Vasoconstrictor Responses Research Articles

Abstract 13332: Assessment of Myocardial Oxygenation Response to Vasoactive Breathing Maneuvers in Patients With Repaired Dextro-Transposition of the Great Arteries an OS-CMR Study

Introduction: Long-term outcomes of patients with repaired Dextro-transposition of the great arteries (D-TGA) by arterial switch operation (ASO) are excellent. However, studies have suggested impaired myocardial blood flow reserve. Oxygen-sensitive cardiac magnetic resonance (OS-CMR) with vasoactive breathing maneuvers (BM) offers a contrast-free tool for evaluating myocardial oxygenation. Hypothesis: Evaluate myocardial oxygenation reserve and microvascular function in repaired D-TGA post-ASO using OS-CMR with BM. Methods: In this single-center study, we analyzed OS-CMR images (basal and mid-left ventricular slices) of 9 D-TGA post-ASO patients (mean age 29 ±6.52yrs, 33.3% females) and 10 healthy participants (mean age 33 ±8.9 yrs, 40% females) who completed the BM. The BM consisted of free breathing, then hyperventilation, causing vasoconstriction, then breath hold, causing vasodilatation. End-systolic OS-CMR signal intensity (SI) was measured at baseline, after hyperventilation (closest to 0 sec of breath hold), and at closest to 30 sec of breath hold. Changes in SI (ΔSI) in % were calculated in response to the different periods and compared using independent samples t-test. Results: In the D-TGA cohort, the coronary response to hyperventilation was abnormal compared to healthy subjects (5.8±19.9% vs -15.1±13.3%, p=0.01). No difference was observed in ΔSI% during breath hold (mean TGA:3.0±10.5% vs mean healthy:5.7±6%, p=0.5). No differences were observed in mid-slices for either period. Conclusions: Our findings suggest patients with D-TGA may have an impaired vasoconstrictor response to a hyperventilation maneuver. Further studies should explore the associated pathophysiology and potential impact on clinical management.

412 Awardee Talk: New Insights into Mechanisms of Serotonin Receptor-Mediated Vasoactivity and Complex Interactions with Ergot Alkaloids in Bovine Vasculature

Abstract Ergovaline (ERV), produced in toxic endophyte-infected tall fescue, causes potent vasoconstriction of bovine vasculature by interacting with serotonin (5-HT) receptors. Ergovaline acts as a partial agonist of 5-HT2A-mediated vasoconstriction. The duration of ERV exposure affects 5-HT-mediated vasoactivity of mesenteric blood vessels. If ERV and 5-HT exposure occur simultaneously, ERV can increase 5-HT-mediated vasoconstriction. If 5-HT exposure occurs after blood vessels have had prior ERV exposure, increasing levels of 5-HT can induce vasorelaxation of blood vessels. To better understand mechanisms of 5-HT-mediated vasorelaxation, lateral saphenous veins from steers (n = 5) were assessed for vasoactivity in response to increasing concentrations of selective 5-HT receptor agonists Isolated vessel segments were suspended in chambers of a multi-myograph containing 5 mL of continuously oxygenated Krebs-Henseleit buffer and equilibrated to 1 g tension for 90 min. Vessels were pre-contracted with 1×10-4 M phenylephrine and exposed to increasing concentrations of 5-HT or 5-HT receptor agonists that were selective for 5-HT1B, 5-HT2B, 5-HT4, and 5-HT7. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre-contraction. Increasing concentrations of 5-HT resulted in divergent vasoconstriction and vasorelaxation responses that were dose-dependent. Serotonin caused an 86.3% increase (P < 0.01) in relaxation activity at 1×10-7 M and 5-HT caused a 166% increase (P < 0.01) in contraction activity at 1x10-4 M. Increasing concentrations of the selective 5-HT1B agonist did not result in any vasoactive response. Increasing concentrations of agonists selective for 5-HT2B, 5-HT4, or 5-HT7 resulted in a 27.3%, 91.6%, or 43.9% (P < 0.01) increase in maximal vasorelaxation activity. Of these 5-HT receptor agonists, the selective 5-HT4 receptor agonist resulted in the lowest -log IC50 value (6.30) compared with 5-HT2B and 5-HT7 receptor agonists (4.21 and 4.66, respectively). To confirm the involvement of 5-HT4 in 5-HT-mediated vasorelaxation, blood vessels were exposed to either DMSO (control), a selective 5-HT2A antagonist (1×10-5M), or selective antagonists of 5-HT2A and 5-HT4 simultaneously for 5-min before the pre-contraction with phenylephrine and additions of 5-HT. Antagonism of the 5-HT2A receptor did not result in increased vasorelaxation activity compared with control. Antagonism of the 5-HT2A receptor and 5-HT4 receptor simultaneously inhibited vasorelaxation activity and increased (P < 0.01) the maximal contractile response occurring at 1×10-4 M by 47% compared with control. Approximately 84% of the maximal vasorelaxation activity occurring in response to 5-HT could be accounted for through 5-HT4. These data provide strong evidence that 5-HT4 is the primary receptor involved with 5-HT-mediated vasorelaxation in bovine lateral saphenous vein. More research is needed to determine if 5-HT4-mediated vasorelaxation is responsible for relaxation responses observed in blood vessels with prior ERV exposure. This will aid in the development of strategies for alleviating symptoms of sustained vasoconstriction that occur during fescue toxicosis in ruminants.

The effects of inflammation and acidosis on placental blood vessels reactivity

IntroductionInflammation and acidosis are two stress stimuli that correspond to pathophysiological processes occurring in placental-mediated vascular disorders. We aimed to investigate the effects of these stimuli on placental chorionic blood vessels reactivity using the ex-vivo placental perfusion model. MethodsTerm placentas were obtained immediately after cesarean deliveries, and selected cotyledons were cannulated and dually perfused ex-vivo. Placentas were perfused with three different protocols: culture medium (M199-controls, n = 5), culture medium with lipopolysaccharide (inflammatory stimuli) (LPS,1 μg/ml, n = 7), and acidotic culture medium (M − 199, pH: 6.9–7, n = 6). Each perfusion experiment was maintained for 180 min. Fetal perfusion pressure was continuously measured. Measurements in response to angiotensin II (AT II) at the end of the perfusion were compared between the treatment groups, including amplitude of the contraction response, relaxation factor, time to maximal constriction and the area under the pressure curve (AUC). ResultsIn response to ATII there was a significant difference in the amplitude of the contraction and the AUC between the treatment groups, (p = 0.049, p = 0.015, respectively). As compared with control perfused cotyledon, the inflammatory stimuli significantly increased the vasoconstriction response to ATII in fetal placental blood vessels, as expressed by increased AUC - median (IQR): 555 (235–1184) vs. 133 (118–207), respectively, p = 0.017. The time to maximal constriction and the relaxation factor did not differ between the groups. DiscussionInflammatory stimuli but not acidosis impact fetal-placental vasculature in response to ATII, suggesting that inflammation can compromise vascular function.

Changes in the blood flow in the uterine and umbilical arteries during the second trimester of pregnancy in exacerbation of bronchial asthma associated with reactivation of cytomegalovirus infection

Aim. To evaluate changes in blood flow in the uterine and umbilical arteries in the second trimester of gestation in women with exacerbation of bronchial asthma associated with reactivation of cytomegalovirus infection (CMVI).Materials and methods. Using Doppler analysis, 115 patients were examined at 21-24 weeks of pregnancy, uncomplicated and complicated by exacerbation of mild to moderate asthma of cytomegalovirus etiology. The first group was represented by 30 seronegative women with uncomplicated pregnancy. The second group included 30 patients with mild asthma in the stage of exacerbation associated with CMVI, leading to chronic compensated placental insufficiency. The third group consisted of 30 patients with exacerbation of moderate asthma caused by CMVI reactivation, which initiated the development of chronic compensated placental insufficiency. The fourth group consisted of 25 women with moderate asthma in the acute stage against the background of the acute phase of CMVI, leading to the formation of chronic subcompensated placental insufficiency.Results. In women in the second group, in comparison with the first group, the following changes were determined: in the right uterine artery, the systolic-diastolic ratio (SDR) was, respectively, 2.75±0.07 and 2.04±0.03 rel. units (р<0.001), pulsation index (PI) – 1.15±0.04 and 0.76±0.02 rel. units (p<0.001), resistance index (RI) – 0.63±0.01 and 0.51±0.01 rel. units (p<0.001); in the left uterine artery, SDR was, respectively, 2.84±0.09 and 1.98±0.05 rel. units (p<0.001), PI – 1.20±0.05 and 0.74±0.03 rel. units (p<0.001), RI – 0.64±0.01 and 0.49±0.01 rel. units (p<0.001); in the absence of statistically significant differences in the indicators of SDR in the umbilical artery – 3.62±0.09 and 3.41±0.06 rel. units, respectively (р>0.05), PI – 1.23±0.03 and 1.19±0.03 rel. units (p>0.05) and RI – 0.73±0.01 and 0.70±0.01 rel. units (p>0.05). In the third group, in comparison with the second one, vascular resistance did not differ significantly in the right, left uterine arteries and the umbilical cord artery. In patients of the fourth group, in contrast to the third one, higher values of resistance to blood flow were observed: in the right uterine artery – SDR (3.41±0.07 and 2.87±0.07 rel. units, p<0.001), PI (1.48±0.07 and 1.18±0.03 rel. units, p<0.001), RI (0.70±0.01 and 0.65±0.01 relative units, p<0.001); in the left uterine artery – SDR (3.33±0.11 and 2.88±0.09 rel. units, p<0.01), PI (1.45±0.05 and 1.19±0.05 rel. units, p<0.001), RI (0.70±0.01 and 0.68±0.01 rel. units, p<0.01); and also in the umbilical artery – SDR (4.39±0.13 and 3.65±0.12 rel. units, p<0.001), PI (1.45±0.04 and 1.24±0.03 rel. units, p<0.001), RI (0.79±0.01 and 0.72±0.01 rel. units, p<0.001).Conclusion. In the pathogenesis of reduced blood flow in the basin of the uterine and umbilical arteries in women with exacerbation of moderately severe asthma of cytomegalovirus etiology, leading to the development of chronic subcompensated placental insufficiency, compared with uterine cord hemodynamics in asthma in the acute stage, caused by reactivation of CMVI in the second trimester of gestation, which initiates the formation of a chronic compensated form of placental dysfunction in the third trimester of pregnancy, an important role is played by viral stimulation of vasoconstrictor responses.

Exaggerated Pressor And Vasoconstrictor Responses To A Novel Graded Metaboreflex Protocol In Adults With Hypertension

Exaggerated Pressor And Vasoconstrictor Responses To A Novel Graded Metaboreflex Protocol In Adults With Hypertension

Evidence of impaired functional sympatholysis in patients with heart failure with preserved ejection fraction.

Exercising muscle blood flow is reduced in patients with heart failure with a preserved ejection fraction (HFpEF), which may be related to disease-related changes in the ability to overcome sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, (i.e., "functional sympatholysis"). Thus, in 12 patients with HFpEF (69 ± 7 yr) and 11 healthy controls (Con, 69 ± 4 yr), we examined forearm blood flow (FBF), mean arterial pressure (MAP), and forearm vascular conductance (FVC) during rhythmic handgrip exercise (HG) at 30% of maximum voluntary contraction with or without lower-body negative pressure (LBNP, -20 mmHg) to increase SNS activity and elicit peripheral vasoconstriction. SNS-mediated vasoconstrictor responses were determined as LBNP-induced changes (%Δ) in FVC, and the "magnitude of sympatholysis" was calculated as the difference between responses at rest and during exercise. At rest, the LBNP-induced change in FVC was significantly lesser in HFpEF compared with Con (HFpEF: -9.5 ± 5.5 vs. Con: -21.0 ± 8.0%; P < 0.01). During exercise, LBNP-induced %ΔFVC was significantly attenuated in Con compared with rest (HG: -5.8 ± 6.0%; P < 0.05) but not in HFpEF (HG: -9.9 ± 2.5%; P = 0.88). Thus, the magnitude of sympatholysis was lesser in HFpEF compared with Con (HFpEF: 0.4 ± 4.7 vs. Con: -15.2 ± 11.8%; P < 0.01). These data demonstrate a diminished ability to attenuate SNS-mediated vasoconstriction in HFpEF and provide new evidence suggesting impaired functional sympatholysis in this patient group.NEW & NOTEWORTHY Data from the current study suggest that functional sympatholysis, or the ability to adequately attenuate sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, is impaired in patients with heart failure with preserved ejection fraction (HFpEF). These observations extend the current understanding of HFpEF pathophysiology by implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

Diabetic neuropathy results in vasomotor dysfunction of medium sized peripheral arteries.

The effect of the sympathetic nervous system on peripheral arteries causes vasoconstriction when smooth muscle cells in the walls of blood vessels contract, which leads to narrowing of arteries and reduction of the blood flow. To compare sympathetic vasomotor activation of the brachial arteries in healthy subjects and patients with painful diabetic neuropathy; and therefore, to assess whether there is significant vasomotor dysfunction of medium sized arteries in diabetic neuropathy. The study included 41 diabetic neuropathy patients and 41 healthy controls. Baseline diameter and flow rate of the brachial arteries were measured. Then, using a bipolar stimulus electrode, a 10 mA, 1 Hz electrical stimulus was administered to the median nerve at the wrist level for 5 s. The brachial artery diameter and blood flow rate were re-measured after stimulation. In the control group, the median flow rate was 70.0 mL/min prior to stimulation and 35.0 mL/min after stimulation, with a statistically significant decrease (P < 0.001), which is consistent with sympathetic nervous system functioning (vasoconstriction). In the diabetic neuropathy group, median flow rate before the stimulation was 35.0 mL/min. After stimulation, the median flow rate was 77.0 mL/min; thus, no significant decrease in the flow rate was detected. In the control group, the median brachial artery diameter, which was 3.6 mm prior to stimulation, decreased to 3.4 mm after stimulation, and this decrease was also statistically significant (P = 0.046). In the diabetic neuropathy group, the median brachial artery diameter increased from 3.4 mm to 3.6 mm following nerve stimulation. Once again, no narrowing was observed. Our research suggests that diabetic neuropathy results in significant vasomotor dysfunction of medium sized peripheral arteries. Physiological vasoconstriction in response to sympathetic activation is impaired in diabetic neuropathy.

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.

The vasoconstrictor activities of prostaglandin D2 via the thromboxane prostanoid receptor and E prostanoid receptor-3 outweigh its concurrent vasodepressor effect mainly through D prostanoid receptor-1 ex vivo and in vivo

Prostaglandin (PG) D2, a commonly considered vasodilator through D prostanoid receptor-1 (DP1), might also evoke vasoconstriction via acting on the thromboxane (Tx)-prostanoid receptor (the original receptor of TxA2; TP) and/or E prostanoid receptor-3 (one of the vasoconstrictor receptors of PGE2; EP3). This study aimed to test the above hypothesis in the mouse renal vascular bed (main renal arteries and perfused kidneys) and/or mesenteric resistance arteries and determine how the vasoconstrictor mechanism influences the overall PGD2 effect on systemic blood pressure under in vivo conditions. Experiments were performed on control wild-type (WT) mice and mice with deficiencies in TP (TP−/−) and/or EP3 (EP3−/−). Here we show that PGD2 indeed evoked vasoconstrictor responses in the above-mentioned tissues of WT mice, which were however not only reduced by TP−/− or EP3−/−, but also reversed by TP−/−/EP3−/− in some of the above tissues (mesenteric resistance arteries or perfused kidneys) to dilator reactions that were reduced by non-selective DP antagonism. A slight or mild pressor response was also observed with PGD2 under in vivo conditions, and this was again reversed to a depressor response in TP−/− or TP−/−/EP3−/− mice. Non-selective DP antagonism reduced the PGD2-evoked depressor response in TP−/−/EP3−/− mice as well. These results thus demonstrate that like other PGs, PGD2 activates TP and/or EP3 to evoke vasoconstrictor activities, which can outweigh its concurrent vasodepressor activity mediated mainly through DP1, and hence result in a pressor response, although the response might only be of a slight or mild extent.

Novel endovascular transmural technique for pharmacological block of superior cervical ganglion prevents sympathetic-mediated cerebral vasospasm

BackgroundSympathetic-mediated vasoconstriction from the superior cervical ganglion (SCG) is a significant contributor to cerebral vasospasm. Inhibition of the SCG has been shown to improve cerebral blood flow and reverse cerebral...

Posterior Reversible Leucoencephalopathy Syndrome: Case Series, Comments, and Diagnostic Dilemma.

To report a series of patients with clinical and radiological features suggestive of posterior reversible encephalopathy syndrome (PRES) related to diverse etiologies emphasizing its pathophysiological basis. Posterior reversible encephalopathy syndrome (PRES) may present with a broad range of clinical symptoms from headache and visual disturbances to seizure and altered mentation. Typical imaging findings include posterior-circulation predominant vasogenic edema. Although there are many well-documented diseases associated with PRES, the exact pathophysiologic mechanism has yet to be fully elucidated. Generally accepted theories revolve around disruption of the blood-brain barrier secondary to elevated intracranial pressures or endothelial injury induced by ischemia from a vasoconstrictive response to rising blood pressure or toxins/cytokines. While clinical and radiographic reversibility is common, long-standing morbidity and mortality can occur in severe forms. In patients with malignant forms of PRES, aggressive care has markedly reduced mortality and improved functional outcomes. Various factors that have been associated with poor outcome include altered sensorium, hypertensive etiology, hyperglycemia, longer time to control the causative factor, elevated C reactive protein, coagulopathy, extensive cerebral edema, and hemorrhage on imaging. Reversible cerebral vasoconstriction syndromes (RCVS) and primary angiitis of the central nervous system (PACNS) are invariably considered in the differential diagnosis of new cerebral arteriopathies. Recurrent thunderclap headache (TCH), and single TCH combined with either normal neuroimaging, border zone infarcts, or vasogenic edema, have 100% positive predictive value for diagnosing RCVS or RCVS-spectrum disorders. Diagnosis of PRES in some circumstances can be challenging and structural imaging may not be sufficient to distinguish it from other differential diagnostic considerations like ADEM. Advanced imaging techniques, such as MR spectroscopy or positron emission tomography (PET) can provide additional information to determine the diagnosis. Such techniques are more useful to understand the underlying vasculopathic changes in PRES and may answer some of the unresolved controversies in pathophysiology of this complex disease. Eight patients with PRES resulting from different etiologies varying from pre-eclampsia/eclampsia, post-partum headache with seizures, neuropsychiatric systemic lupus erythematosus, snake bite, Dengue fever with encephalopathy, alcoholic liver cirrhosis with hepatic encephalopathy, and lastly reversible cerebral vasoconstriction syndrome (RCVS). Additionally, a diagnostic dilemma between PRES and acute disseminated encephalomyelitis (ADEM) was notable in one patient. Some of these patients did not have or only very transiently had arterial hypertension. PRES may underlie the clinical conundrum of headache, confusion, altered sensorium, seizures, and visual impairment. PRES need not necessarily be always associated with high blood pressure. Imaging findings may also be variable. Both clinicians and radiologists need to familiarize themselves with such variabilities.

Nicotine and Microvascular Responses in Skeletal Muscle from Acute Exposure to Cigarettes and Vaping.

Despite claims of safety or harm reduction for electronic cigarettes (E-cig) use (also known as vaping), emerging evidence indicates that E-cigs are not likely safe, or necessarily safer than traditional cigarettes, when considering the user's risk of developing vascular dysfunction/disease. E-cigs are different from regular cigarettes in that E-cig devices are highly customizable, and users can change the e-liquid composition (such as the base solution, flavors, and nicotine level). Since the effects of E-cigs on the microvascular responses in skeletal muscle are poorly understood, we used intravital microscopy with an acute (one-time 10 puff) exposure paradigm to evaluate the individual components of e-liquid on vascular tone and endothelial function in the arterioles of the gluteus maximus muscle of anesthetized C57Bl/6 mice. Consistent with the molecular responses seen with endothelial cells, we found that the peripheral vasoconstriction response was similar between mice exposed to E-cig aerosol or cigarette smoke (i.e., 3R4F reference cigarette); this response was not nicotine dependent, and endothelial cell-mediated vasodilation was not altered within this acute exposure paradigm. We also report that, regardless of the base solution component [i.e., vegetable glycerin (VG)-only or propylene glycol (PG)-only], the vasoconstriction responses were the same in mice with inhalation exposure to 3R4F cigarette smoke or E-cig aerosol. Key findings from this work reveal that some component other than nicotine, in inhaled smoke or aerosol, is responsible for triggering peripheral vasoconstriction in skeletal muscle, and that regardless of one's preference for an E-cig base solution composition (i.e., ratio of VG-to-PG), the acute physiological response to blood vessels appears to be the same. The data suggest that vaping is not likely to be 'safer' than smoking towards blood vessels and can be expected to produce and/or result in the same adverse vascular health outcomes associated with smoking cigarettes.

Intrapulmonary arterial contraction assay reveals region-specific deregulation of vasoreactivity to lung injuries.

Intrapulmonary arteries located in the proximal lung differ from those in the distal lung in size, cellular composition, and the surrounding microenvironment. However, whether these structural variations lead to region-specific regulation of vasoreactivity in homeostasis and following injury is unknown. Herein, we employ a two-step method of precision-cut lung slice (PCLS) preparation, which maintains almost intact intrapulmonary arteries, to assess contractile and relaxation responses of proximal preacinar arteries (PaAs) and distal intraacinar arteries (IaAs) in mice. We found that PaAs exhibited robust vasoconstriction in response to contractile agonists and significant nitric oxide (NO)-induced vasodilation. In comparison, IaAs were less contractile and displayed a greater relaxation response to NO. Furthermore, in a mouse model of pulmonary arterial hypertension (PAH) induced by chronic exposure to ovalbumin (OVA) allergen and hypoxia (OVA-HX), IaAs demonstrated a reduced vasocontraction despite vascular wall thickening with the emergence of new αSMA+ cells coexpressing markers of pericytes. In contrast, PaAs became hypercontractile and less responsive to NO. The reduction in relaxation of PaAs was associated with decreased expression of protein kinase G, a key component of the NO pathway, following chronic OVA-HX exposure. Taken together, the PCLS prepared using the modified preparation method enables functional evaluation of pulmonary arteries in different anatomical locations and reveals region-specific mechanisms underlying the pathophysiology of PAH in a mouse model.NEW & NOTEWORTHY Utilizing mouse precision-cut lung slices with preserved intrapulmonary vessels, we demonstrated a location-dependent structural and contractile regulation of pulmonary arteries in health and on noxious stimulations. For instance, chronic ovalbumin and hypoxic exposure increased pulmonary arterial pressure (PAH) by remodeling intraacinar arterioles to reduce vascular wall compliance while enhancing vasoconstriction in proximal preacinar arteries. These findings suggest region-specific mechanisms and therapeutic targets for pulmonary vascular diseases such as PAH.

The Effect Of Relaxation Education To Reduce Pain In Post-Operative Patients

Pain can provide a peripheral vasoconstriction response which causes blood pressure and pulse to rise. Providing relaxation to post-operative patients can reduce post-operative pain. Relaxation education often proves effective in reducing pain levels in post-operative patients. Relaxation techniques such as deep breathing, meditation, and visualization can help reduce the physical and emotional tension that is often associated with pain. Apart from reducing physical pain, relaxation education can also improve the patient's psychological well-being. Patients can feel calmer, better able to deal with stress, and better able to control reactions to pain. By reducing pain levels, patients may require smaller amounts of pain medication or may not need medication at all. This can reduce the risk of side effects from painkillers and speed up the patient's recovery. By reducing pain and stress levels, relaxation education can help speed up the recovery process for post-operative patients. After this community service activity, patients feel more comfortable and are better able to move, which can help reduce the risk of post-operative complications.

A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES

Objective: Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity. Design and method: We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus. Results: 100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P &lt; 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P &lt; 0.01). Conclusions: A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.

Effect of obesity on the vascular response to sympathetic activation during hypoxia in female participants

Background: Activation of the sympathetic nervous system causes vasoconstriction and an acute reduction in peripheral blood flow. However, during hypoxia, sympathetically-mediated vasoconstriction is attenuated in young females without obesity. Given sustained increases in sympathetic activity associated with obesity may create a greater propensity to vasoconstrict in response to sympathetic activation, we sought to examine the effect of obesity on the vascular response to sympathetic activation during hypoxia. We hypothesized sympathetically-mediated vasoconstriction during hypoxia would be greater in premenopausal female adults with obesity when compared to females without obesity. Methods: Blood pressure (BP, finger photoplethysmography) and forearm blood flow (FBF, venous occlusion plethysmography) were assessed in premenopausal female adults with obesity (n=5, 25±3 yrs, 37±1 kg/m2, 48±1% body fat) and without obesity [n=19, 23±1 yrs, 23±1 kg/m2, (33±2% body fat, n=8)]. Data were combined from two cohorts (IRB #2022525, 2011312) to test present hypotheses. Participants completed two trials consisting of a 2-min cold pressor test (CPT) during baseline normoxia (98±1% SpO2) and following 3-5 min of steady-state hypoxia (0.10±0.01 FiO2, 82±1% SpO2). FBF was normalized for BP (forearm vascular conductance, FVC) and a change in FVC during the last 1-min of CPT was calculated (ΔFVC). The main effect of group (obese, non-obese), condition (normoxia, hypoxia) and the interaction of group and condition were compared using a two-way repeated measures ANOVA. Results: In female participants without obesity, ΔFVC during normoxia was attenuated during hypoxia (-0.57±0.19 vs +0.36±0.34 mL/dL/100mmHg/min; p=0.009). Conversely, in female participants with obesity, ΔFVC during normoxia did not differ from the response during hypoxia (-0.31±0.46 vs -0.87±0.34 mL/dL/100mmHg/min; p=0.382). Group differences in ΔFVC were not observed during normoxia (p=0.657), but were present during hypoxia (p=0.039). Conclusion: Sympathetically-mediated vasoconstriction is attenuated during steady-state hypoxia in premenopausal females without obesity, whereas this response is not observed in female adults with obesity. These preliminary data advance our understanding of the impact of obesity on hypoxic vascular control in premenopausal female participants and have implications for conditions in which hypoxia and sympathetic activation are observed ( e.g., sleep apnea, heart failure, COVID-19). NIH HL130339 (JKL), NIH HL153523 (JKL), AHA 909014 (DWJ) This is the full abstract presented at the American Physiology Summit 2023 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.

Hydration as a modulator of renal vascular control during physical work in the heat

Occupational heat stress increases the risk of developing kidney injury (KI), which is due to the development of hyperthermia and/or hypohydration. It is speculated that this KI is caused by a relative mismatch in oxygen supply (i.e., reductions in renal perfusion) and demand (due to increased sodium reabsorption) in the renal tubules. That said, the modulatory role of hydration on renal vascular control during physical work in the heat is largely unknown. Recent observations indicate that ad lib drinking largely prevents hypohydration during simulated occupational heat stress. Thus, we tested the hypothesis that, compared to ad libitum drinking, fluid restriction induces a pro-vasoconstrictor state in the renal vasculature during physical work in the heat.On two occasions, six healthy adults (1 woman) completed 2 h of exercise in a wet bulb globe temperature of 30±0°C, conditions that are commonly experienced by U.S. outdoor workers. Exercise consisted of completing eight circuits involving treadmill walking (10 min) and rowing (5 min) at a workload eliciting an oxygen uptake of 1.2 L/min, the work intensity observed during agriculture work. In the drinking trial (Drink), subjects were provided 237 mL of sport drink every 15 min and drank ad libitum, which is compliant with workplace hydration recommendations. In the fluid restriction trial (NoDrink), no fluid was provided. Rectal temperature and body mass loss were recorded in each trial. Blood pressure and right renal segmental blood velocity (BV, Doppler ultrasound) was measured before, and following 60 and 120 min of exercise. Before and following exercise, a cold pressor test (CPT) was used to assess the renal vasoconstrictor response to sympathetic activation by immersing the subject’s foot in an agitated ice slurry for 2 min. Blood pressure and segmental BV were measured during each minute of the CPT. Segmental artery vascular resistance (VR) was calculated as mean arterial pressure divided by segmental BV. Data presented as mean ± SD.Average rectal temperature was not different between Drink (37.8±0.4°C) and NoDrink (37.9±0.4°C, p=0.517). Body mass loss was greater in NoDrink (3.1±0.7%) vs. Drink (1.8±0.8%, p=0.014). Segmental BV did not change differently between trials (interaction: p=0.651). Segmental VR did not differ between trials before (Drink: 2.7±0.6, NoDrink: 2.5±0.6 mmHg/cm/s) or after 60 (Drink: 2.8±0.7, NoDrink: 2.6±0.6 mmHg/cm/s) and 90 (Drink: 2.5±0.3, NoDrink: 2.3±0.8 mmHg/cm/s) min of exercise (interaction: p=0.988). Peak increases in segmental VR during the CPT did not differ between trials before (Drink: 0.5 ± 0.7, NoDrink: 0.9 ± 0.6 mmHg/cm/s) or after (Drink: 0.4 ± 0.7, NoDrink: 0.4 ± 0.6 mmHg/cm/s) exercise (interaction: p=0.405).These findings preliminarily indicate that fluid replacement does not modify renal vascular control during physical work in the heat. NCT: NCT05458843. Supported by: R01OH011528 This is the full abstract presented at the American Physiology Summit 2023 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.

Toll-like receptor 4 activation contributes to systemic vascular dysfunction in pregnant rats fed a high cholesterol diet during pregnancy

Background: Hypercholesterolemia is a hallmark clinical feature of cardiovascular diseases. Vascular adaptations to pregnancy include withstanding pregnancy-induced hypercholesterolemia, a physiological process required for fetus development. However, excessive (pathological) hypercholesterolemia during pregnancy has been linked to an increased risk of complications (e.g., preeclampsia); still, the underlying mechanisms are unclear. Toll-like receptor 4 (TLR4) is an innate immune receptor modulated by high cholesterol levels (in non-pregnant animals), but whether TLR4 activation also plays a role in vascular dysfunction in pregnancies complicated with hypercholesterolemia is unknown. Hypothesis: Pathological hypercholesterolemia during pregnancy causes maternal vascular dysfunction via activation of TLR4. Methods: Sprague Dawley rats were fed a standard (CD) or high cholesterol diet (HCD; 2% cholesterol and 0.5% cholic acid) from gestational day (GD) 6 to GD20 (term=22 days; n=9-10). Blood pressure was assessed before pregnancy and on GD19, and the results are presented as delta change. On GD20, body weight and pregnancy outcomes were recorded, and mesenteric arteries (systemic resistance arteries) were assessed using wire myography to evaluate vasoconstriction capacity to phenylephrine and endothelial-dependent vasodilation responses to methacholine. Experiments were conducted in the presence or absence of L-NAME (a pan-NOS inhibitor, 100 mmol/l) and/or CLI-095 (a TLR4 inhibitor, 10 mmol/l). Functional data were summarized as Emax (maximum response) or pEC50 (concentration required to produce 50% of Emax). Statistics: Student’s t-test or two-way ANOVA with Sidak post hoc test (significance: p&lt;0.05). Results: The HCD prevented the late gestation systolic (p=0.0004) and diastolic (p=0.0066) blood pressure reduction observed in the CD group, and impaired male (p=0.0062) and female (p=0.0352) fetoplacental efficiency. Total body weight gain during pregnancy was not different between CD and HCD dams (p&gt;0.05). In mesenteric arteries, vasoconstriction responses to phenylephrine (Emax) were increased in HCD dams (p=0.0056), and TLR4 inhibition with CLI-095 reduced the sensitivity (pEC50) of phenylephrine in these vessels (p=0.0147). Additionally, HCD dams presented higher sensitivity (pEC50) to methacholine (p=0.0169), which was not modified by the TLR4 inhibitor (p&gt;0.05). Incubation of arteries with L-NAME abolished the increased sensitivity to methacholine (p&gt;0.05), which was not further altered by CLI-095 (p&gt;0.05). Conclusion: Inhibition of TLR4 ( ex vivo) reduced the enhanced vasoconstriction observed in HCD dams but did not alter endothelial-dependent vasodilation responses. Thus, if inhibiting TLR4 could block the vasoconstrictor effects of excessive hypercholesterolemia during pregnancy, this may be a target for future therapy development. This work was supported by a foundation grant from CIHR (FS154313) and by the generosity of the Stollery Children's Hospital Foundation and the Alberta Women's Health Foundation through the Women and Children's Health Research Institute (WCHRI). This is the full abstract presented at the American Physiology Summit 2023 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.

Autonomic control of heart and vessels in patients with very early stage of Parkinson disease

Objective. Non-motor symptoms including those reflecting autonomic cardiovascular dysregulation are often present in Parkinson disease. It is unclear whether it is possible to detect cardiovascular autonomic dysregulation in the very early stage of Parkinson disease potentially supporting the concept of the upstream propagation of nervous system damage through autonomic nerves. We hypothesized that cardiovascular dysregulation should precede the motor symptoms and at the time of their occurrence autonomic dysregulation should be clearly demonstrable. Therefore, the aim of this study was to assess the various aspects of autonomic cardiovascular control in the very early stage of Parkinson disease. Approach. We performed prospective case-control study on 19 patients with Parkinson disease (<6 months after motor signs occurrence) and 19 healthy control subjects. For each phase of study protocol (supine, head-up tilt, supine recovery), we calculated a wide array of cardiovascular control related parameters reflecting cardiac chronotropic, cardiac inotropic and vasomotor control and baroreflex mediated cardiovascular response. Main results. We observed the well-preserved heart rate and blood pressure control in patients with early stage of Parkinson disease. However, causal analysis of interactions between heart rate and blood pressure oscillations revealed subtle differences in baroreflex function and baroreflex mediated vasoconstriction response to orthostasis. Furthermore, a tendency towards a decreased contraction strength in Parkinson disease was observed. Significance. Considering only subtle cardiovascular control impairment in our study employing a wide array of sensitive methods at the time when motor signs were clearly expressed, we suggest that motor signs dominated in this stage of Parkinson disease.

The Acute Effect of Trimethylamine-N-Oxide on Vascular Function, Oxidative Stress, and Inflammation in Rat Aortic Rings.

A growing body of evidence suggests that the gut microbiota affects the cardiovascular system directly and indirectly via biologically active molecules. TMAO, a key metabolite produced by gut bacteria is implicated in atherosclerosis and chronic endothelial dysfunction, but with an unclear effect on vascular tone, oxidative stress, and inflammation. Our study aimed to evaluate the acute effects of TMAO on vascular contractility in relation with oxidative stress markers and inflammation. Aortic rings were harvested from laboratory rats and placed in a tissue bath system containing TMAO in concentrations of 300, 100, 10µM, and control. Vascular tone under the influence of vasoconstrictor phenylephrine and non-endothelial-dependent vasodilator sodium nitroprusside was assessed using force transducers connected to a computer-based acquisition system. Oxidative stress and inflammation were quantified by vascular assessment of the activity of NF-κB, NRF2, SOD1, and iNOS by western-blotting and MDA by spectrofluorimetry. After the incubation of the aortic rings in TMAO solutions for 1h, there was no difference in vasoconstrictor and non-endothelial vasodilator response between the studied doses. TMAO acutely induced oxidative stress and inflammation, significantly increasing levels of MDA and the expression of NF-κB, NRF2, SOD1, and iNOS, mostly in a dose-dependent manner. Our study showed the lack of a short-term effect of studied TMAO doses on vascular contractility, but demonstrated an acute prooxidative effect and activation of major inflammatory pathways, which can partially explain the detrimental effects of TMAO in cardiovascular disease.