oxHDL on Vessel Wall Inflammation

High density lipoprotein (HDL) concentration is inversely correlated with cardiovascular disease and exerts atheroprotective effects on endothelial (EC) and smooth muscle cells (SMC). Oxidation of LDL (oxLDL) is a well-appreciated driver of atherosclerosis. What is less well known is that HDL can become oxidized (oxHDL) by myeloperoxidase, which may negate its beneficial effects. Further, previous mechanistic studies of HDL were performed on static culture ECs or SMCs that do not take into consideration in vivo hemodynamics; a critical regulator of vascular phenotype. Regional hemodynamics prime EC/SMCs towards either an atheroprotective phenotype or, in regions such as bifurcations, towards an atheroprone, pro-inflammatory phenotype. We assessed the role of the hemodynamic environment in modulating the differential response of vascular cells to human HDL or oxHDL from normal donors. To test this, HDL was added to EC/SMC cocultures primed by atheroprotective or atheroprone shear stresses derived from the human carotid bifurcation or an “Advanced Inflammatory” condition that combines atheroprone shear stress with additional atherogenic factors such as oxLDL and TNFα. In the presence of HDL, ECs under Advanced Inflammatory conditions reduced pro-inflammatory (NFkB Activity, IL6, COX2), and oxidative stress (SOD2), but did not have an effect in baseline atheroprotective and atheroprone conditions. Many of the anti-inflammatory responses of endothelial cells were retained when HDL was oxidized. Conversely, while HDL had minimal effect on SMC gene expression, oxHDL was found to reduced the atheroprotective phenotype by potently inducing oxidative and inflammatory cytokine genes/secreted proteins (IL1B, IL6). Overall, this study illustrates the importance of reproducing relevant in vivo environments in order to understand HDL-mediated mechanisms in vascular biology in vitro. This study supports that oxidation dysfunctionally transforms HDL from an atheroprotective to an inflammatory and intrinsically oxidative particle and might damage otherwise healthy regions of the vasculature. Thus, measurement of circulating HDL without consideration of HDL composition and oxidation may limit its predictive value for cardiovascular risk.

Resistance exercise improves autonomic regulation at rest and haemodynamic response to exercise in non-alcoholic fatty liver disease

Autonomic dysfunction has been reported in patients with NAFLD (non-alcoholic fatty liver disease) and is associated with clinical presentations. To date, there are no therapies to improve autonomic regulation in people with NAFLD. The present study defines the impact of a short-term exercise programme on cardiac autonomic and haemodynamic regulation in patients with NAFLD. A total of 17 patients with clinically defined NAFLD [age, 55±12 years; BMI (body mass index), 33±5 kg/m²; liver fat, 17±9%] were randomized to 8 weeks of resistance exercise or a control group to continue standard care. Resting and submaximal exercise (50% of peak oxygen consumption) autonomic and cardiac haemodynamic measures were assessed before and after the intervention. Resistance exercise resulted in a 14% reduction in HR (heart rate) and 7% lower SBP (systolic blood pressure) during submaximal exercise (16 beats/min, P=0.03 and 16 mmHg, P=0.22). Sympathovagal balance, expressed as LF/HF (low-frequency/high-frequency) ratio of the mean HR beat-to-beat (R-R) interval, was reduced by 37% (P=0.26). Similarly sympathovagal balance of DBP (diastolic blood pressure) and SBP variability decreased by 29% (P=0.33) and 19% (P=0.55), respectively in the exercise group only. BRS (baroreflex sensitivity) increased by 31% (P=0.08) following exercise. The mean R-R interval increased by 23% (159 ms, P=0.09). Parasympathetic regulation was decreased by 17% (P=0.05) and overall sympathovagal balance in BP regulation (LF/HF ratio) increased by 26% (P=0.02) following resistance exercise. Resting haemodynamic measures remained similar between groups. Resistance exercise therapy seems to improve autonomic and submaximal exercise haemodynamic regulation in NAFLD. Further studies are required to define its role in clinical management of the condition.

The Effects of Continuous‐flow Left Ventricular Assist Devices on Peripheral Vascular Function

Peripheral endothelial function is known to be impaired in patients with heart failure (HF), but the vascular effects of continuous‐flow left ventricular assist device (LVAD) implantation, now employed as either a bridge to transplantation or as destination therapy, remain unclear. Using flow‐mediated vasodilation (FMD) and passive leg movement, this study aimed to provide greater insight into LVAD‐induced changes in vascular function. 8 healthy age‐matched controls (61 ± 3 yrs), 10 HF patients (61 ± 2 yrs), and 12 LVAD patients (57 ± 3 yrs) underwent FMD testing of the brachial artery and passive leg movement‐induced hyperemia assessment, with blood flow velocity and artery diameters assessed by ultrasound Doppler. FMD was significantly lower in HF (4.7 ± 0.7%) compared to the healthy controls (7.1 ± 1.2%) and lower than both of these groups in the LVAD patients (2.7 ± 0.8%). The change in leg blood flow from baseline to peak during passive movement followed a similar pattern. The hyperemic response in patients with HF was significantly attenuated compared to the controls (90 ± 9%Δ and 160 ± 27%Δ, respectively) and the response in the LVAD patients was significantly lower than both groups (45 ± 10%Δ). These results suggest that despite circulatory assistance, peripheral vascular function and hemodynamic regulation are attenuated in patients following LVAD implantation.

Serine proteases affect in situ vasa recta capillary diameter: mechanism for kidney failure associated with pancreatitis?

Serine proteases are proteolytic enzymes involved in the regulation of renal function and hemodynamics. Serum trypsin (the archetypal serine protease) levels are elevated in a number of pathophysiological conditions, notably pancreatitis, which is associated with acute renal failure.Here we use the kidney slice model to investigate the effect of trypsin on vasa recta diameter in situ. Kidney slices (200 μm thick) were obtained from adult male rats as previously described [1]. Kidney slices were superfused with trypsin and DIC video imaging techniques were used to record real‐time changes in vasa recta diameter.Application of trypsin (2 U/ml) caused a significant constriction of vasa recta capillaries, specifically at smooth muscle‐like pericyte cell sites (15.5±1.4% p&lt;0.05).Here we demonstrate that acute application of trypsin (at levels similar to those detected in patients with severe acute pancreatitis) significantly decreases vasa recta diameter and thus renal medullary blood flow, specifically via its action at pericytes. Data presented here identifies a novel potential role for pericytes in the acute renal failure observed in patients with acute pancreatitis.Research supported by BBSRC, Wellcome Trust and the MRC

Influence of regular endurance training on postexercise hemodynamic regulation to orthostatic challenge

Although postexercise syncope in endurance athletes is well recognized, the underlying mechanism is unknown. To determine whether endurance athletes exhibit the substantial hypotension during postexercise orthostatic stimulation, we conducted 5‐min head‐up tilt (HUT) tests before and after the 1‐hour moderate intensity cycling in young sedentary (S: n=8), endurance‐trained (E: n=8), and resistance‐trained (R: n=8) men. After the exercise the HUT‐induced vasoconstriction was significantly blunted in S and E groups. Significantly larger increase in the HUT‐induced fall of stroke volume was seen in E and R groups. Contrast to our hypothesis, endurance trained men did not exhibit a substantial drop of mean arterial pressure and/or pre‐syncope symptom during postexercise HUT despite the accumulated factors which facilitates orthostatic hypotension. This phenomenon might be explained by the greater augmentation of HUT‐induced tachycardia: the postexercise increase in tachycardia response was significantly greater in the endurance‐trained (+118% from preexercise) than those in the other groups (+45–50%). Collectively, during postexercise orthostatic challenge (at least in an early phase), endurance athletes maintain arterial pressure mainly by the enhanced tachycardia response.Grant: Nakatomi Foundation, Japan.

Hypothalamic mTORC1 Signaling Controls Sympathetic Nerve Activity and Arterial Pressure and Mediates Leptin Effects

The fundamental importance of the hypothalamus in the regulation of autonomic and cardiovascular functions is well established. However, the molecular processes involved are not well understood. Here, we show that the mammalian (or mechanistic) target of rapamycin (mTOR) signaling in the hypothalamus is tied to the activity of the sympathetic nervous system and to cardiovascular function. Modulation of mTOR complex 1 (mTORC1) signaling caused dramatic changes in sympathetic traffic, blood flow, and arterial pressure. Our data also demonstrate the importance of hypothalamic mTORC1 signaling in transducing the sympathetic and cardiovascular actions of leptin. Moreover, we show that the PI3K pathway links the leptin receptor to mTORC1 signaling and that changes in its activity impact sympathetic traffic and arterial pressure. These findings establish mTORC1 activity in the hypothalamus as a key determinant of sympathetic and cardiovascular regulation and suggest that dysregulated hypothalamic mTORC1 activity may influence the development of cardiovascular diseases.

Morphogenesis and reaction to hypoxia of atrial myoendocrine cells in chick embryos (Gallus gallus)

The ultrastructural and stereomorphometrical study of the right atrium of chick embryos at the 14th day of incubation has shown the cardiomyocytes to divide by mitosis and to be at different stages of differentiation. In the cytoplasm of some muscle cells we detected secretory granules that by their sizes and morphology can be classified into the forming, mature, and dissolved forms. By the 18th day of incubation most cardiomyocytes are already differentiated, and the number of secretory granules in them rises. Under conditions of hypoxia, after 3 days, in myoendocrine cells there are noted signs of accelerated release of the peptides synthesized earlier and accumulated in granules, while after one week - of enhancement of their synthesis. It can be concluded that in chick embryos, beginning from at least the 14th incubation day, the system of natriuretic heart peptides takes part in regulation of hemodynamics and of water-salt balance and responds to hypoxia.

Knockout of the Na,K-ATPase α2-isoform in cardiac myocytes delays pressure overload-induced cardiac dysfunction

The α2-isoform of the Na,K-ATPase (α2) is the minor isoform of the Na,K-ATPase expressed in the cardiovascular system and is thought to play a critical role in the regulation of cardiovascular hemodynamics. However, the organ system/cell type expressing α2 that is required for this regulation has not been fully defined. The present study uses a heart-specific knockout of α2 to further define the tissue-specific role of α2 in the regulation of cardiovascular hemodynamics. To accomplish this, we developed a mouse model using the Cre/loxP system to generate a tissue-specific knockout of α2 in the heart using β-myosin heavy chain Cre. We have achieved a 90% knockout of α2 expression in the heart of the knockout mice. Interestingly, the heart-specific knockout mice exhibit normal basal cardiac function and systolic blood pressure, and in addition, these mice develop ACTH-induced hypertension in response to ACTH treatment similar to control mice. Surprisingly, the heart-specific knockout mice display delayed onset of cardiac dysfunction compared with control mice in response to pressure overload induced by transverse aortic constriction; however, the heart-specific knockout mice deteriorated to control levels by 9 wk post-transverse aortic constriction. These results suggest that heart expression of α2 does not play a role in the regulation of basal cardiovascular function or blood pressure; however, heart expression of α2 plays a role in the hypertrophic response to pressure overload. This study further emphasizes that the tissue localization of α2 determines its unique roles in the regulation of cardiovascular function.

Abstract TP369: Blood Pressure Dynamics During Long Sitting Position In Acute Ischemic Stroke Patients: Prevalence Of Orthostatic Hypotension.

Background and Purpose: Long sitting positioning (LSP) using head of bed elevation is an important part of early rehabilitation and mobilization for patients with acute ischemic stroke. However, little is known about orthostatic hypotension (OH) during LSP, which is potential risk factor for ischemic stroke recurrence. This study aimed to investigate the prevalence of OH during LSP and its related factors. Methods: Patients with acute ischemic stroke were enrolled in this study (n=246, male: 68.1%, mean age 74.7y). Ten-minutes LSP by 70-degree head of bead elevation with successive blood pressure (BP) measurement was conducted a week after their stroke. BP was measured for three times on un-affected arm: pre-measurement in supine position, 1 and 10 minutes after beginning of LSP. OH was defined as ≥20 mmHg fall in systolic BP (SBP) and/ or ≥10 mmHg fall in diastolic BP (DBP) from pre-measurement in supine position. Potential related factors such as demographics, comorbidities, stroke severity, baseline BP were investigated by multivariate logistic analysis. Results: The overall prevalence of OH were 15.0% (n=37) at 1 minute and 20.3% (n=50) at 10 minutes after beginning of LSP. Patients with OH at 1 minute were more likely to have higher supine DBP (p=0.034), and patients with OH at 10 minutes were more likely to have higher supine SBP (p=0.004) and DBP (p&lt;0.001). In multivariate logistic analysis showed that older age (OR [95%CI], 1.05[1.01-1.09]), male gender (3.15[1.19-8.33]) and higher supine DBP (1.03[1.00-1.06]) were independently associated with the OH at 1 minute after LSP. Similarly, older age (1.05[1.01-1.08]) and higher supine DBP (1.05[1.03-1.08]) were independently associated with OH at 10minutes after LSP. Conclusions: The OH prevalence at 1 minute after beginning of LSP was similar to previous studies which defined OH as hypotension in upright position. However, the prevalence rose remarkably at 10 minutes after LSP, while temporary hemodynamic instability would recover within one minute in healthy adults. These results implicated that impaired activity of the autonomic nervous system in acute ischemic stroke patients was associated with defect in hemodynamics regulation, especially in the patients with older age and/or higher supine BP.

The pulmonary vascular response to combined activation of the muscle metaboreflex and mechanoreflex

Muscle metabo- and mechanoreflexes are known to influence systemic cardiovascular responses to exercise. Whether interplay between these reflexes is operant in the control of the pulmonary vascular response to exercise is unknown. The aim of this study was to assess the pulmonary vascular response to the combined activation of the two muscle reflexes. Nine healthy subjects performed a bout of isometric calf plantarflexion exercise during local circulatory occlusion, which was continued for 9 min postexercise (PECO). At 5 min into PECO the calf muscle was passively stretched for 180 s. A control (no exercise) protocol was also undertaken. Heart rate, blood pressure measurements and echocardiographically determined estimates of systolic pulmonary artery pressure (SPAP) and cardiac output ( ) were obtained at intervals throughout the two protocols. Elevations in SPAP (by 22.51 ± 2.61%), (by 26.92 ± 2.99%) and mean arterial pressure (by 15.38 ± 2.29%) were noted during isometric exercise in comparison to baseline (all P < 0.05). Increases in SPAP and mean arterial pressure persisted during PECO (All P < 0.05), whereas returned to resting levels. These increases in mean arterial pressure and SPAP were sustained during stretch which significantly elevated (All P < 0.05). These data suggest that activation of the muscle mechanoreflex attenuated the increases in pulmonary vascular resistance caused by metaboreflex activation. This finding has important implications for the regulation of pulmonary haemodynamics during human exercise.

Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors

Increased angiotensin II (ANG II) or adenosine can potentiate each other in the regulation of renal hemodynamics and tubular function. Diabetes is characterized by hyperfiltration, yet the roles of ANG II and adenosine receptors for controlling baseline renal blood flow (RBF) or tubular Na(+) handling in diabetes is presently unknown. Accordingly, the changes in their functions were investigated in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of the ANG II AT1 receptor antagonist candesartan, the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or their combination. Compared with controls, the baseline blood pressure, RBF, and renal vascular resistance (RVR) were similar in diabetics, whereas the glomerular filtration rate (GFR) and filtration fraction (FF) were increased. Candesartan, DPCPX, or the combination increased RBF and decreased RVR similarly in all groups. In controls, the GFR was increased by DPCPX, but in diabetics, it was decreased by candesartan. The FF was decreased by candesartan and DPCPX, independently. DPCPX caused the most pronounced increase in fractional Na(+) excretion in both controls and diabetics, whereas candesartan or the combination only affected fractional Li(+) excretion in diabetics. These results suggest that RBF, via a unifying mechanism, and tubular function are under strict tonic control of both ANG II and adenosine in both control and diabetic kidneys. Furthermore, increased vascular AT1 receptor activity is a contribution to diabetes-induced hyperfiltration independent of any effect of adenosine A1 receptors.

Regulation of Renin Release via Cyclic ADP-Ribose-Mediated Signaling: Evidence from Mice Lacking CD38 Gene

Background/Aims: Despite extensive studies, the intracellular regulatory mechanism of renin production and release is still poorly understood. The present study was designed to test whether CD38-ADP-ribosylcyclase signaling pathway contributes to the regulation of renin production and release, and to examine whether CD38 gene knockout (CD38^-/-) can change this important renal endocrinal function. Methods: ADP–ribosylcyclase activity was estimated utilizing HPLC, cADPR levels from western blot, plasma renin activity from RIA kit, urinary sodium and potassium excretion from fame photometry. Results: The expression of CD38 and the activity of ADP-ribosylcyclase to produce cyclic ADP-ribose (cADPR) were nearly abolished in the kidney from CD38^-/- mice, indicating that CD38 gene is a major enzyme responsible for the generation of cADPR in vivo. Mice lacking CD38 gene showed increased plasma renin activity (PRA) in either conscious or anesthetized status (P<0.05). Low salt intake significantly increased, but high salt intake significantly decreased renin release in both CD38^+/+ and CD38^-/- mice. In acute experiments, it was demonstrated that plasma renin activity (PRA) significantly increased upon isoprenaline infusion in CD38^-/- mice compared to CD38^+/+ mice. Accompanied with such increase in PRA, glomerular filtration rate (GFR), renal blood flow (RBF), urine volume (UV) and sodium excretion (U_NaV) more significantly decreased in CD38^-/- than CD38^+/+ mice. Similarly, more increases in PRA but more decreases in GFR, RBF, UV and U_NaV were observed in CD38^-/- than CD38^+/+ mice when they had a low renal perfusion pressure (RPP). Conclusion: CD38-cADPR-mediated signaling may importantly contribute to the maintenance of low PRA and participate in the regulation of renal hemodynamics and excretory function in mice.

Hemodynamic Correlates of Late Systolic Flow Velocity Augmentation in the Carotid Artery

Background. The contour of the common carotid artery (CCA) blood flow velocity waveform changes with age; CCA flow velocity increases during late systole, and this may contribute to cerebrovascular disease. Late systolic flow velocity augmentation can be quantified using the flow augmentation index (FAIx). We examined hemodynamic correlates of FAIx to gain insight into determinants of CCA flow patterns. Methods. CCA Doppler ultrasound and wave intensity analysis (WIA) were used to assess regional hemodynamics in 18 young healthy men (age 22 ± 1 years). Forward waves (W 1) and backward waves (negative area, NA) were measured and used to calculate the reflection index (NA/W 1 = RIx). Additional parameters included W 2 which is a forward travelling expansion/decompression wave of myocardial origin that produces suction, CCA single-point pulse wave velocity (PWV) as a measure of arterial stiffness, and CCA pressure augmentation index (AIx). Results. Primary correlates of FAIx included W 2 (r = − 0.52, P < 0.05), logRIx (r = 0.56, P < 0.05), and AIx (r = 0.60, P < 0.05). FAIx was not associated with CCA stiffness (P > 0.05). Conclusions. FAIx is a complex ventricular-vascular coupling parameter that is associated with both increased expansion wave magnitude (increased suction from the left ventricle) and increased pressure from wave reflections.

Натрийуретические пептиды сердца и артериальная гипертензия: экспериментальное исследование

The peculiarities of cardiac natriuretic peptide secretion have been investigated during ontogenesis using the hypertonic disease model in ISIAH rat line (with inherited stress induced arterial hypertension). The qualitative and quantitative ultrastructural investigations of right atrium myocardium revealed that the cardiac hormonal synthetic and secretory activities in ISIAH rats are higher as compared with normotensive even-aged rats from control group. Secretory hyperactivity of atrial myocytes in ISIAH rats during early ontogeny precedes the manifestations of hereditary hypertension. Natriuretic peptides present the hypotensive circuit of hemodynamic regulation during the whole ontogeny and the complementary chain in hypertension development.

Black Currant Anthocyanins Normalized Abnormal Levels of Serum Concentrations of Endothelin-1 in Patients with Glaucoma

Our recent study, which involved a randomized, placebo-controlled, double-masked 24-month trial (Ophthalmologica 2012;228:26-35), revealed that oral administration of black currant anthocyanins (BCACs) slowed down the visual field deterioration and elevation of ocular blood flow of open-angle glaucoma (OAG). To elucidate the underlying mechanisms of these BCAC-induced effects, as possible factors affecting glaucomatous optic neuropathy, changes of serum endothelin-1 (ET-1), nitric oxide (NO), and antioxidative activities were examined in the present study. From among patients with OAG who participated in the randomized, placebo-controlled, double-masked trial, serum specimens were obtained from BCAC-treated (n=19) or placebo-treated (n=19) patients at baseline and every 6 months. Healthy volunteers (n=20) with age and gender matching the patients were used as a control. Serum ET-1 concentration, [NO2(-)] and [NO2(-) + NO3(-)] levels, advanced oxidation protein products (AOPP), and antioxidant activities were measured by using commercially available kits. At the trial baseline, serum ET-1 concentrations were significantly lower in patients with OAG (BCACs, 3.18±1.06 pg/mL; placebo, 3.44±0.84 pg/mL) than those in healthy volunteers (4.38±1.03 pg/mL) (one-way analysis of variance and a Tukey's multiple comparison post hoc test, P<0.05). Upon administration of BCACs, serum ET-1 concentrations increased to the levels of those in healthy volunteers during the 24-month period. In contrast, those of placebo-treated patients remained at lower levels (3.82±1.14 pg/mL). While [NO2(-)] and [NO2(-)+NO3(-)] levels, AOPP, and antioxidative activities of patients from both the BCACs and placebo groups showed comparable levels to those of healthy subjects at baseline, no significant changes were observed during the observational period in either the BCAC or placebo groups. Among the possible beneficial effects of BCACs toward visual field progression in patients with OAG, our present results suggest that BCACs caused normalization of serum ET-1 levels, and this may modulate ET-1-dependent regulation of the ocular blood hemodynamics.