Increase In Local Blood Flow Research Articles

(007) TESTOSTERONE POSITIVELY REGULATES ADENOSINE-INDUCED RELAXATION IN THE VAGINA: AN EXPERIMENTAL STUDY IN RATS

Abstract Introduction It has been previously demonstrated that testosterone (T) has a pivotal role in controlling vaginal relaxation through the related molecular machinery, i.e., improving the nitric oxide (NO)/protein kinase G (PKG)/cyclic guanosine monophosphate (cGMP) vaginal signaling and maintaining the integrity of the muscular wall. Adenosine (ADO) is a purinergic neuromodulator that, in the male, shows a positive effect on penile erection by controlling smooth muscle relaxation and local blood flow increase. However, the role, if any, of T on the ADO-induced relaxation signaling is yet to be investigated. Objective The aim of this study was to evaluate the effect of sex steroids on ADO-mediated vaginal relaxation using a validated animal model of ovariectomized (OVX) and sex steroid supplemented Sprague-Dawley rats. Methods Subgroups of OVX rats were treated with 17β-estradiol (E2; 10 mg/kg/die), testosterone (T; 30 mg/kg/week), or testosterone and letrozole (T+L, 2.5 mg/kg/die) for 6 weeks. The experimental groups were compared with a group of intact rats. In vitro contractility studies were performed on noradrenaline (NA) pre-contracted distal vaginal strips, isolated from each experimental group, stimulated with increasing doses of ADO (1 μM - 1 mM), with or without NO-synthase inhibitor L-NAME (100 μM) pretreatment, or treated with ADORA2A selective agonist CGS21680 (10 Pm-100 μM). Messenger ribonucleic acid (mRNA) isolated from vaginal tissue was analyzed by semi-quantitative Reverse Transcriptase-Polymerase Chain Reaction. Results The results showed that OVX resulted in a decreased responsiveness to ADO, completely restored by T supplementation, with or without letrozole. In contrast, E2 did not affect the hyporesponsiveness to ADO in OVX rats. Likewise, ADO induced dose-dependent relaxation was significantly reduced by in vitro L-NAME (100 μM) only in the OVX animals treated with T or T+L. Accordingly, vagina expressed all ADO receptors (ADORA1, ADORA2A, ADORA2B, ADORA3) mRNAs, with pro-relaxant ADORA2A (ADO receptor coupled to adenylyl cyclase activation) being significantly modulated by hormonal treatments: OVX significantly reduced ADORA2A mRNA expression, an effect counteracted by either T or T+L administration, but not by E2. These data are supported by the observed T-induced upregulation of cyclic adenosine monophosphate (cAMP)-dependent genes, where T, but not E2, treatment upregulated the mRNA expression of the ubiquitous isoform of ADCY (ADCY4), protein kinase A (PKA) catalytic subunit b (PKAcb), PKA regulatory subunit 2b (PKAr2b) and cAMP responsive element modulator (CREM). Finally, as further demonstration of the functional activity of ADO signaling in distal vagina, stimulation by increasing doses of CGS21680, a selective agonist of ADORA2A receptor, enhanced the relaxant effect induced by T and T+L treatments but not by E2. Conclusions Our data demonstrated for the first time a novel ADO-mediated relaxant mechanism in vagina and suggested that T positively modulates the responsiveness to ADO stimulation, thus confirming this process as a major player in the relaxant mechanism regulation of muscle contractility in vagina. Disclosure No.

Simulation of Conducted Responses in Microvascular Networks: Role of Current Rectification by Endothelial Cell Gap Junctions

Neuronal activity in the brain stimulates local increases in blood flow. Such flow increases require dilation of feeding arterioles, which can be initiated by upstream conducted responses in the form of electrical currents transmitted along the endothelial lining of the vessels. One potential trigger for this response is hyperpolarization of capillary endothelial cells in active regions resulting from local elevation of extracellular K+ concentration. The conducted hyperpolarization causes arteriolar dilation. For this mechanism to be effective in delivering increased flow to a specific location, the conducted response must travel in the upstream direction only, without reentry into adjacent parallel flow pathways. Such specificity in the response to activation has been observed in skeletal muscle, and may result from partial rectification of current in gap junctions connecting adjacent endothelial cells. The goal of this work is to simulate the spread of hyperpolarizing currents along vessel walls in microvascular networks of the cerebral circulation, including the effects of rectification in gap junctions. A theoretical model was developed for the spread of electrical current in the endothelial cells of a network of microvessels in response to local K+- induced hyperpolarization. Transmembrane currents are represented in the model by a KIR-channel conductance, a non-voltage-dependent K+ conductance, and a background conductance. Currents along vessel walls are represented assuming asymmetric gap junction conductance between adjacent endothelial cells, with higher conductance for downstream currents (causing upstream hyperpolarization) than for upstream currents. The model was applied to a synthetic network of 45 segments, assuming 20 nS conductance for upstream propagation, while a range of values was used for downstream propagation. The model shows effective upstream propagation of conducted responses when the gap junction conductance for downstream propagation is 1 nS or less. This result was confirmed in a simulation of a reconstructed murine cerebral cortex network with 4881 segments. In conclusion, partial current rectification by endothelial gap junctions can result in preferential upstream propagation of conducted responses, consistent with experimental observations of local flow regulation. Supported by NIH grant U01 HL133362. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Restoring capillary-to-arteriole signaling in Alzheimer's Disease

There is growing evidence for vascular contributions to cognitive impairments in Alzheimer’s Disease (AD). Functional hyperemia, which refers to local increases in blood flow in response to local increases in brain activity, is impaired early in patients and animal models of AD. The mechanisms underlying functional hyperemia are referred to as neurovascular coupling (NVC). A key player in NVC is the inward rectifying K+ channel (Kir2.1) in capillary endothelial cells (cECs). Activation of Kir2.1 channels initiates a retrograde hyperpolarizing signal which causes upstream arterioles to dilate and increase local blood flow. Studies have shown that Kir2.1 channel function is impaired in the 5xFAD mouse model for AD, and administration of Kir2.1 cofactor, phosphatidylinositol 4,5-bisphosphate (PIP2), was suffcient to restore channel function and functional hyperemia deficits. The objective of this study is to characterize the effect of AD on NVC. Since AD is characterized by the deposition of amyloid beta (Aβ), we hypothesize that Aβ is impairing Kir2.1 function in cECs at an early stage of the disease. Using 6-month-old female and male 5xFAD mice, we performed our ex vivo capillary-parenchymal arteriole (CaPA) technique to investigate NVC responses by directly stimulating capillaries and recording upstream arteriolar dilation in real time. We further tested the direct effect of Aβ oligomers (200 nM) and reactive oxygen species (ROS) scavengers (superoxide dismutase 120 U/mL + catalase 1000 U/mL), to probe their effect on the NVC response. Finally, to test the ability of PIP2 to rescue the NVC response, systemic administration via intraperitoneal injection was performed one hour before CaPA experiment. Consistent with a NVC impairment in AD, capillary stimulation with 10 mM K+ failed to evoke upstream arteriolar dilation in 5xFAD mice at an early stage, and this impairment was recapitulated in wild type mice after treatment with Aβ. Importantly, Aβ only caused a modest arteriole constriction (20.11% ± 5.24 %) but did not impair its ability to dilate in response to direct stimulation with 10 mM K+, suggesting an effect on cECs. ROS scavenging during Aβ treatment prevented NVC impairment as 10 mM K+ capillary stimulation induced an upstream arteriolar dilation of 59% of max dilation. Finally, systemic administration of PIP2 also rescued the NVC response to the levels observed in control conditions. Taken together, our results suggest that Aβ is causing impairment in NVC via increasing ROS production, specifically at the capillary endothelial level. This increase in ROS is likely leading to PIP2 degradation and causing Kir2.1 channel dysfunction. Administration of PIP2 was suffcient to rescue the NVC response, suggesting a possible strategy for rescuing functional hyperemia in AD. This study was supported by a research grant from the Center for Women’s Health Research located at the University of Colorado Anschutz Medical Campus; 2 research grants from the University of Pennsylvania Orphan Disease Center in partnership with the cureCADASIL (2019 and 2022), the National Institute of Neurological Disorders and Stroke RF1/R01NS129022, and the National Heart, Lung, and Blood Institute R01HL136636 to FD. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Possibilities of ultrasound diagnostics of paragangliomas of the neck

The purpose of the study is to evaluate the results of ultrasound examination, generalize the criteria for differential diagnosis of various types of paragangliomas in neck area and the development of a standard ultrasound protocol that provides information about the resectability of formations.Material and methods. 91 patients (100 tumors) with a clinical diagnosis of neurogenic neck tumor were examined, of which 71 (71%) were carotid paragangliomas, 18 (18%) – vagal paragangliomas, 10 (10%) – neurinomas and 1 (1%) – neurofibroma. All patients underwent ultrasound examination, including examination of the tumor structure in B-mode, assessment of the size and prevalence formations relative to the base of the skull and color Doppler mapping to assess the degree of intra-tumor blood flow and the relationship of formations with carotid arteries.The study allowed us to systematize the main ultrasound signs characteristic of various neurogenic neck tumors, among which we identified: clear, even contours; the presence of a capsule; a heterogeneous, predominantly hypoechoic structure with hyperechoic inclusions resembling “salt–pepper”. The following parameters played a crucial role in differential diagnosis: localization of formation, features of intra-tumor blood flow and the relationship of paragangliomas with carotid arteries.Results. Evaluation of the structural features of the tumor in the B-mode did not show significant differences between various paragangliomas, neurinomas and neurofibromas, all formations had clear, even contours, their capsule was clearly visualized. For carotid paragangliomas in all 71 (100%) observations, the characteristic feature was the location in the bifurcation area of the common carotid artery, with the mouths of the internal and external carotid arteries moving apart, which was 100% the diagnostic criterion of this group of formations. Vagal paragangliomas or neurinomas in all cases were located outside the bifurcation of the carotid artery, although in close proximity to the carotid arteries. The nature and degree of intra–tumor vasularization is another argument in the differential diagnosis of paragangliomas, which, unlike other neurogenic tumors, are highly vascularized tumors. The study of the nature of the intracellular blood flow showed that arterial paragangliomas predominate vessels, unlike neurinomas and neurofibromas, have significantly poorer vascularization with a predominance of venous vessels in the structure of the tumor. In 8 (44%) cases, vagal paragangliomas sprouted into the adventitia of the carotid arteries, which was characterized by a local increase in blood flow in this area in combination with turbulence during ultrasound.Conclusion. The proposed algorithm of ultrasound examination of neurogenic formations in the neck area makes it possible already at the primary stage instrumental diagnostics to identify volumetric formations, differentiate them between themselves and with other neck formations and to assume the degree of traumatism of the proposed surgical intervention.

Infant brain regional cerebral blood flow increases supporting emergence of the default-mode network.

Human infancy is characterized by most rapid regional cerebral blood flow (rCBF) increases across lifespan and emergence of a fundamental brain system default-mode network (DMN). However, how infant rCBF changes spatiotemporally across the brain and how the rCBF increase supports emergence of functional networks such as DMN remains unknown. Here, by acquiring cutting-edge multi-modal MRI including pseudo-continuous arterial-spin-labeled perfusion MRI and resting-state functional MRI of 48 infants cross-sectionally, we elucidated unprecedented 4D spatiotemporal infant rCBF framework and region-specific physiology-function coupling across infancy. We found that faster rCBF increases in the DMN than visual and sensorimotor networks. We also found strongly coupled increases of rCBF and network strength specifically in the DMN, suggesting faster local blood flow increase to meet extraneuronal metabolic demands in the DMN maturation. These results offer insights into the physiological mechanism of brain functional network emergence and have important implications in altered network maturation in brain disorders.

Local vasoregulative interventions impact drug concentrations in the skin after topical laser-assisted delivery.

The ability of ablative fractional lasers (AFL) to enhance topical drug uptake is well established. After AFLdelivery, however, drug clearance by local vasculature is poorly understood. Modifications in vascular clearance may enhance AFL-assisted drug concentrations and prolong drug dwell time in the skin. Aiming to assess the role and modifiability of vascular clearance after AFL-assisted delivery, this study examined the impact of vasoregulative interventions on AFL-assisted 5-fluorouracil (5-FU) concentrations in in vivo skin. 5-FU uptake was assessed in intactand AFL-exposed skin in a live pig model. After fractional CO2 laser exposure (15 mJ/microbeam, 5% density), vasoregulative intervention using topical brimonidine cream, epinephrine solution, or pulsed dye laser (PDL) was performed in designated treatment areas, followed by a single 5% 5-FU cream application. At 0, 1, 4, 48, and 72 h, 5-FU concentrations were measured in 500 and 1500 μm skin layers by mass spectrometry (n = 6). A supplemental assessment of blood flow following AFL ± vasoregulation was performed using optical coherence tomography (OCT) in a human volunteer. Compared to intact skin, AFL facilitated a prompt peak in 5-FU delivery that remained elevated up to 4 hours(1500 μm: 1.5 vs. 31.8 ng/ml [1 hour,p = 0.002]; 5.3 vs. 14.5 ng/ml [4 hours, p = 0.039]). However, AFL's impact was transient, with 5-FU concentrations comparable to intact skin at later time points. Overall, vasoregulative intervention with brimonidine or PDL led to significantly higher peak 5-FU concentrations, prolonging the drug's dwell time in the skin versus AFL delivery alone. As such, brimonidine and PDL led to twofold higher 5-FU concentrations than AFL alone in both skin layers by 1 hour(e.g., 500 μm: 107 ng/ml [brimonidine]; 96.9 ng/ml [PDL], 46.6 ng/ml [AFL alone],p ≤ 0.024), and remained significantly elevated at 4 hours(p ≤ 0.024). A similar pattern was observed for epinephrine, although trends remained nonsignificant (p ≥ 0.09). Prolonged 5-FU delivery was provided by PDL, resulting in sustained drug deposition compared to AFL alone at both 48 and 72 hoursin the superficial skin layer (p ≤ 0.024). Supporting drug delivery findings, OCT revealed that increases in local blood flow after AFL were mitigated in test areas also exposed to PDL, brimonidine, or epinephrine, with PDL providing the greatest, sustained reduction in flow over 48 hours. Vasoregulative intervention in conjunction with AFL-assisted delivery enhances and prolongs 5-FU deposition in in vivo skin.

A theoretical model for flow regulation in the cerebral cortex: role of penetrating arterioles

Activation of a region of the brain results in a local increase in blood flow, a process known as neurovascular coupling (NVC). Here, a theoretical model of blood flow regulation in the cerebral cortex is utilized to investigate the potential role of penetrating arterioles as the primary mechanism for local control of blood flow. Penetrating arterioles connect pial arterioles with the capillary meshwork deeper in the cortex and have a typical length of approximately 600 μm. This is about one‐sixth of the length of corresponding small arterioles in skeletal muscle. The question arises whether these relatively short arterioles can achieve the range of flow modulation observed in the cerebral cortex. A previously developed compartmental model for flow regulation in skeletal muscle was modified to represent the structure of cerebral microvasculature. A compartment consisting of penetrating arterioles with a reference diameter of 14.8 μm and a length of 600 μm is assumed to provide active control of blood flow. Smooth muscle tone in these arterioles is assumed to depend on a combination of signals representing myogenic, shear‐dependent, and metabolic responses. The metabolic response is represented by a change in endothelial cell membrane potential, propagated upstream along arterioles by conducted responses. Sensitivity of diameter to membrane potential was determined based on experimental data. According to the model, a hyperpolarization of 40 mV can result in an increase in local blood flow by approximately 70%. Since increases in local blood flow of 50% with activation have been observed, these results imply that vasoconstriction and vasodilation by penetrating arterioles can provide typical levels of blood flow control seen in neurovascular coupling.

Vascular Injury in the Zebrafish Tail Modulates Blood Flow and Peak Wall Shear Stress to Restore Embryonic Circular Network.

Mechano-responsive signaling pathways enable blood vessels within a connected network to structurally adapt to partition of blood flow between organ systems. Wall shear stress (WSS) modulates endothelial cell proliferation and arteriovenous specification. Here, we study vascular regeneration in a zebrafish model by using tail amputation to disrupt the embryonic circulatory loop (ECL) at 3 days post fertilization (dpf). We observed a local increase in blood flow and peak WSS in the Segmental Artery (SeA) immediately adjacent to the amputation site. By manipulating blood flow and WSS via changes in blood viscosity and myocardial contractility, we show that the angiogenic Notch-ephrinb2 cascade is hemodynamically activated in the SeA to guide arteriogenesis and network reconnection. Taken together, ECL amputation induces changes in microvascular topology to partition blood flow and increase WSS-mediated Notch-ephrinb2 pathway, promoting new vascular arterial loop formation and restoring microcirculation.

Activation of Glutamate Transport Increases Arteriole Diameter in v ivo: Implications for Neurovascular Coupling.

In order to meet the energetic demands of cell-to-cell signaling, increases in local neuronal signaling are matched by a coordinated increase in local blood flow, termed neurovascular coupling. Multiple different signals from neurons, astrocytes, and pericytes contribute to this control of blood flow. Previously, several groups demonstrated that inhibition/ablation of glutamate transporters attenuates the neurovascular response. However, it was not determined if glutamate transporter activation was sufficient to increase blood flow. Here, we used multiphoton imaging to monitor the diameter of fluorescently labeled cortical arterioles in anesthetized C57/B6J mice. We delivered vehicle, glutamate transporter substrates, or a combination of a glutamate transporter substrate with various pharmacologic agents via a glass micropipette while simultaneously visualizing changes in arteriole diameter. We developed a novel image analysis method to automate the measurement of arteriole diameter in these time-lapse analyses. Using this workflow, we first conducted pilot experiments in which we focally applied L-glutamate, D-aspartate, or L-threo-hydroxyaspartate (L-THA) and measured arteriole responses as proof of concept. We subsequently applied the selective glutamate transport substrate L-THA (applied at concentrations that do not activate glutamate receptors). We found that L-THA evoked a significantly larger dilation than that observed with focal saline application. This response was blocked by co-application of the potent glutamate transport inhibitor, L-(2S,3S)-3-[3-[4-(trifluoromethyl)-benzoylamino]benzyloxy]-aspartate (TFB-TBOA). Conversely, we were unable to demonstrate a reduction of this effect through co-application of a cocktail of glutamate and GABA receptor antagonists. These studies provide the first direct evidence that activation of glutamate transport is sufficient to increase arteriole diameter. We explored potential downstream mechanisms mediating this transporter-mediated dilation by using a Ca2+ chelator or inhibitors of reversed-mode Na+/Ca2+ exchange, nitric oxide synthetase, or cyclo-oxygenase. The estimated effects and confidence intervals suggested some form of inhibition for a number of these inhibitors. Limitations to our study design prevented definitive conclusions with respect to these downstream inhibitors; these limitations are discussed along with possible next steps. Understanding the mechanisms that control blood flow are important because changes in blood flow/energy supply are implicated in several neurodegenerative disorders and are used as a surrogate measure of neuronal activity in widely used techniques such as functional magnetic resonance imaging (fMRI).

Evaluation of Local Skeletal Muscle Blood Flow in Manipulative Therapy by Diffuse Correlation Spectroscopy.

Manipulative therapy (MT) is applied to motor organs through a therapist’s hands. Although MT has been utilized in various medical treatments based on its potential role for increasing the blood flow to the local muscle, a quantitative validation of local muscle blood flow in MT remains challenging due to the lack of appropriate bedside evaluation techniques. Therefore, we investigated changes in the local blood flow to the muscle undergoing MT by employing diffuse correlation spectroscopy, a portable and emerging optical measurement technology that non-invasively measures blood flow in deep tissues. This study investigated the changes in blood flow, heart rate, blood pressure, and autonomic nervous activity in the trapezius muscle through MT application in 30 volunteers without neck and shoulder injury. Five minutes of MT significantly increased the median local blood flow relative to that of the pre-MT period (p < 0.05). The post-MT local blood flow increase was significantly higher in the MT condition than in the control condition, where participants remained still without receiving MT for the same time (p < 0.05). However, MT did not affect the heart rate, blood pressure, or cardiac autonomic nervous activity. The post-MT increase in muscle blood flow was significantly higher in the participants with muscle stiffness in the neck and shoulder regions than in those without (p < 0.05). These results suggest that MT could increase the local blood flow to the target skeletal muscle, with minimal effects on systemic circulatory function.

Correlation of Caesarean Section Rates to Maternal and Neonatal Mortality in the Eastern Mediterranean Region; A Population-Based Ecological Study

The physiological reaction of postocclusive local reactive hyperemia is regulated by neurovascular mechanisms and it reflects the function of microcirculation. Thermoregulatory changes occur first, in the form of increased skin surface temperature, which is usually followed by an increase in local blood flow. This study investigated a correlation between tourniquet duration on the upper arm, and the appearance of reactive hyperemia in the distal parts of the upper limb. Changes were registered with infrared thermometer and infrared thermography, which provided us a highly precise view of distribution of reactive hyperemia. Changes of oxygen saturation of peripheral arterial blood and blood pressure were also recorded. Our research has shown that longer duration of tourniquet leads to more intense and longer lasting reactive hyperemia in the palmar region, followed by higher temperatures of the skin surface, without any changes in postocclusive values of SpO2. Keywords: Infrared thermography, Microcirculation, Postocclusive hyperemia, Skin temperature, Tourniquet, Thermoregulatory changes.

Dilation of cortical capillaries is not related to astrocyte calcium signaling.

The brain requires an adequate supply of oxygen and nutrients to maintain proper function as neuronal activity varies. This is achieved, in part, through neurovascular coupling mechanisms that mediate local increases in blood flow through the dilation of arterioles and capillaries. The role of astrocytes in mediating this functional hyperemia response is controversial. Specifically, the function of astrocyte Ca2+ signaling is unclear. Cortical arterioles dilate in the absence of astrocyte Ca2+ signaling, but previous work suggests that Ca2+ increases are necessary for capillary dilation. This question has not been fully addressed in vivo, however, and we have reexamined the role of astrocyte Ca2+ signaling in vessel dilation in the barrel cortex of awake, behaving mice. We recorded evoked vessel dilations and astrocyte Ca2+ signaling in response to whisker stimulation. Experiments were carried out on WT and IP3R2 KO mice, a transgenic model where astrocyte Ca2+ signaling is substantially reduced. Compared to WT mice at rest, Ca2+ signaling in astrocyte endfeet contacting capillaries increased by 240% when whisker stimulation evoked running. In contrast, Ca2+ signaling was reduced to 9% of WT values in IP3R2 KO mice. In all three conditions, however, the amplitude of capillary dilation was largely unchanged. In addition, the latency to the onset of astrocyte Ca2+ signaling lagged behind dilation onset in most trials, although a subset of rapid onset Ca2+ events with latencies as short as 0.15 s occurred. In summary, we found that whisker stimulation-evoked capillary dilations occurred independent of astrocyte Ca2+ increases in the cerebral cortex.

Effects of combined hot and hypoxic conditions on muscle blood flow and muscle oxygenation during repeated cycling sprints.

The purpose of the present study was to determine muscle blood flow and muscle oxygenation during repeated-sprint exercise under combined hot and hypoxic conditions. In a single-blind, cross-over research design, 11 active males performed three sets of 5 × 6-s maximal sprints with 30-s active recovery on a cycling ergometer under control (CON; 23°C, 50% rH, 20.9% FiO2), normobaric hypoxic (HYP; 23°C, 50% rH, 14.5% FiO2), or hot + normobaric hypoxic (HH; 35°C, 50% rH, 14.5% FiO2) conditions. The vastus lateralis muscle blood flow after each set and muscle oxygenation during each sprint were evaluated using near-infrared spectroscopy methods. Despite similar repeated-sprint performance among the three conditions (peak and mean power outputs, percent decrement score), HH was associated with significantly higher muscle blood flow compared with CON after the first set (CON: 0.61 ± 0.10mL/min/100g; HYP: 0.81 ± 0.13mL/min/100g; HH: 0.99 ± 0.16mL/min/100g; P < 0.05). The tissue saturation index was significantly lower in HYP than in CON during the latter phase of the exercise (P < 0.05), but it did not differ between HH and CON. These findings suggest that a combination of normobaric hypoxia and heat stress partially facilitated the exercise-induced increase in local blood flow, but it did not enhance tissue desaturation.

Effect of Glabridin on Microvascular Permeability of Plasma Proteins Induced by Carrageenan

In the present study, investigate the anti-inflammatory effects of glabridin (GLA) in the carrageenan-induced paw edema test of rats. Inflammation is an answer to the body's immune response to various stimuli such as physical trauma, various antigens, chemicals, microorganisms, radiation-damaged tissues. The cause of this edema is the increase of vascular permeability, an increase in local blood flow, as well as the penetration of neutrophils and macrophages into the inflamed tissue. The current study aimed to determine the mechanism of microvascular leakage on carrageenan (CAR)-induced paw edema of GLA. Therefore, 10, 20 and 40 mg / kg doses of GLA were given intraperitoneal 3 days before intraplantar administration of CAR by using Evans blue (EB) method and by measuring paw thickness with electronic digital calipers. As a result, GLA inhibited both edema and microvascular leak. The results of our study suggest that pretreat-GLA to CAR-induced paw edema of rats via anti-inflammatory potential through inhibition of parameters such as microvascular escape and anti-edematous effect. These findings may be a new treatment of inflammation by anti-protein leakage of GLA.

The cerebral haemodynamic response to somatosensory stimulation in preterm newborn lambs is reduced with dopamine or dobutamine infusion

BackgroundIn the adult brain, increases in neural activity lead to increases in local blood flow. However, in the preterm neonate, studies of cerebral functional haemodynamics have yielded inconsistent results, including negative responses suggesting decreased perfusion and localised tissue hypoxia, probably due to immature neurovascular coupling. Furthermore, the impact of vasoactive medications, such as dopamine and dobutamine used as inotropic therapies in preterm neonates, on cerebrovascular responses to somatosensory input is unknown. We aimed to characterise the cerebral haemodynamic functional response after somatosensory stimulation in the preterm newborn brain, with and without dopamine or dobutamine treatment. MethodsWe studied the cerebral haemodynamic functional response in 13 anaesthetised preterm lambs, using near infrared spectroscopy to measure changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb) following left median nerve stimulation using stimulus trains of 1.8, 4.8 and 7.8 s. The 4.8 and 7.8 s stimulations were repeated during dopamine or dobutamine infusion. ResultsStimulation always produced a somatosensory evoked response. Majority of preterm lambs demonstrated positive functional responses (i.e. increased ΔoxyHb) in the contralateral cortex following stimulus trains of all durations. Dopamine increased baseline oxyHb and total Hb, whereas dobutamine increased baseline deoxyHb. Both dopamine and dobutamine reduced the evoked ΔoxyHb responses to 4.8 and 7.8 s stimulations. ConclusionsSomatosensory stimulation increases cerebral oxygenation in the preterm brain, consistent with increased cerebral blood flow due to neurovascular coupling. Notably, our results show that dopamine/dobutamine reduces oxygen delivery relative to consumption in the preterm brain during somatosensory stimulations, suggesting there may be a risk of intermittent localised tissue hypoxia which has clear implications for clinical practice and warrants further investigation.

NEUROINFLAMMATION

Inflammation is a complex process, mediated by cellular and molecular mechanisms caused by a response to a tissue damage from an aggressive agent, whether if biological, chemical or physical origin. This process occurs, ultimately, with the purpose of promoting defense, repair and tissue regeneration. The inflammatory process leads to changes in blood vessels that have their diameter and flow altered, with the objective of leading to increased vascular permeability and consequent leakage of fluids and cells into the extracellular space of the affected tissue. This sequence of events generates the cardinal signs of inflammation, which are: pain, heat, redness, edema, with loss or alteration of function. The process occurs through mechanisms induced by cytokines and that despite having local manifestation, it can lead to systemic responses involving the whole organism with fever, chills, tremors, tachycardia, leukocytosis, sweating, diuresis and blood dyscrasias. In the cascade of events related to inflammation, there is initially a local stimulus that promotes morphological and functional changes in the attacked tissue that trigger the release of signaling molecules, the defensins that have a chemotactic effect on monocytes, neutrophils and lymphocytes, and pro-inflammatory mediators. that are directly involved in the next inflammatory phases. There is, then, the recognition of aggression and the aggressor agent by the receptors of cells of the immune system and release of inflammatory mediators, of the cyclooxygenase pathway that will release prostaglandin, prostacyclins and thromboxanes and by the lipooxygenase pathway that will produce leukotrienes (Figure 1). Then, there is a modification of the local microcirculation promoting vasodilation, initially arteriolar and subsequently of the venules by the action of histamine release by mast cells, and associated with an increase in local blood flow, generate the cardinal flushing and heat signals.

Artificial Co 2 -water Immersion Facilitates Recovery From Muscle Fatigue Caused By High Intensity Anaerobic Exercise

In response to the CO2-water (CO2≥1000 ppm) immersion, the reduction of sympathetic nerve activity may imply the facilitation of muscle fatigue recovery. PURPOSE: In the present study, we investigated whether the whole body bath with CO2-water influences recovery of the muscle fatigue after high intensity exercise. METHODS: The healthy male college students (n=6, 18-21yrs, 171.3±6.7cm, 73.6±13.0kg) participated in this study. The cycle ergometer work tests lasting 30 seconds were used to estimate anaerobic power with leg pedaling exercises. Exercise loads of the tests were 0.075kp per body weight. Anaerobic power was determined by measuring the highest power output during 30 seconds. Core temperature (CoreT) and ECG were recorded continuously throughout the experiment. The subjects performed 30-s maximal pedaling exercise, and took bath in tap- or CO2-water at 35 °C for 10 minute after exercise. Subjective thermal sensation (TS) in the body bath was also recorded. Vastus lateralis (VL) dominant muscle hardness using the elastography. , muscle pain by visual analog scale (VAS), and blood lactate (BLa) and were evaluated at pre- and immediately after-exercise, and at 10 min after exercise. RESULTS: The strain ratio (SR) between the VL and a reference material was calculated. TS in the CO2-water was significantly higher than in the tap-water (tap-water vs. CO2-water, -0.17±0.76 vs. 1.17±0.41, p<0.01). At 10 min in recovery, in the CO2-water compared with the tap-water, SR significantly decreased quicker (0.49±0.25 vs. 0.91±0.25, p<0.01). However, there was no significant difference in CoreT, BLa and VAS between these two water kinds. CONCLUSIONS: We reported previously that the muscle blood flow in the immersed part was larger in CO2-water than tap-water of a same temperature. In addition to a local effect of CO2, suppression of muscular sympathetic activity may also contribute to the increase in local blood flow. Facilitation of muscle hardness recovery shown in this study might be caused by the increased muscle blood flow. The present results suggested that CO2-water immersion may contribute to rapid recovery from the muscular hardness induced by high intensity exercise.

The origins of the eastern meridian system

There is no doubt that the mechanical effect on the so-called bioactive points and areas may be extremely useful and leads sometimes to a complete cure for various ailments. The existence and benefits of a reflex therapy are absolutely indisputable. Indeed, from ancient times to the present, the unique experience and empirical knowledge about the meridians connecting the points of influence and the skin with all body systems have been accumulated in the depths of Eastern medicine. Until now, the physical nature of the meridians is unknown and has not been explained by anyone, that’s why the reflex therapy stands apart from standard medicine and is practiced as a semi-legal occupation, despite its obvious benefits and effectiveness. In this paper, an attempt was made to reveal the physical nature of the meridians and, thereby, legalize this ancient and extremely necessary discipline. The authors propose a coherent hypothesis, the main idea of which is the statement that if there is even a slightest wound, the nervous system will immediately send the impulse to increase the blood supply to this spot, in other words, a special address appears, the fresh blood directs that way and causes the healing. The mechanism of redistribution of blood flow is that there is a certain low-frequency modulation of the heart rate, which leads to a local increase in blood flow, as impact zones are characterized by certain reductions in time with the modulations. The corresponding organ in the body also has a similar address (i.e. a certain frequency), and therefore an intensified blood flow rushes there too, providing a vital effect on this organ. As a result, the supported organ more effectively fights the disease. This, in short, is the mechanism of recovery that nature has in place in the presence of heart rhythm modulations that can be made manageable. Naturally, by saturating the blood with exposure agents, we will obtain an increase in their effectiveness due to local penetration directly into the painful area.

Blood Flow Control of the Microcirculation by KATP Channels in Ventricular Myocytes

The metabolic demands of the working myocardium underlies the control of blood flow to the cardiac myocytes. However, little is known about the details of the signals that are generated by metabolic need and how these signals are linked into a rapid‐response negative feedback control of blood flow. Here, using the state‐of‐the‐art confocal microscopy and whole mount immunostaining techniques and other fluorescent labels, we have investigated both the anatomic organization of the vasculature and the control mechanisms of blood flow. Our results show the key cellular elements of the system are connected to each other electrically by means of gap junctions (Connexin 43). They connect ventricular myocytes to capillary endothelial cells which are connected to pericytes and the small artery endothelium. Gap junctions thus allow the time‐averaged hyperpolarization of ventricular myocytes (due to the opening of ATP‐sensitive K+ channels (KATP) following metabolic need) to produce hyperpolarization in the rest of the system. By this means relaxation of the pericytes and the smooth muscle cells could produce an increase in blood flow with O2 and nutrition to the ventricular myocytes. Initial results showing this physiological feedback control system that appear to manage blood flow control in heart were tested in a perfused mouse cardiac papillary muscle preparation. The functional changes of arterioles and capillaries in the ex vivo heart were monitored using high‐speed confocal microscopes that include a combination of XY (Nipkow disk) and point‐scanner confocals. Our results suggest that KATP opener pinacidil caused perfusion pressure decrease (blood flow increase) while KATP blocker glibenclamide causes perfusion pressure increase in paced or quiescent heart, indicating the functional involvement of KATP channels in local blood flow control. Pinacidil‐induced perfusion pressure reduction does not differ on smooth muscle specific Kir6.1 mutated mice, suggesting the least role of smooth muscle KATP in the local blood flow regulation. An additional contribution to blood flow elevation may be attributed to extracellular K+ ([K+]o) increases (from ventricular myocyte KATP and other K+ channels), which leads to the hyperpolarization of capillary endothelial cells through the activation of inward rectifier K+ channels (Kir). Thus, the activation of KATP in cardiomyocytes caused by metabolic increase links to the local increase in blood flow. Taken together, these data provide compelling evidence that blood flow control in the mammalian heart is a classic negative‐feedback signaling mechanism that links the metabolism of ventricular myocytes to locally increased blood flow through an electrically controlled signaling system.

Effect of Cupping Therapy on Skin Surface Temperature in Healthy Individuals

Purpose: The purpose of this study was to examine the effect of cupping therapy on skin surface temperature, and therefore local blood flow, at the medial forearm. Methods: 32 healthy subjects [13 females (age = 21.14 ± 1.70, height = 168.00 ± 9.70 cm, mass = 67.07 ± 16.93) and 16 males (age = 21.78 ± 1.90, height = 180.62 ± 6.09, mass = 88.35 ± 14.66) participated in this study. A mark was made with a permanent marker 7 cm distal to the medial forearm. Cupping therapy was performed over this mark with the use of a plastic pump cup for 15 minutes. Every 5 minutes the cup was removed in order for skin surface temperature to be taken. Skin surface temperature was taken with the use of an infrared thermometer at base line, 5 minutes into treatment, 10 minutes into treatment, 15 minutes into treatment, and 5 minutes after treatment. A one way repeated measures ANOVA was performed to analyze the difference in skin surface temperature over time. Significance was set at an alpha level p < 0.05. Results: Significant differences were found between all conditions (baseline = 89.37 ± 2.09, 5 minutes into treatment = 90.49 ± 2.08, 10 minutes into treatment = 91.65 ± 2.18, 15 minutes into treatment = 91.62 ± 2.26, 5 minutes after treatment = 92.40 ± 2.03, p < 0.001). Conclusion: A single cupping therapy treatment appears to significantly increase skin surface temperature at the treatment site. Increases in skin surface temperature have been suggested as a representation of increases in local blood flow. These findings suggest that a single cupping therapy treatment may increase local blood flow at the medial forearm.