Changes In Transmural Pressure Research Articles

Influence of Blood Pressure Reduction on Pulse Wave Velocity in Primary Hypertension: A Meta-Analysis and Comparison With an Acute Modulation of Transmural Pressure.

Increased arterial stiffness and pulse wave velocity (PWV) of the aorta and large arteries impose adverse hemodynamic effects on the heart and other organs. Antihypertensive treatment reduces PWV, but it is unknown whether this results from an unloading of stiffer elements in the arterial wall or is due to an alternate functional or structural change that might differ according to class of antihypertensive drug. We performed a systematic review and meta-analysis of the effects of different antihypertensive drug classes and duration of treatment on PWV with and without adjustment for change in mean arterial blood pressure (BP; study 1) and compared this to the change in PWV after an acute change in transmural pressure, simulating an acute change in BP (study 2). A total of 83 studies involving 6200 subjects were identified. For all drug classes combined, the reduction of PWV was 0.65 (95% CI, 0.46-0.83) m/s per 10 mm Hg reduction in mean arterial BP, a change similar to that induced by an acute change in transmural pressure in a group of hypertensive subjects. When adjusted for change in mean arterial BP, the reduction in PWV after treatment with beta-blockers or diuretics was less than that after treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists or calcium channel antagonists. Reduction in PWV after antihypertensive treatment is largely explained by the reduction in BP, but there are some BP-independent effects. These might increase over time and contribute to better outcomes over the long term, but this remains to be demonstrated in long-term clinical trials.

Supporting evidence for an "arterial pump" venous return mechanism in humans.

Blood flow in large veins is dependent on arterial-atrial pressure gradients and pumping mechanisms in concert with valve recruitment. Classic descriptions of muscle and respiratory pumps describe venous transmural pressure changes that cause flow. Not often considered is the transmission of pulsatile energy from arteries to veins directly adjacent to each other. Recently, an ex vivo study demonstrated a novel arterial pump effect in venoarterial bundles when valves were active in managing venous flow. We sought to show in vivo evidence of this arterial pump mechanism in 16 healthy young adults. Venous blood flow was measured in the venoarterial bundled deep femoral vein (DFV) and the greater saphenous vein (GSV), which is not bundled with an artery. Veins were studied through randomized body positions of -6° head-down tilt (HDT), supine, 20° head-up tilt (HUT), and 40° HUT, with the assumption that greater HUT postures increased valve dependence to observe the arterial pump effect. Between 20° and 40° HUT conditions, bundled DFV blood flow did not change (68 ± 36 vs. 71 ± 56 mL·min-1; Padj > 0.99), whereas nonbundled GSV blood flow decreased (6.1 ± 4.8 vs. 3.5 ± 3.9 mL·min-1; P = 0.01). Diameters between 20° and 40° HUT conditions increased in DFV (0.90 ± 0.16 vs. 1.04 ± 0.19 cm; P < 0.01), but not in GSV (0.33 ± 0.10 vs. 0.32 ± 0.08 cm; P = 0.60). These data support previous ex vivo observations that when venous pressure gradients rely on valve recruitment, presence of an adjacent artery may protect against further decreases in blood flow. The arterial pump mechanism is an underappreciated contributor to venous return and warrants further investigation.NEW & NOTEWORTHY Venous return mechanisms have classically considered muscle and respiratory pumps; however, recent ex vivo evidence suggests that pulsatile energy imparted from arteries to adjacent bundled veins can increase venous flow under certain driving pressures. We tested this concept in humans by manipulating hydrostatic pressures and measuring flow in bundled and nonbundled veins. The bundled vein exhibited flow preservation at the highest hydrostatic pressure. We suggest a novel conservation of energy mechanism within the circulatory system.

Abstract P1163: Identifying Novel Intracellular Interactions Driving Membrane-bound Tumour Necrosis Factor-mediated Signalling In The Microvasculature

Elevated total peripheral resistance (TPR) is a hallmark of many cardiovascular diseases and furthers disease progression. We previously demonstrated that myogenic tone, regulated by membrane-bound tumour necrosis factor (mTNF) reverse signalling, is a primary modulator of TPR. Thus, inhibiting mTNF reverse signalling should reduce TPR with the potential to improve disease outcome. However, since mTNF is a ubiquitous protein with critical biological functions, its indiscriminate inhibition can cause widespread side effects. Therefore, therapeutics aiming to reduce myogenic tone and TPR must target other elements of mTNF reverse signalling. To identify these unknown participants of mTNF reverse signalling, we used proximity-dependent biotinylation coupled to mass spectrometry (BioID). Our search identified 42 high confidence hits that interact with and/or are proximal to mTNF’s cytoplasmic domain. Gene ontology (GO) analysis revealed that molecularly, these proteins are structural constituents of the cytoskeleton involved in actin and cell adhesion molecule binding. This aligns with our underlying hypothesis that mTNF functions as a mechanosensor that tethers to its receptors and initiates myogenic vasoconstriction in response to changes in transmural pressure. GO also identified proteins involved in MAPK and RhoA signalling, which are critically involved in myogenic vasoconstriction. Our most abundant hit (fold change = 12.6, p-value = 0.0023) is a cytoskeletal protein that plays a role in maintaining the structural integrity of cells. This protein also interacts with proteins involved in various signalling cascades, namely, RhoA and calcium-dependent signalling pathways. Thus, we hypothesize that this protein is essential for formation of signalling complexes with mTNF and interacts with other proteins to mediate reverse signalling . We will employ a bioluminescence-based approach to quantify the strength of all interactions detected by BioID and identify small molecule inhibitors that can disrupt these interactions. These newly discovered inhibitors could potentially be used as novel therapeutics targeting myogenic tone and hence, elevated TPR to improve disease management and clinical outcome of cardiovascular diseases.

Microgravity-induced reduced jugular vein flow is more pronounced on the non-dominant side

An astronaut developed a left-sided internal jugular vein (IJV) thrombosis while in orbit, likely due to reduced IJV blood flow. We hypothesized that microgravity-induced flow reductions would be greatest on the non-dominant (usually left) side thereby increasing thrombosis risk. A Simulink®-based lumped parameter model (LPM) was used to explore causes of jugular flow reduction and asymmetric thrombosis risk. Vessel behavior is described by combinations of four discrete components: hydrostatic gradients, vessel compliance, flow resistance, and flow inertia. The cranial venous system features drainage pathways through the right IJV, the left IJV and the vertebral plexus. The right jugular vein was modeled as the dominant jugular pathway (60% of total undeformed jugular cross-sectional area). The left side accounted for the remaining 40% of jugular flow. Multiple variables were adjustable in the LPM: body position (supine, prone, head-down tilt), and gravity. A key feature of this LPM is the incorporation of extravascular pressure on the vessels by the weight of tissues.Relative to a supine baseline, simulated total IJV flow changed from an average of 10.7 to 1.7 mL/s in weightlessness. The left and right IJV flow in microgravity was 0.6 and 1.2 mL/s, respectively (33.3% and 66.6% of total jugular venous flow, respectively). Not only was average flow reduced, but the flow pulsatility in the left IJV matched the observations made by Marshall-Goebel et al. in microgravity, where blood flowed forward, but with periodic zero-velocity flow. In microgravity, simulated left IJV was reduced to 33.3% from 40% of total jugular flow because the reduction in vein diameter in response to the transmural pressure changes is non-linear.

In Vitro Irradiation of Lymphatic Vessels Enhances Lymphatic Pump Function

Active lymphatic pumping is critical for propulsion of lymph against a pressure gradient as well as transport of lipids and immune cells to the central venous circulation. When lymphatic pumping is impaired, diminished lymph flow leads to interstitial edema, immune cell accumulation and sustained inflammation. However, a majority of radiation biology research has primarily focused on the effects of ionizing radiation (IR) on blood vessels. These studies reported that IR induces imbalance between vaso‐dilatory and ‐constrictive pathways and impairs vascular tone. Only a handful of the studies have investigated the acute effects of IR on lymphatic vessels. Furthermore, the studies evaluating IR‐induced changes in lymphatic tone and pumping in vivo are limited because, in addition to the intrinsic contractility of the lymphatic muscle, lymphatic tone and pumping in vivo is modulated by a variety of substances present in the luminal lymph and the surrounding interstitial fluid. Therefore, the goal of the present study was to characterize the effects of IR on lymphatic tone and pumping independent of the confounding effects of IR on the other tissues.Mesenteric lymphatic vessels (MLVs), isolated from male Sprague Dawley rats, were randomly divided into SHAM and IR groups and were placed in chilled APSS. MLVs from the IR group were then irradiated with X‐rays at 10 Gray Dose. Immediately after irradiation, MLVs from both groups were placed in chilled APSS until further use. MLVs were then cannulated and perfused with warm APSS. Lymphatic pumping was assessed in spontaneously contracting vessels. Role of nitric oxide (NO) and cyclooxygenase (COX) pathways was evaluated by assessing pump function in separate MLVs before and after incubation in N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME; 100 µM) and Indomethacin (INDO; 10 µM).Evaluation of the lymphatic pumping in response to changes in transmural pressure revealed significantly increased contraction frequency and calculated active lymph flow in IR MLVs compared to those in SHAM MLVs. However, stroke volume normalized to passive volume and diastolic tone were not significantly different between the IR and SHAM MLVs. The increase in contraction frequency in IR MLVs was partially restored by the blockade of COX pathways with INDO. Blockade of NOS with L‐NAME, however, led to further increase in contraction frequency of IR MLVs, which was significantly higher than that in SHAM MLVs.Early studies investigating the IR effects on lymphatic endothelial cells reported that lymphatic endothelium is resistant to IR. Conflicting findings of the in vivo lymphatic studies have further confounded the insights into the lymphatic responses to IR. It has been widely believed that lymphatic vessels are unaffected by IR, and therefore, the role of the lymphatic system‐ the other half of the circulatory system, in radiation injury has been mostly ignored. However, it is evident from the findings of the present study that lymphatic vessels are indeed affected by IR. Furthermore, IR‐induced increase in contraction frequency observed in the present study suggests that lymphatic acute responses to IR differ from the blood vessel responses.

Biventricular Physiology of Iatrogenic Atrial Septal Defects Following Transcatheter Mitral Valve Edge-to-Edge Repair.

The study sought to assess the acute hemodynamic effects of iatrogenic atrial septal defect (iASD) closure following transcatheter mitral valve edge-to-edge repair (TMVR). The potential hemodynamic and clinical consequences of an iASD following TMVR are currently subject to controversial debates. In 21 patients with relevant left-to-right shunt flow (50% [IQR: 38% to 60%] of systemic perfusion volume) across an iASD following TMVR, interventional closure was performed with recordings of left ventricular (LV) and right ventricular (RV) pressure-volume loops during iASD occlusion. iASD occlusion led to a volume shift from the RV (RV end-diastolic volume index: pre 102 [IQR: 80 to 120] ml/m2, post 92 [IQR: 70 to 111] ml/m2; p<0.001) to the LV (LV end-diastolic volume index: pre 91 [IQR: 74 to 124] ml/m2, post 97 [IQR: 77 to 127] ml/m2; p<0.001) with reduced RV (3.49 [IQR: 2.07 to 3.58] l/min/m2 vs. 2.68 [IQR: 2.07 to 3.58] l/min/m2; p<0.001) but increased LV cardiac index (2.25 [IQR: 1.80 to 3.28] l/min/m2 vs. 2.77 [IQR: 1.90 to 3.34] l/min/m2; p=0.039). Although RV end-diastolic pressure decreased (pre 5.0 [IQR: 4.0 to 8.5] mmHg, post 4.5 [IQR: 3.0 to 8.3] mmHg; p=0.024), LV end-diastolic pressure remained unchanged (pre 11.0 [IQR: 9.5 to 14.0] mmHg, post 13.0 [IQR: 9.0 to 15.5] mmHg; p=0.142). LV transmural pressure increased (7.0 [IQR: 4.0 to 11.0] mmHg vs. 11.0 [IQR: 7.0 to 15.0] mmHg; p=0.001) and LV eccentricity index decreased (p<0.001). The change in LV transmural pressure correlated significantly with the change in LV-to-RV end-diastolic volume ratio (r=0.674; p=0.018). Right heart failure symptoms declined at 1-month follow-up (71% vs. 35%; p=0.003) as did New York Heart Association functional class (≥III: 48% vs. 25%; p<0.001). iASD closure following TMVR leads to a volume shift from the RV to the LV with reduced pulmonary but increased systemic cardiac index and with favorable biventricular interaction at maintained LV filling pressure, resulting in a decline in heart failure symptoms at 1-month follow-up.

Noninvasive measurement of venous wall deformation induced by changes in transmural pressure shows altered viscoelasticity in patients with chronic venous disease

The noninvasive measurement of venous wall deformation induced by changes in transmural pressure could allow for the assessment of viscoelasticity and differentiating normal from diseased veins. In 57 patients with limbs in the C1s (telangiectasia or reticular veins and symptoms), C3 (edema), or C5 (healed venous ulcer) CEAP (clinical, etiologic, anatomic, pathophysiologic) category of chronic venous disease and 54 matched healthy controls, we measured the changes in the cross-sectional area of the small saphenous vein and a deep calf vein in the supine and standing positions and under compression with an ultrasound probe using ultrasonography. The small saphenous vein, but not the deep calf vein, cross-sectional area was smaller in the limbs of the controls than in the limbs with C3 or C5 disease but was not different from that in C1s limbs. When changing from the supine to the standing position, a greater force was required to collapse the leg veins. Their cross-sectional area increased in most subjects but decreased in 31.5% of them as for the small saphenous veins and 40.5% for the deep calf vein. The small saphenous vein area vs compression force function followed a hysteresis loop, demonstrating viscoelastic features. Its area, which represents the viscosity component, was greater (P< .001) in the pooled C3 and C5 limbs (median, 2.40N⋅mm2; lower quartile [Q1] to upper quartile [Q3], 1.65-3.88N⋅mm2) than in the controls (median, 1.24N⋅mm2; Q1-Q3, 0.64-2.14N⋅mm2) and C1s limbs (median, 1.15N⋅mm2; Q1-Q3, 0.71-2.97N⋅mm2). The area increased (P< .0001) in the standing position in all groups. Postural changes in the cross-sectional area of the leg veins were highly diverse among patients with chronic venous disease and among healthy subjects and appear unsuitable for pathophysiologic characterization. In contrast, small saphenous vein viscoelasticity increased consistently in the standing position and the viscosity was greater in limbs with C3 and C5 CEAP disease than in controls.

Acute Unloading Effects of Sildenafil Enhance Right Ventricular–Pulmonary Artery Coupling in Heart Failure

BackgroundPhosphodiesterase-5A inhibitors (PDE5i) are sometimes used in patients with advanced heart failure with reduced ejection fraction before heart transplant or left ventricular assist device implantation to decrease right ventricular (RV) afterload and mitigate the risk of right heart failure. Conflicting evidence exists regarding the impact of these drugs on RV contractility. The aim of this study was to explore the acute effects of PDE5i on ventricular–vascular coupling and load-independent RV contractility. MethodsTwenty-two patients underwent right heart catheterization and gated equilibrium blood pool single photon emission computed tomography, before and after 20 mg intravenous sildenafil. Single photon emission computed tomography and right heart catheterization-derived data were used to calculate RV loading and contractility. ResultsPDE5i induced a decrease in the right atrial pressure (–43%), pulmonary artery (PA) mean pressure (–26%), and PA wedge pressure (PAWP; –23%), with favorable reductions in pulmonary vascular resistance (–41%) and PA elastance (–40%), and increased cardiac output (+13%) (all P < 0.01). The RV ejection fraction increased with sildenafil (+20%), with no change of RV contractility (P = 0.74), indicating that the improvement in the RV ejection fraction was related to enhanced RV–PA coupling (r = 0.59, P = 0.004) by a decrease in the ventricular load. RV diastolic compliance increased with sildenafil. The decrease in the PAWP correlated with RV end-diastolic volume decrease; no relationship was observed with the change in LV transmural pressure, suggesting decreased pericardial constraint. ConclusionsAcute PDE5i administration has profound RV afterload-reducing effects, improves the RVEF, decreases RV volumes, and decreases the PAWP, predominantly through relief of pericardial constraint, without effects on RV chamber contractility. These findings support further study of PDE5i in protection of RV function in advanced heart failure with reduced ejection fraction who are at risk of RV failure.

Renal lymphatic vessel dynamics.

Similar to other organs, renal lymphatics remove excess fluid, solutes, and macromolecules from the renal interstitium. Given the kidney's unique role in maintaining body fluid homeostasis, renal lymphatics may be critical in this process. However, little is known regarding the pathways involved in renal lymphatic vessel function, and there are no studies on the effects of drugs targeting impaired interstitial clearance, such as diuretics. Using pressure myography, we showed that renal lymphatic collecting vessels are sensitive to changes in transmural pressure and have an optimal range of effective pumping. In addition, they are responsive to vasoactive factors known to regulate tone in other lymphatic vessels including prostaglandin E2 and nitric oxide, and their spontaneous contractility requires Ca2+ and Cl-. We also demonstrated that Na+-K+-2Cl- cotransporter Nkcc1, but not Nkcc2, is expressed in extrarenal lymphatic vessels. Furosemide, a loop diuretic that inhibits Na+-K+-2Cl- cotransporters, induced a dose-dependent dilation in lymphatic vessels and decreased the magnitude and frequency of spontaneous contractions, thereby reducing the ability of these vessels to propel lymph. Ethacrynic acid, another loop diuretic, had no effect on vessel tone. These data represent a significant step forward in our understanding of the mechanisms underlying renal lymphatic vessel function and highlight potential off-target effects of furosemide that may exacerbate fluid accumulation in edema-forming conditions.

Numerical Bifurcation Analysis of Pacemaker Dynamics in a Model of Smooth Muscle Cells.

Evidence from experimental studies shows that oscillations due to electro-mechanical coupling can be generated spontaneously in smooth muscle cells. Such cellular dynamics are known as pacemaker dynamics. In this article, we address pacemaker dynamics associated with the interaction of [Formula: see text] and [Formula: see text] fluxes in the cell membrane of a smooth muscle cell. First we reduce a pacemaker model to a two-dimensional system equivalent to the reduced Morris-Lecar model and then perform a detailed numerical bifurcation analysis of the reduced model. Existing bifurcation analyses of the Morris-Lecar model concentrate on external applied current, whereas we focus on parameters that model the response of the cell to changes in transmural pressure. We reveal a transition between Type I and Type II excitabilities with no external current required. We also compute a two-parameter bifurcation diagram and show how the transition is explained by the bifurcation structure.

An in silico simulation of flow-mediated dilation reveals that blood pressure and other factors may influence the response independent of endothelial function.

Endothelial dysfunction is thought to underpin atherosclerotic cardiovascular disease. The most widely used in vivo test of endothelial function is flow-mediated dilation (FMD). However, the results of FMD may be subject to some confounding factors that are not fully understood. We investigated potential biophysical confounding factors that could cause a disassociation between FMD and true endothelial cell shear stress response (the release of endothelium-dependent relaxing factors in response to wall shear stress). Arterial hemodynamics during FMD was simulated using a novel computational modeling approach. The model included an endothelial response function relating changes in wall shear stress to changes in local vascular stiffness in the arm arteries and accounted for vascular stiffening with increasing blood pressure. The hemodynamic effects of cuff inflation and deflation were modeled by prescribing intraluminal arterial pressure changes and peripheral vasodilation. Evolution of arterial diameter and flow velocity during FMD was assessed by comparison against in vivo data. Our model revealed that vasoconstriction occurring immediately after cuff deflation is independent of endothelial response function and entirely caused by the change in transmural pressure along conduit arteries. Moreover, for the same endothelial response function model, FMD values increased exponentially with increasing peak flow velocity, decreased linearly with increasing arterial stiffness at a rate of 0.95%/MPa, and increased linearly with increasing central blood pressure at a rate of 0.22%/mmHg. Dependence of FMD on confounding factors, such as arterial stiffness and blood pressure, suggests that the current FMD test may not reflect the true endothelial cell response.NEW & NOTEWORTHY First, a novel computational model simulating arterial hemodynamics during flow-mediated dilation (FMD) was proposed. Second, the model was used to explain why FMD may be influenced by endothelium-independent factors, showing that FMD results are 1) partly masked by the vasoconstriction due to the change in transmural pressure and 2) affected by physiological factors (i.e., arterial stiffness and arterial blood pressure) that are difficult to eliminate due to their multiple interactions.

P2561Withdrawal of simulated obstructive sleep apnea partially reverses atrial arrhythmogenic substrate in rats

Abstract Background Obstructive sleep apnea (OSA) is associated with structural alterations of the left atria (LA) and increased occurrence of atrial fibrillation (AF). Obstructive respiratory events lead to intermittent hypoxia (IH) and ineffective inspiration against the occluded upper airways, which result in intrathoracic and cardiac transmural pressure changes. Data on reversibility of LA-structural remodeling processes after withdrawal of OSA are still missing. Objectives Aim of the study was to develop a novel AF animal model mimicking intrathoracic pressure changes in addition to IH and to analyze the effect of OSA-withdrawal on atrial remodeling reversibility. Method In sedated rats (2% isoflurane), IH (n=9) was applied by intermittent increase in the respiratory dead volume. Standardized obstructive respiratory events were induced by defined intermittent negative upper airway pressure (INAP = inverse CPAP) applied via a customized mask connected to a negative pressure device (n=9). One minute of IH or INAP was followed by a rest period of nine minutes for four hours every second day. Rats with comparable anesthesia were used as controls (CTR). After three weeks, the animals were sacrificed. To analyze atrial structural remodeling reversibility, additional INAP-rats (n=5) were sacrificed after INAP-withdrawal of three weeks and compared to respective CTR (n=7). Result Blood pressure was not affected by IH or INAP. Intermittent desaturation and post-apneic hyperventilation were comparable in INAP- and IH-rats, but INAP-rats showed significantly higher breathing efforts during apneas compared to IH-rats. LA connexin43 (Cx43) protein expression assessed by quantitative immunofluorescence was reduced in both groups compared to CTR (0.77±0.07% in CTR vs. 0.45±0.06% in IH, p=0.02; CTR vs. 0.39±0.06% in INAP, p=0.005). However, LA interstitial fibrosis content (7.03±0.58% vs. CTR, p=0.01) and LA myocyte diameters (13.23±0.34μm vs. CTR, p=0.03) were increased in INAP-rats, but not in IH-rats. This was associated with longer inducible AF-durations in INAP-rats (11.65±4.43s vs. 0.72±0.33s in CTR, p=0.03) but not in IH-rats (1.28±0.33s vs. CTR, p=0.31). Three weeks of INAP-withdrawal (INAP-W) normalized interstitial fibrosis content (INAP-W vs. CTR, p=0.50) and LA-myocyte diameter (INAP-W vs. CTR, p=0.31). However, LA Cx43 protein expression remained low after three weeks of INAP withdrawal and inducible AF-episodes were still prolonged compared to respective CTR. Conclusion Application of INAP in rats mimics important components of OSA beyond IH and allows the study of an arrhythmogenic substrate in the atrium independent of the development of risk factors. In our model, withdrawal of INAP resulted in partial reversibility of structural LA remodeling but was not sufficient to abolish inducible AF-episodes completely. Future clinical studies are warranted to determine the anti-arrhythmic effect of isolated sleep apnea treatment in AF-patients. Acknowledgement/Funding Else Kröner-Fresenius-Stiftung, SFB-TRR219-M02/S-02

Airway Transmural Pressures in an Airway Tree During Bronchoconstriction in Asthma.

Airway transmural pressure in healthy homogeneous lungs with dilated airways is approximately equal to the difference between intraluminal and pleural pressure. However, bronchoconstriction causes airway narrowing, parenchymal distortion, dynamic hyperinflation, and the emergence of ventilation defects (VDefs) affecting transmural pressure. This study aimed to investigate the changes in transmural pressure caused by bronchoconstriction in a bronchial tree. Transmural pressures before and during bronchoconstriction were estimated using an integrative computational model of bronchoconstriction. Briefly, this model incorporates a 12-generation symmetric bronchial tree, and the Anafi and Wilson model for the individual airways of the tree. Bronchoconstriction lead to the emergence of VDefs and a relative increase in peak transmural pressures of up to 84% compared to baseline. The highest increase in peak transmural pressure occurred in a central airway outside of VDefs, and the lowest increase was 27% in an airway within VDefs illustrating the heterogeneity in peak transmural pressures within a bronchial tree. Mechanisms contributing to the increase in peak transmural pressures include increased regional ventilation and dynamic hyperinflation both leading to increased alveolar pressures compared to baseline. Pressure differences between intraluminal and alveolar pressure increased driven by the increased airway resistance and its contribution to total transmural pressure reached up to 24%. In conclusion, peak transmural pressure in lungs with VDefs during bronchoconstriction can be substantially increased compared to dilated airways in healthy homogeneous lungs and is highly heterogeneous. Further insights will depend on the experimental studies taking these conditions into account.

Maxi-K channel (BKC a ) activity veils the myogenic tone of mesenteric artery in rats

Arterioles and small arteries change their tone in response to transmural pressure changes, called myogenic tone (MT). In comparison to the branches of cerebral arteries (CA) showing prominent MT, the third branches of mesenteric arteries (MA) with similar diameters show weaker MT. Here, we aimed to analyze the electrophysiological differences responsible for the weaker MT in MA (MTMA) than MT in CA (MTCA). We measured ionic current using patch clamp in isolated MA smooth muscle cells (MASMCs) and CA smooth muscle cells (CASMCs) of rats. MT was analyzed using video analysis of pressurized small arteries. Quantitative‐PCR (q‐PCR) and immunofluorescence confocal microscopy were used to compare the mRNA and protein expression level of big‐conductance Ca2+‐activated K+ channel (BKC a) subunits (Slo1α and Sloβ1). Whole‐cell patch clamp study revealed higher density of voltage‐operated Ca2+ channel current (IC aV) in the MASMCs than in CASMCs. Although voltage‐gated K+ channel current (IK v) was also higher in MASMCs, treatment with Kv inhibitor (4‐aminopyridine) did not affect MTMA. Interestingly, BKC a current density and the frequency of spontaneous transient outward currents (STOCs) were consistently higher in MASMCs than in CASMCs. Inside‐out patch clamp showed that the Ca2+‐sensitivity of BKC a is higher in MASMCs than in CASMCs. Iberiotoxin, a selective BKC a inhibitor, augmented MTMA by a larger extent than MTCA. Although q‐PCR analysis did not reveal a significant difference of mRNAs for Slo1α and Sloβ1, immunofluorescence image suggested higher expression of Slo1α in MASMCs than in CASMCs. Despite the large IC aV density, the high activities of BKC a including the more frequent STOCs in MASMCs veils the potentially strong MTMA.

Constitutive smooth muscle tumour necrosis factor regulates microvascular myogenic responsiveness and systemic blood pressure

Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, the induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively expressed TNF regulates myogenic signalling and systemic haemodynamics under non-pathological settings. Here we show that acutely deleting the TNF gene in smooth muscle cells or pharmacologically scavenging TNF with etanercept (ETN) reduces blood pressure and resistance artery myogenic responsiveness; the latter effect is conserved across five species, including humans. Changes in transmural pressure are transduced into intracellular signals by membrane-bound TNF (mTNF) that connect to a canonical myogenic signalling pathway. Our data positions mTNF ‘reverse signalling’ as an integral element of a microvascular mechanosensor; pathologic or therapeutic perturbations of TNF signalling, therefore, necessarily affect microvascular tone and systemic haemodynamics.

Effect of lingual gauze swab placement on pulse oximeter readings in anaesthetised dogs and cats

This study aimed to evaluate the effect of lingual gauze swab placement on pulse oximeter readings in anaesthetised dogs and cats. Following anaesthetic induction, the following pulse oximeter probe configurations...

Microstructure and mechanics of human resistance arteries.

Vascular diseases such as diabetes and hypertension cause changes to the vasculature that can lead to vessel stiffening and the loss of vasoactivity. The microstructural bases of these changes are not presently fully understood. We present a new methodology for stain-free visualization, at a microscopic scale, of the morphology of the main passive components of the walls of unfixed resistance arteries and their response to changes in transmural pressure. Human resistance arteries were dissected from subcutaneous fat biopsies, mounted on a perfusion myograph, and imaged at varying transmural pressures using a multimodal nonlinear microscope. High-resolution three-dimensional images of elastic fibers, collagen, and cell nuclei were constructed. The honeycomb structure of the elastic fibers comprising the internal elastic layer became visible at a transmural pressure of 30 mmHg. The adventitia, comprising wavy collagen fibers punctuated by straight elastic fibers, thinned under pressure as the collagen network straightened and pulled taut. Quantitative measurements of fiber orientation were made as a function of pressure. A multilayer analytical model was used to calculate the stiffness and stress in each layer. The adventitia was calculated to be up to 10 times as stiff as the media and experienced up to 8 times the stress, depending on lumen diameter. This work reveals that pressure-induced reorganization of fibrous proteins gives rise to very high local strain fields and highlights the unique mechanical roles of both fibrous networks. It thereby provides a basis for understanding the micromechanical significance of structural changes that occur with age and disease.

Arteries Stiffen With Age, but Can Retain an Ability to Become More Elastic With Applied External Cuff Pressure.

It is accepted that arterial compliance decreases with age, with changes in the arterial pulse shape measured at the periphery. The aim of this study was to determine the relationship between arterial transmural pressure changes and changes in peripheral finger pulse shape characteristics for both older and younger subjects.Finger photoplethysmographic pulses were recorded noninvasively from the right index fingers of 100 healthy normotensive subjects. Their median age was 43 years (range 20–71 years) allowing two distinct age groups to be compared (older group ≥45 and younger group < 45 years). Arterial transmural pressures on the whole right arm were reduced with a 50 cm long cuff inflated to 10, 20, 30, and 40 mmHg. Pulse maximum amplitude and rise time were calculated for each age group, and for each cuff pressure level.Gradual and significant decreases in both pulse maximum amplitude and rise time were found with increasing cuff pressure for both age groups. With an external cuff pressure of 40 mmHg, there was an average maximum amplitude and rise time decrease of 27.1% (P < 0.001) and 7.5% (P < 0.001) respectively. The changes in the older group were significantly greater than those in the younger group for maximum amplitude (30.3% vs 24.4%, P = 0.006), but not for rise time (8.0% vs 6.7%, P = 0.23).Our results show that arterial compliance of the arm artery increases with reduced transmural pressure for both older and younger groups, and demonstrate that the aged arm artery can become more elastic with applied external cuff pressure.

Integrins mediate mechanical compression-induced endothelium-dependent vasodilation through endothelial nitric oxide pathway.

Cardiac and skeletal muscle contraction lead to compression of intramuscular arterioles, which, in turn, leads to their vasodilation (a process that may enhance blood flow during muscle activity). Although endothelium-derived nitric oxide (NO) has been implicated in compression-induced vasodilation, the mechanism whereby arterial compression elicits NO production is unclear. We cannulated isolated swine (n = 39) myocardial (n = 69) and skeletal muscle (n = 60) arteriole segments and exposed them to cyclic transmural pressure generated by either intraluminal or extraluminal pressure pulses to simulate compression in contracting muscle. We found that the vasodilation elicited by internal or external pressure pulses was equivalent; moreover, vasodilation in response to pressure depended on changes in arteriole diameter. Agonist-induced endothelium-dependent and -independent vasodilation was used to verify endothelial and vascular smooth muscle cell viability. Vasodilation in response to cyclic changes in transmural pressure was smaller than that elicited by pharmacological activation of the NO signaling pathway. It was attenuated by inhibition of NO synthase and by mechanical removal of the endothelium. Stemming from previous observations that endothelial integrin is implicated in vasodilation in response to shear stress, we found that function-blocking integrin α5β1 or αvβ3 antibodies attenuated cyclic compression-induced vasodilation and NOx (NO(-)2 and NO(-)3) production, as did an RGD peptide that competitively inhibits ligand binding to some integrins. We therefore conclude that integrin plays a role in cyclic compression-induced endothelial NO production and thereby in the vasodilation of small arteries during cyclic transmural pressure loading.

Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps.

Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca(2+) in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca(2+) concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca(2+) concentration.