Vasomotor Responses Research Articles

Blockade of endothelial Mas receptor restores the vasomotor response to phenylephrine in human resistance arterioles pretreated with captopril and exposed to propofol

BackgroundHypotension that is resistant to phenylephrine is a complication that occurs in anesthetized patients treated with angiotensin converting enzyme (ACE) inhibitors. We tested the hypothesis that Ang 1–7 and the endothelial Mas receptor contribute to vasodilation produced by propofol in the presence of captopril.MethodsThe internal diameters of human adipose resistance arterioles were measured before and after administration of phenylephrine (10–9 to 10–5 M) in the presence and absence of propofol (10–6 M; added 10 min before the phenylephrine) or the Mas receptor antagonist A779 (10–5 M; added 30 min before phenylephrine) in separate experimental groups. Additional groups of arterioles were incubated for 16 to 20 h with captopril (10–2 M) or Ang 1–7 (10–9 M) before experimentation with phenylephrine, propofol, and A779.ResultsPropofol blunted phenylephrine-induced vasoconstriction in normal vessels. Captopril pretreatment alone did not affect vasoconstriction, but the addition of propofol markedly attenuated the vasomotor response to phenylephrine. A779 alone did not affect vasoconstriction in normal vessels, but it restored vasoreactivity in arterioles pretreated with captopril and exposed to propofol. Ang 1–7 reduced the vasoconstriction in response to phenylephrine. Addition of propofol to Ang 1–7-pretreated vessels further depressed phenylephrine-induced vasoconstriction to an equivalent degree as the combination of captopril and propofol, but A779 partially reversed this effect.ConclusionsMas receptor activation by Ang 1–7 contributes to phenylephrine-resistant vasodilation in resistance arterioles pretreated with captopril and exposed to propofol. These data suggest an alternative mechanism by which refractory hypotension may occur in anesthetized patients treated with ACE inhibitors.

Not just sensitization: sympathetic mechanisms contribute to expand experimental referred pain.

BackgroundWidespread pain partially depends upon sensitization of central pain mechanisms. However, mechanisms controlling pain distribution are not completely known. The present study sought to assess skin temperature variations in the area of experimentally-induced pain and potential sex differences.MethodsPressure-pain thresholds (PPTs) were measured on the right infraspinatus muscle. At the end of Day 0, all participants performed an eccentric exercise of the shoulder external rotators to induce muscle soreness 24 hours after. On Day 1, participants indicated on a body chart the area of pain induced by 60 seconds of suprathreshold pressure stimulation (STPS; PPT + 20%) on the right infraspinatus muscle. Skin temperature variations in the area of referred pain were recorded with an infrared thermography camera, immediately before and after the STPS.ResultsTwenty healthy, pain-free individuals (10 females) participated. On Day 0, the pre-STPS temperature was higher than the post-STPS temperature on the arm (P = 0.001) and forearm (P = 0.003). On Day 1, the pre-STPS temperature was higher than the post-STPS temperature on the shoulder (P = 0.015), arm (P = 0.001), and forearm (P = 0.010). On Day 0, the temperature decrease after STPS in females was greater than in males on the forearm (P = 0.039). On Day 1, a greater temperature decrease was found amongst females compared with males at the shoulder (P = 0.018), arm (P = 0.046), and forearm (P = 0.005).ConclusionsThese findings indicate that sympathetic vasomotor responses contribute to expand pressure-induced referred pain, especially among females.

The course of adrenomedullin and endothelin levels in patients with vasodilatory shock after cardiac surgery compared to patients after uncomplicated elective cardiac surgery.

The aim of this study was to analyse the course of adrenomedullin (ADM) and endothelin-1 (ET-1) levels in patients with vasodilatory shock after cardiac surgery and to explore differences compared to patients after uncomplicated coronary artery bypass graft (CABG) surgery. ADM and ET-1 are involved in the vasomotor response during vasodilatory shock. We included 32 patients with vasodilatory shock (study group) and 10 patients after uncomplicated CABG surgery (control group). Daily measurements of MR-proADM and CT-proET-1 (stable surrogate markers for ADM and ET-1) were collected during the first 7 postoperative days. MR-proADM and CT-proET-1 levels were significantly elevated in the study group when compared to the control group. In addition, the course of both biomarkers was significantly different in the study versus control group. Higher levels of both biomarkers were associated with organ dysfunction (higher maximum multiple organ dysfunction score, acute kidney injury). Significantly higher levels of MR-proADM and CT-proET-1 and a different course of both biomarkers were observed in patients with vasodilatory shock after cardiac surgery and seemed to be associated with organ dysfunction.

Artificial sweeteners sucralose and acesulfame potassium: A bittersweet story for the cardiovascular system?

Artificial sweeteners (AS) are well known to activate two categories of receptors; sweet taste receptor with high affinity and bitter taste receptors with low affinity. Interestingly, recent data from our and other groups suggested that these two receptors families are expressed throughout the arterial tree. Therefore, it could be interesting to explore if AS may have an impact on vascular function, and to decipher the role of these taste receptors. The aims of this ongoing work is to investigate whether AS, like sucralose and acesulfame potassium (AceK) (1) exhibit vasomotor effect and (2) in that case determine the underlying mechanisms. Biomolecular and functional investigations have been performed on isolated rodent aortas, human dermal micro-arteries and omental arteries. Ex vivo vasomotor function was assessed using isometric tension measurements in organ bath systems. We first confirmed that both endothelial and smooth muscle cells from rodent and human arteries express the transcripts encoding for TAS1R2 and TAS1R3; the heterodimer receptor known to be responsible for the sweet taste. Our ex vivo data showed that only high concentrations (about 10 mM) of AceK and sucralose induce vasomotor responses. While AceK exhibited a vasoconstrictive effect, sucralose induced vasorelaxation. Both responses were found to be independent of the endothelium. Pharmacological inhibition (gurmarin and lactisol) and the use of a TAS1R3 KO mice model demonstrated that AS vasomotor effects do not rely on the sweet taste receptors. In contrast, inhibition of TAS2Rs abolished all responses suggesting that bitter taste receptors are more likely responsible for the AS-induced vascular effects. Additionally, our last observations show that the vasoconstrictive effect of AceK is mediated by RhoA/ROCK pathway. These evidences support the idea that AS can alter vasomotor signaling in the smooth muscle cells. These acute effects are probably mediated by the bitter taste receptor family. Their activation at the vascular level as well as the underlying pathways remains poorly understood, and the physiopathological consequences need to be further investigated.

0081 Physiologic anatomy, use of Infra-Red Thermography in Hypersomnia

Abstract Introduction In the words of Michel Salmon, " Between anatomy and physiology there is room for a functional anatomy and for a physiologic anatomy “. This concept was applied to analyze our (1) Sleep Research 21, 1992,341 (2) Sleep Research 22, 1993, 363, and (3) SLEEP 31, 2008, A219 publications on patients with Hypersomnia who had intracranial and extracranial blood flow evaluations. Methods For “Functional Anatomy”, Intracranial cerebral blood flow was done with Xenon 133 inhalation. For “Physiologic Anatomy”, Extracranial facial blood flow Imaging, Infra-Red thermography was done. 1992,3 and 2008 data was classified: Groups I, II and III. Group I had Intracranial and Extracranial blood flow study, 5% CO2 inhalation. Groups II had Extracranial flow study with 5 % CO2 and 100 % Oxygen inhalation. Groups III had Extracranial flow study 100 % Oxygen inhalation. Response interpretation: Normal response to 5% CO2, vasodilation. For 100% Oxygen / hyperoxia, vasoconstriction. Response is considered as normal or abnormal, if response is absent or paradoxical. Results Group I: All three patients 5% CO2 inhalation, intracranial Functional anatomy vasomotor response normal. Physiological Anatomy response abnormal. Group II, Physiological Anatomy study. 8 patients. CO2 response, 7/8 vasoconstriction, abnormal response. 100% Oxygen challenge, 4/8 had no vasoconstriction, abnormal response. Group III: Physiological anatomy. 7 patients tested with 100% Oxygen challenge. 6/7 abnormal response, (1 vasoconstriction, 4 no response, 2 vasodilation). Total of 18 patients in all groups, physiological anatomy/ Extracranial flow vasomotor response was abnormal in 16/18, (Group I = 3, Group II = 7, and Group III = 6) Conclusion In hypersomnia patients vasomotor testing, Functional Anatomy, intracranial flow vasomotion normal in 3/3 for hypercarbia inhalation. For Physiologic Anatomy, using Infra-Red Thermography to image extracranial facial blood flow (not coupled with metabolism) vasomotion was abnormal in 16/18 patients. 5% CO2 and 100% Oxygen inhalation used as contrast agents is well tolerated and facilitates imaging vasomotor dysfunction in the facial blood flow, trigeminal angiosomes, which can be correlated with hypersomnia. Association between trigeminal system and the hypocretin receptor 1 gene HCRTR1 gene has been reported. Support (If Any) None.

HYBRID MECHANICAL CIRCULATORY LOOPS – AN EMERGING NEED FOR TOTAL ARTIFICIAL HEARTS WITH NOVEL TECHNOLOGIES.

Circulatory assist devices need to be tested at various levels prior to human implantation. These include numerical simulations, lab and animal testing, tissue computability prior to human trials that would scale in terms of complexity of indications and participant load. Mock circulatory loops though not ideal offer the best current equivalents of gold standard for such purposes in the in vitro domain. These could be very simple hydraulic loops to complex hydraulic loop interface with computers. These need to replicate both right and left circulatory systems coupled with vascular compliances and resistances. It should recreate the perfusion rates and pressures that exist in normal systemic and pulmonary vasculature for both normal and heart failure models. These rigs greatly reduce the device evaluation costs by mimicking nature though vasomotor responses in the normal human body may require complicated evaluation models to be deciphered in future by use of evolving technologies. Following mechanical evaluation on the mock circulatory loop actual animal testing would give the experimental proof of concept. The basic requirements are that of a pump, ow channels, compliance chambers with monitoring of pressure and resistance changes using pressure and ow sensors. It serves as a safe low cost training and evaluating platform. Virtual mock loop simulation tool can simulate the hemodynamics using a lumped-parameter model for systemic/pulmonary circulation characteristic inputs values for impedance, systolic and diastolic ventricular compliance, beat rate, and blood volume and characteristics of the cardiac chambers and valves. VML contains several different lumped parameter models for selection and evaluation. It also stores and organizes data from different origins that makes comparison easier. For new total articial heart models the advantage of a dual approach emerges with use of hybrid mechanical circulatory loop.

Diminished Pulmonary Arterial Smooth Muscle Cell Membrane Cholesterol Unmasks EGFR‐dependent Vasoconstriction

IntroductionChronic hypoxia (CH) leads to increased pulmonary vascular resistance and resultant pulmonary hypertension (PH) in patients with chronic obstructive pulmonary disease, sleep apnea, or in residents at high altitude. Recent studies from our laboratory have demonstrated that CH augments vasoconstrictor reactivity to a variety of stimuli, including pulmonary arterial smooth muscle cell (PASMC) stretch, membrane depolarization, and stimulation of G protein‐coupled receptors. This effect of CH is mediated by a switch in PASMC signaling from Ca2+‐dependent mechanisms towards a novel epidermal growth factor receptor (EGFR)‐NADPH oxidase 2 (NOX2)‐Rho kinase (ROK) Ca2+ sensitization pathway. The overall objective of this study is to understand the mechanism by which CH mediates this switch in signaling. We have recently demonstrated that CH decreases membrane cholesterol, a component of lipid membrane domains that can regulate both EGFR and NOX2 activity in other cell types. Therefore, we hypothesized that this EGFR‐NOX2‐ROK signaling pathway is intact in PASMC from control animals but quiescent due to inhibition by membrane cholesterol.MethodsWe first validated our ability to manipulate membrane cholesterol levels by treating primary cultures of PASMCs from Sprague Dawley rats with either cholesterol (2 mM), epicholesterol (an epimeric form of cholesterol; 2 mM), or MβCD (cholesterol chelator; 10 mM). Membrane cholesterol content was quantified by filipin (50 mg/ml) fluorescence using confocal microscopy. Subsequently, we examined vasoconstrictor responses to increasing concentrations of epidermal growth factor (EGF) (10‐10 – 10‐6 M) in pressurized, endothelium‐disrupted rat pulmonary arteries (~150 mm diameter). The effect of diminished membrane cholesterol on vasomotor responses was tested by substituting native cholesterol with epicholesterol (2 mM), which lacks the ability participate in protein‐sterol interactions while maintaining normal membrane fluidity. Vessels were additionally treated with the selective NOX2 inhibitor gp91ds‐tat (50 mM), the selective Rho kinase inhibitor fasudil (10 mM), or their respective vehicles.ResultsCholesterol supplementation significantly increased PASMC membrane cholesterol as indicated by filipin fluorescence. Conversely, treatment with either MβCD or epicholesterol significantly decreased membrane cholesterol compared to vehicle‐treated cells (Figure 1). In agreement with our hypothesis, epicholesterol‐dependent substitution of cholesterol revealed concentration‐dependent vasoconstriction to EGF in pulmonary arteries (Figure 2A). Treatment with either fasudil (Figure 2A) or gp91ds‐tat (Figure 2B) attenuated this effect.ConclusionsThe EGFR‐NOX2‐RhoA signaling cascade is present in arteries from normoxic animals but is normally inhibited by membrane cholesterol. The results of this study will allow for improved mechanistic analysis of how cholesterol regulates this pathway that is central to enhanced vasoconstrictor reactivity in PH.

Metformin Exposure in uteroProgrammes Hypertension in a Sex‐Specific Manner in Adult Offspring of Obese Mice

IntroductionMetformin is the first‐line pharmacological treatment for gestational diabetes in many countries. Although effective at improving maternal glycaemia, metformin readily crosses the placenta and could directly affect the fetus. Indeed, metformin exposure in utero increases postnatal adiposity. However, other long‐term effects on offspring exposed to metformin in utero have not been investigated. Here we explored the impact of maternal metformin treatment during obese, glucose‐intolerant pregnancy on offspring cardiovascular function at one year of age using an established mouse model of maternal diet‐induced obesity.MethodsFemale C57Bl/6J mice were fed either a standard chow diet [Control dams (Con)] or an obesogenic diet [Obese (Ob) and Obese‐Metformin (Ob‐Met) dams] from weaning up to and including pregnancy and lactation. Ob‐Met dams received a clinically relevant dose of metformin orally from one week prior to mating until day 19 of gestation. All offspring were weaned onto standard chow fed ad libitum at three weeks of age. At one year of age, systolic blood pressure (SBP) was measured by tail cuff plethysmography in the conscious animal and echocardiography was performed under anaesthesia. Post‐mortem, femoral arteries were isolated and vasomotor reactivity tested using in vitro wire myography. Myography dose‐response curves were analysed using mixed effects models, all other data were analysed by One‐Way ANOVA. Post‐hoc multiple comparisons were performed where appropriate. Significance was accepted when P<0.05.ResultsRelative to controls, female offspring of Ob‐Met dams had increased SBP. However, no differences in SBP were observed in male offspring (Fig.1A). Female offspring of both Ob and Ob‐Met dams had enhanced femoral vasoconstrictor reactivity to K+ (Fig. 1B) but normal cardiac function (Fig. 1C). In contrast, male offspring of both Ob and Ob‐Met dams showed indices of diastolic dysfunction (Fig. 1C) and male offspring of Ob‐Met dams had enhanced femoral vasoconstrictor reactivity to phenylephrine (PE) (Fig.1B).ConclusionsMaternal obesity and metformin exposure in utero caused sex‐specific changes in cardiovascular function in 12‐month‐old offspring. In female offspring, exposure to maternal obesity and metformin programmed hypertension with enhanced peripheral vasoconstrictor reactivity. In male offspring, maternal obesity alone programmed echocardiographic indices of left ventricular restrictive filling which were not corrected by metformin treatment, while combined exposure to maternal obesity and metformin also programmed enhanced peripheral vasoconstrictor reactivity. These findings provide novel insight into the long‐term effects of in utero metformin exposure on the cardiovascular health of the next generation in obese pregnancy, and highlight the importance of considering offspring sex in developmental programming studies.

Exercise training improves cerebral endothelial function in juvenile and mature Ossabaw miniature‐pigs

BackgroundChronic hyperglycemia promotes excessive production of endothelial reactive oxygen species (ROS), which may impair nitric oxide (NO) signaling, a hallmark of vascular disfunction. How maturation and exercise training influence this process in the cerebrovasculature has yet to be explored. The purpose of this study was to examine the role of ROS on endothelial‐dependent cerebral dilation at different stages of maturation in sedentary and exercise trained hyperglycemic pigs. It was hypothesized that mature pigs would display reduced endothelial NO‐dependent dilation coinciding with augmented NAD(P)H Oxidase (NOX; involved in ROS production) activity and reduced superoxide dismutase (SOD; involved in ROS clearance) activity compared with juvenile pigs. Furthermore, compared with sedentary (SED) pigs, pigs that completed high‐intensity interval training (HIIT) would exhibit enhanced endothelial NO‐dependent dilation coupled with decreased NOX and increased SOD signaling.MethodsTwenty juvenile (n=10F/10M; 3±1 mo.) and 17 mature (n=9F/7M; 14±1 mo.) Ossabaw miniature‐pigs were divided into SED or HIIT groups. The HIIT consisted of 3 sessions per week (5X3 min intervals interspersed with 1 min recovery periods performed on a motorized treadmill) for 8 weeks. Animals were group housed with access to 1 kg of feed/pig/day and ad libitum access to a 10% sugar water solution. At the end of the intervention pigs were euthanized, and cerebral arteries were harvested for arterial myography experiments. To examine endothelial NO‐dependent relaxation, vasomotor responses to bradykinin (BK; 3e‐15M to 1e‐6M) were studied in the presence or absence of NO synthase inhibition (L‐NAME; 3e‐4 M). Further, to examine the role of ROS signaling, vasodilatory responses to BK were studied under the following conditions: 1) NOX inhibition (Apocynin; 1e‐4 M) and 2) SOD mimetic (TEMPOL; 1e‐4 M).ResultsAt the end of the trial all groups were considered hyperglycemic (mean plasma glucose> 8.5 mmol/L), and plasma glucose values were lower in mature (8.8±1.6 mmol//L) vs. juvenile pigs (10.3±2.2 mmol/L; main effect; P<0.05). Regarding cerebral vasomotor control, BK‐induced dilation was greater in HIIT vs. SED groups (main effect; P<0.01), owing to enhanced NO signaling (main effect; P=0.05). Treatment with a NOX inhibitor increased BK‐induced dilation in juvenile (P=0.05) and mature SED pigs (P=0.01). Treatment with a SOD mimetic did not influence dilation in juvenile SED pigs (P=0.87), and increases in BK‐induced dilation in mature SED pigs approached significance (P=0.07).ConclusionThese results show that despite being hyperglycemic, HIIT improved endothelial‐dependent cerebral dilation in juvenile and mature pigs likely owing to enhanced NO bioavailability, secondary to decreased NOX and increased SOD signaling. Maturity was associated with lower levels of hyperglycemia and did not impair cerebral endothelial‐dependent dilation.

Effect of Hyperinsulinemia on Cerebral Autoregulation and Myogenic Control of Cerebral Blood Flow in Healthy Young Adults

ObjectiveHyperinsulinemia has marked vasodilatory effects within the skeletal muscle vasculature in healthy young adults; however, the magnitude of insulin‐stimulated cerebrovascular vasodilation is less clear. Differences between circulations may be due to a greater importance of the cerebral circulation to maintain a constant level of blood flow (i.e., cerebral autoregulation) during hyperinsulinemia. We hypothesized cerebral autoregulation would increase during hyperinsulinemia. Autoregulatory mechanisms, such as myogenic control, play important roles in mediating cerebral vasomotor responses. Thus, we further sought to examine the contribution of the myogenic mechanism to the control of cerebral blood flow during hyperinsulinemia.MethodsMiddle cerebral artery blood velocity (MCAv) and femoral artery blood velocity (FAV) were measured with Doppler ultrasound and femoral artery blood flow (FBF) was calculated in 17 healthy adults (11M/6F, 28±2 yrs, 24±1 kg/m2) at baseline and following a hyperinsulinemic (40 mU/m2body surface area/min), euglycemic infusion. Finger plethysmography was used to assess mean blood pressure (MBP). Normalized transfer function gain between changes in MBP and MCAv were estimated in the 0.02‐0.07 Hz (very low frequency, VLF) and 0.07–0.20 Hz (low frequency, LF) ranges using the Welch method. Interactions between MBP and MCAv or FAV were determined using cross‐correlation analyses.ResultsIntravenous insulin infusion increased plasma insulin concentrations (6±1 to 50±3 μIU/mL, p<0.01) with blood glucose maintained at baseline levels (p=0.33). There was a significant increase in FBF (121±15 to 151±19 mL/min, p=0.03) during hyperinsulinemia, with no change in MCAv (61±4 to 59±4 cm/s, p=0.28) or MBP (86±2 to 89±2 mmHg, p=0.10). There was no effect of hyperinsulinemia on normalized transfer function gain in the VLF (p=0.25) or LF ranges (p=0.46). Hyperinsulinemia had no effect on the association between MBP and MCAv (p=0.15) or FAV (p=0.82).ConclusionsHyperinsulinemia in healthy young adults elicits peripheral vasodilation, but no change in MCAv. Contrary to our hypothesis, the sensitivity of the cerebrovascular circulation to changes in MBP (i.e., cerebral autoregulation) is not altered during systemic hyperinsulinemia in healthy adults. Furthermore, the contribution of the myogenic mechanism to the control of blood flow in the peripheral and cerebral circulations is unaffected by hyperinsulinemia. Whether these results translate to disease states (e.g., diabetes) and the implications for cerebrovascular health warrant further exploration.

Young, non-Hispanic Black men and women exhibit divergent peripheral and cerebral vascular reactivity.

What is the central question of the study? Do peripheral and cerebral vascular function differ between young non-Hispanic Black men and women? What is the main finding and its importance? The non-Hispanic Black women in this study presented greater peripheral conduit artery and cerebrovascular reactivity, yet similar peripheral microvascular function relative to the non-Hispanic Black men. These preliminary findings suggest that young Black women and men possess divergent vascular function, possibly contributing to the unique non-Hispanic Black sex differences in cardiovascular and cerebrovascular diseases. In the USA, cardiovascular and cerebrovascular diseases remain more prominent in the non-Hispanic Black (BL) population relative to other racial/ethnic groups. Typically, sex differences emerge in the manifestation of these diseases, though these differences may not fully materialize in the BL population. While numerous mechanisms are implicated, differences in vascular function likely contribute. Research has demonstrated blunted vasodilatation in several vascular regions in BL versus non-Hispanic White individuals, though much of this work did not assess sex differences. Therefore, this study aimed to ascertain if indices of vascular function are different between young BL women (BW) and men (BM). Eleven BW and 15BM (22 (4) vs. 23 (3) years) participated in this study. Each participant underwent testing for brachial artery flow-mediated dilatation (FMD), post-occlusive reactive hyperaemia and cerebral vasomotor reactivity during rebreathing-induced hypercapnia. BW exhibited greater adjusted FMD than BM (P<0.05 for all), but similar or lower reactive hyperaemia when assessed as blood velocity (P>0.39 for all) or blood flow reactivity (P<0.05 for all), respectively. Across a range of hypercapnia, BW had greater middle cerebral artery blood velocity and cerebrovascular conductance index than BM (P<0.001 for both). These preliminary data suggest that young BW have greater vascular function relative to young BM, though this was inconsistent across different indices. These findings provide insight into the divergent epidemiological findings between BM and BW. Further research is needed to elucidate possible mechanisms and relate these physiological responses to epidemiological observations.

Effect of High-Intensity Interval Training, Moderate Continuous Training, or Guideline-Based Physical Activity on Peak Oxygen Uptake and Myocardial Fibrosis in Patients With Myocardial Infarction: Protocol for a Randomized Controlled Trial.

IntroductionHigh-intensity interval training (HIIT) is an emerging method of cardiac rehabilitation, which is more and more popular in recent years. Research into the effect of HIIT on peak oxygen uptake (VO2 peak) and myocardial fibrosis among patients with myocardial infarction (MI) is lacking. Here, we describe the rationale along with the protocol for a clinical trial to test the following hypotheses: (1) compared with the control group, VO2 peak will be increased in both the moderate-intensity continuous training (MICT) and HIIT groups and (2) compared with the control group, myocardial fibrosis due to MI will be improved by HIIT and MICT.Methods and AnalysisThis is a single-center, randomized controlled clinical trial. In total, 180 patients with MI are to be recruited for this study. VO2 peak will be tested by cardiopulmonary exercise testing (CPET) and myocardial fibrosis will be evaluated by cardiac MR. A variety of blood and psychometric tests and also the peripheral arterial tonometry, reactive hyperemia index for microvascular endothelial function, and microvascular blockage or digital vasomotor response are included.Ethics and DisseminationThe ethics committee of the Guangdong Provincial People's Hospital has authorized this mechanistic clinical research. Peer-reviewed articles and conference presentations will be used to disseminate the findings.Trial Registration NumberNCT04863677.

Acute Revascularization Induced Reversed Robin Hood Syndrome

Paradoxical intracranial hemodynamic steal (IHS) is a contradictory reduction of cerebral blood flow volume in the territory of the impaired perfusion area occurring spontaneously or in response to vasodilatory stimuli, which can be recorded and evaluated on transcranial doppler (TCD). IHS followed by early neurological worsening (change in National Institute of Health Stroke Scale [NIHSS]&gt; 2) in acute ischemic stroke patients has been described as reversed Robin Hood syndrome (RRHS). We describe two cases of RRHS following carotid artery stenting (CAS) in patients with contralateral carotid occlusion and its further management. Two patients with a history of anterior circulation strokes presented with recent complaints of dizziness and a sensation of being pulled back (patient 1), and episodic numbness of upper limbs (patient 2). On CT angiogram, both of the patients had severe extracranial internal carotid artery (ICA) stenosis on the symptomatic side associated with complete occlusion of the ICA on the contralateral side. In addition, both patients had impaired vasomotor reactivity (VMR) on TCD in the bilateral middle cerebral artery (MCA). Therefore, CAS on the symptomatic side was performed in both patients by femoral artery access without any periprocedural and postprocedural complications. However, on day 1 post CAS, complaints of transient upper limb tingling (patient 1) and limb shaking (patient 2) were reported corresponding to the completely occluded ICA, and TCD examinations confirmed RRHS in both patients. Patients were managed by decreasing the dose of antihypertensive medication to augment the blood pressure for 2 weeks. Normalization of the VMR on TCD was seen on follow-up, and both patients remain asymptomatic.

Longitudinal Progression of Magnetic Resonance Imaging Markers and Cognition in Dutch-Type Hereditary Cerebral Amyloid Angiopathy.

Background:Hemorrhagic and ischemic magnetic resonance imaging lesions as well as the more recently described decrease in vasomotor reactivity have been suggested as possible biomarkers for cerebral amyloid angiopathy (CAA). Analyses of these markers have been primarily cross-sectional during the symptomatic phase of the disease, with little data on their longitudinal progression, particularly in the presymptomatic phase of the disease when it may be most responsive to treatment. We used the unique opportunity provided by studying Dutch-type hereditary cerebral amyloid angiopathy (D-CAA) to determine longitudinal progression of CAA biomarkers during the presymptomatic as well as the symptomatic phase of the disease.Methods:In this longitudinal case-control study, magnetic resonance imaging markers and cognitive performance were assessed at baseline and after ≈4 years in 10 presymptomatic and 6 symptomatic D-CAA mutation carriers and 20 control subjects. These magnetic resonance imaging markers included hemorrhagic and ischemic manifestations, measurements of cerebral blood flow, and vasomotor reactivity to visual stimulation.Results:In presymptomatic D-CAA mutations carriers, vasomotor reactivity showed a decline over time for blood-oxygen-level–dependent amplitude (P=0.011) and prolongation of time to peak (P<0.001). In contrast, no significant changes in hemorrhagic markers, ischemic markers, cerebral blood flow, and cognition were found. In symptomatic D-CAA mutation carriers, the number of intracerebral hemorrhages increased over the 4-year period (P=0.007).Conclusions:Our findings indicate that in the presymptomatic phase of D-CAA, cerebrovascular reactivity measured by the blood-oxygen-level–dependent amplitude and time to peak to visual stimulation progressively worsens and can thus be regarded as a disease progression marker. In the symptomatic phase, the most salient marker of progression appears to be recurrent intracerebral hemorrhage.

Changes in P2Y6 receptor-mediated vasoreactivity following focal and global ischemia.

Ischemia, both in the form of focal thromboembolic stroke and following subarachnoid hemorrhage (SAH), causes upregulation of vasoconstrictive receptor systems within the cerebral vasculature. Descriptions regarding changes in purinergic signaling following ischemia are lacking, especially when the importance of purinergic signaling in regulating vascular tone is taken into consideration. This prompted us to evaluate changes in P2Y6‐mediated vasomotor reactivity in two different stroke models in rat. We used wire myography to measure changes in cerebral vasoreactivity to the P2Y6 agonist UDP‐β‐S following either experimental SAH or transient middle cerebral artery occlusion. Changes in receptor localization or receptor expression were evaluated using immunohistochemistry and quantitative flow cytometry. Transient middle cerebral artery occlusion caused an increase in Emax when compared to sham (233.6 [206.1–258.5]% vs. 161.1 [147.1–242.6]%, p = 0.0365). No such change was seen following SAH. Both stroke models were associated with increased levels of P2Y6 receptor expression in the vascular smooth muscle cells (90.94 [86.99–99.15]% and 93.79 [89.96–96.39]% vs. 80.31 [70.80–80.86]%, p = 0.021) and p = 0.039 respectively. There was no change in receptor localization in either of the stroke models. Based on these findings, we conclude that focal ischemic stroke increases vascular sensitivity to UDP‐β‐S by upregulating P2Y6 receptors on vascular smooth muscle cells while experimental SAH did not induce changes in vasoreactivity in spite of increased P2Y6 receptor expression.

Evaluation of cerebral hemodynamic status in patients with unilateral symptomatic carotid artery stenosis during motor tasks, through use of transcranial Doppler sonography.

Carotid artery stenosis increases cerebral ischemic event risk through changing different cerebral hemodynamic parameters. To investigate how cerebral hemodynamics in the M1 segment of middle cerebral artery change in patients with carotid artery stenosis, after motor tasks using transcranial Doppler sonography (TCD). Thirty-two healthy subjects and 30 patients with unilateral symptomatic carotid artery stenosis were recruited. The patient population was divided into three groups according to the degree of stenosis (group 1: ≥50 to 69%, group 2: 70 to 89% and group 3: ≥90 to 99%). TCD was used to measure the pulsatility index (PI) and cerebral vasomotor reactivity (CVR). In the patient group, significant differences for symptomatic side PI values (p=0.01) and mean CVR increases (p=0.05) were observed, compared with the healthy controls. However, the difference was not statistically significant for asymptomatic side PI values and mean CVR increases. The results from the intergroup comparison showed significantly higher percentages of symptomatic and asymptomatic side CVR increases in group 1, compared with groups 2 and 3 (p=0.001 and p=0.002, respectively). Our study showed that cerebral autoregulation and hemodynamic mechanisms are impaired in patients with carotid artery stenosis. Furthermore, the impairment of PI and CVR tends to get worse with increasing degrees of stenosis. In addition, this study demonstrated that assessment of these two hemodynamic parameters in clinical practice might be helpful for monitoring the progress of carotid artery stenosis.

The Nutraceutical Antihypertensive Action of C-Phycocyanin in Chronic Kidney Disease Is Related to the Prevention of Endothelial Dysfunction.

C-phycocyanin (CPC) is an antihypertensive that is not still wholly pharmacologically described. The aim of this study was to evaluate whether CPC counteracts endothelial dysfunction as an antihypertensive mechanism in rats with 5/6 nephrectomy (NFx) as a chronic kidney disease (CKD) model. Twenty-four male Wistar rats were divided into four groups: sham control, sham-treated with CPC (100 mg/Kg/d), NFx, and NFx treated with CPC. Blood pressure was measured each week, and renal function evaluated at the end of the treatment. Afterward, animals were euthanized, and their thoracic aortas were analyzed for endothelium functional test, oxidative stress, and NO production. 5/6 Nephrectomy caused hypertension increasing lipid peroxidation and ROS production, overexpression of inducible nitric oxide synthase (iNOS), reduction in the first-line antioxidant enzymes activities, and reduced-glutathione (GSH) with a down-expression of eNOS. The vasomotor response reduced endothelium-dependent vasodilation in aorta segments exposed to acetylcholine and sodium nitroprusside. However, the treatment with CPC prevented hypertension by reducing oxidative stress, NO system disturbance, and endothelial dysfunction. The CPC treatment did not prevent CKD-caused disturbance in the antioxidant enzymes activities. Therefore, CPC exhibited an antihypertensive activity while avoiding endothelial dysfunction.

Mechanisms and clinical implications of endothelium-dependent vasomotor dysfunction in coronary microvasculature.

Coronary microvascular disease (CMD), which affects the arterioles and capillary endothelium that regulate myocardial perfusion, is an increasingly recognized source of morbidity and mortality, particularly in the setting of metabolic syndrome. The coronary endothelium plays a pivotal role in maintaining homeostasis, though factors such as diabetes, hypertension, hyperlipidemia, and obesity can contribute to endothelial injury and consequently arteriolar vasomotor dysfunction. These disturbances in the coronary microvasculature clinically manifest as diminished coronary flow reserve, which is a known independent risk factor for cardiac death, even in the absence of macrovascular atherosclerotic disease. Therefore, a growing body of literature has examined the molecular mechanisms by which coronary microvascular injury occurs at the level of the endothelium and the consequences on arteriolar vasomotor responses. This review will begin with an overview of normal coronary microvascular physiology, modalities of measuring coronary microvascular function, and clinical implications of CMD. These introductory topics will be followed by a discussion of recent advances in the understanding of the mechanisms by which inflammation, oxidative stress, insulin resistance, hyperlipidemia, hypertension, shear stress, endothelial cell senescence, and tissue ischemia dysregulate coronary endothelial homeostasis and arteriolar vasomotor function.

Spirulina extract improves age-induced vascular dysfunction

Context Vascular dysfunction is considered a hallmark of ageing that has been associated with altered vasomotor responses, in which nitric oxide (NO) and reactive oxygen species participate. The consumption of Spirulina extracts, with antioxidant properties, increased recently. Objective This study investigates the effect of Spirulina aqueous extract (SAE) on the vascular function of the aorta from aged rats. Materials and methods Aortic segments from aged male Sprague-Dawley rats (20–22 months old) were exposed to SAE (0.1% w/v, for 3 h) to analyse: (i) the vasodilator response induced by acetylcholine (ACh), by the NO donor sodium nitroprusside (SNP), by the carbon monoxide releasing molecule (CORM) and by the KATP channel opener, cromakalim (CK); (ii) the vasoconstrictor response induced by KCl and noradrenaline (NA); (iii) the production of NO and superoxide anion, and (iv) the expression of the p-eNOS and HO-1 proteins. Results Incubation with SAE increased the expression of p-eNOS (1.6-fold) and HO-1 (2.0-fold), enhanced NO release (1.4-fold in basal and 1.9-fold in ACh-stimulated conditions) while decreased the production of superoxide (0.7-fold). SAE also increased the sensitivity (measured as pEC50) to ACh (control: −7.06 ± 0.11; SAE: −8.16 ± 0.21), SNP (control: −7.96 ± 0.16; SAE: −9.11 ± 0.14) and CK (control: −7.05 ± 0.39; SAE: −8.29 ± 0.53), and potentiated the response to KCl (1.3-fold) and to NA (1.7-fold). Conclusion The antioxidant properties of SAE improved the vasomotor responses of aorta from aged rats. These results may support the use of Spirulina as a protection against vascular dysfunction.

Cerebrovascular responses to somatomotor stimulation in Parkinson’s disease: A multivariate analysis

Parkinson’s disease (PD) is a common neurodegenerative disorder, yet little is known about cerebral haemodynamics in this patient population. Previous studies assessing dynamic cerebral autoregulation (dCA), neurovascular coupling (NVC) and vasomotor reactivity (VMR) have yielded conflicting findings. By using multi-variate modelling, we aimed to determine whether cerebral blood flow (CBF) regulation is impaired in PD patients. 55 healthy controls (HC) and 49 PD patients were recruited. PD subjects underwent a second recording following a period of abstinence from their anti-Parkinsonian medication. Continuous bilateral transcranial Doppler in the middle cerebral arteries, beat-to-beat mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram), and end-tidal CO2 (EtCO2; capnography) were measured. After a 5-min baseline period, a passive motor paradigm comprising 60 s of elbow flexion was performed. Multi-variate modelling quantified the contributions of MAP, ETCO2 and neural stimulation to changes in CBF velocity (CBFV). dCA, VMR and NVC were quantified to assess the integrity of CBF regulation. Neural stimulation was the dominant input. dCA, NVC and VMR were all found to be impaired in the PD population relative to HC (p < 0.01, p = 0.04, p < 0.01, respectively). Our data suggest PD may be associated with depressed CBF regulation. This warrants further assessment using different neural stimuli.