Arteriolar Vasoconstriction Research Articles

The Paradise Renal Denervation System: An FDA-approved catheter-based treatment option for resistant hypertension

Resistant hypertension is defined as office blood pressure >140/90 mm Hg with a mean 24-hour ambulatory blood pressure of >130/80 mm Hg in patients who are compliant with 3 or more antihypertensive medications. Those who persistently fail pharmaceutical therapy may benefit from interventional treatment, such as renal denervation. Sympathetic nervous activity in the kidney is a known contributor to increased blood pressure because it results in efferent and afferent arteriole vasoconstriction, reduced renal blood flow, increased sodium and water reabsorption, and the release of renin. The Recor Paradise Renal Denervation System is designed to target renal sympathetic nerves via ultrasound ablation. The RADIANCE trials have demonstrated that patients who underwent renal denervation had a significant decrease in systolic blood pressure as compared with those who underwent a sham procedure. Furthermore, the device was found to have a favorable safety profile, with minimal major adverse events. The Food and Drug Administration granted approval to Recor, and the Paradise system is expected to serve as an adjunctive therapy for patients with true-resistant hypertension.

Angiotensin II as a Vasopressor for Perioperative Hypotension in Solid Organ Transplant.

During the perioperative period of transplantation, patients experience hypotension secondary to the side effects of anesthesia, surgical stress, inflammatory triggering, and intraoperative fluid shifts, among others causes. Vasopressor support, in this context, must reverse systemic hypotension, but ideally, the agents used should benefit allograft function and avoid the adverse events commonly seen after transplantation. Traditional therapies to reverse hypotension include catecholamine vasopressors (norepinephrine, epinephrine, dopamine, and phenylephrine), but their utility is limited when considering allograft complications and adverse events such as arrhythmias with agents with beta-adrenergic properties. Synthetic angiotensin II (AT2S-[Giapreza]) is a novel vasopressor indicated for distributive shock with a unique mechanism of action as an angiotensin receptor agonist restoring balance to an often-disrupted renin angiotensin aldosterone system. Additionally, AT2S provides a balanced afferent and efferent arteriole vasoconstriction at the level of the kidney and could avoid the arrhythmic complications of a beta-adrenergic agonist. While the data, to date, are limited, AT2S has demonstrated safety in case reports, pilot studies, and small series in the kidney, liver, heart, and lung transplant populations. There are physiologic and hemodynamic reasons why AT2S could be a more utilized agent in these populations, but further investigation is warranted.

Treatment of Hypotension with Phenylephrine Increases Cerebral Microvascular Perfusion in a Rat Model of Acute Hemodilution

Intraoperative blood loss is associated with reduced mean arterial blood pressure (MAP), which may endanger vital organ perfusion, including the brain. Phenylephrine (PE), an α1-receptor agonist, is clinically utilized to treat intraoperative hypotension through vasoconstriction of resistance arterioles. Clinical studies suggest that raising MAP with PE may decrease perfusion to vital organs such as the brain. Experimental studies suggest that lower α-receptor density in the cerebral resistance arteries may lead to preserved brain perfusion after PE administration. We hypothesize that treatment of hypotension with PE will result in preserved brain perfusion due to different microvascular blood flow and tissue oxygen tension (pO2) responses in the brain and skeletal muscle in an experimental rat model. With Animal Care and Use Committee approval in accordance with ARRIVE-2 guidelines, spontaneously breathing anesthetized rats (1.5% isoflurane) underwent hemodilution by exchanging 40-50% estimated blood volume 1:1 with saline over 10 minutes to achieve a 10-20 mmHg drop in MAP. MAP (tail artery) was measured continuously. Hypotension was treated with PE (10-20 μg/kg/min iv) to increase MAP to a target above baseline MAP. Shed blood was re-infused after stopping the PE infusion. Microvascular blood flow (Oxyflo; Oxford Optronix, Oxford, UK, n=7) or microvascular pO2 (OxyLED, Oxyphor G4, Oxygen Enterprises Ltd., Philadelphia, PA, n=6) were measured continuously in the cerebral cortex (burr hole) and biceps femoris muscle simultaneously in each rat. Results were analyzed via one or two-way ANOVA, with significance achieved at p<0.05. Baseline and post-hemodilution MAP values were comparable in both groups. PE infusion increased MAP to a mean level near 100 mmHg in both groups (p<0.05). Microvascular blood flow and tissue pO2 were greater in the brain as compared to the muscle at all time points (p<0.01 for both). PE infusion resulted in an increase in cerebral microvascular blood flow from baseline (1465±689 vs. 687±453 blood perfusion units (BPU); p<0.001) that was sustained after discontinuing PE and during blood reinfusion. No changes in muscle microvascular flow were observed after PE infusion (294±129 vs. 168±113 BPU). A sustained increase in cerebral microvascular pO2 was measured following PE infusion (50.2±8.6 vs. 40.6±4.6 mmHg; p=0.02), whereas muscle tissue pO2 did not change (22.2±5.6 vs. 25.0±2.5 mmHg). A differential blood flow and microvascular pO2 response was observed following PE infusion in brain and skeletal muscle. Both cerebral microvascular blood flow and tissue pO2 demonstrated sustained increases after PE infusion. By contrast, no changes were observed in muscle microvascular blood flow and pO2. These results suggest that treatment of hypotension with PE administration preferentially increased cerebral vs. muscle perfusion in an experimental model of acute blood loss and fluid resuscitation. Canadian Anesthesiologists’ Society and University of Toronto Merit Award Support. 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.

Recombinant soluble form of receptor for advanced glycation end products ameliorates microcirculation impairment and neuroinflammation after subarachnoid hemorrhage

Impaired cerebral microcirculation after subarachnoid hemorrhage (SAH) has been shown to be related to delayed ischemic neurological deficits (DIND). We previously demonstrated the involvement of the receptor for advanced glycation end products (RAGE) in the pathogenesis of SAH related neuronal death. In the present study, we aimed to investigate the therapeutic effects of a recombinant soluble form of RAGE (sRAGE) on microcirculation impairment following SAH. Intrathecal injection of autologous blood in rats, mixed primary astrocyte and microglia cultures exposed to hemolysates and endothelial cells ​(ECs) from human brain microvascular exposed to glia-conditioned medium or SAH patient's CSF were used as experimental SAH models in vivo and in vitro. The results indicated that intrathecal administration of recombinant sRAGE significantly ameliorated the vasoconstriction of cortical arterioles and associated perfusion impairment, brain edema, reduced cell death, endothelial dysfunction, and improved motor performance at 24 and 48 ​h after SAH induction in rats. The in vitro results further showed that recombinant sRAGE significantly reduced astrocyte swelling and microglia activation, in parallel with decreased mRNA expression levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-1β (IL-1β) in vitro. Moreover, the in vitro model of SAH-induced p-eNOS and eNOS suppression, along with stress fiber formation in brain microvascular ECs, was effectively reversed by sRAGE treatment and led to a decrease in cleaved-caspase 3 expression. In summary, recombinant sRAGE effectively lessened microcirculation impairment and vascular injury after SAH via the mechanism of anti-inflammation, which may provide a potential therapeutic strategy for SAH.

Особенности изменения гидродинамического сопротивления в сосудах микроциркуляторного русла легких при COVID-19 по результатам морфометрического исследования

Introduction. The nature of damage to the body in COVID-19 is of major interest; however, the cardiac mechanisms of death have not been fully studied. The causes of deaths from CVDs require a search for heart failure mechanisms, one of which is an increased burden on the right ventricle due to changes in the affected pulmonary blood vessels. The aim was to assess changes in hydrodynamic resistance in the pulmonary microvasculature in accordance with the variant of the prevailing pathological process in them and the COVID-19 phase. Materials and methods. We performed clinical and morphological analyses of 20 lethal cases with the primary diagnosis of coronavirus infection caused by SARS-CoV-2. We used morphometry to measure the internal diameter of arterioles and venules, the specific capillary area (SCA), and the total radius of the capillary bed. The vascular radius formed the basis for calculating the hydrodynamic resistance in the sections of the microvasculature of the pulmonary circulation. Results. The exudation phase is accompanied by an increased lumen of arterioles and venules against the background of a decreased specific density of the capillary bed. In the early proliferation phase, the capillary bed reduces significantly, and dilatation is replaced by spastic manifestations in arterioles and, to a lesser extent, in venules. The late proliferative phase has similar reduction levels in the total capillary radius and the degree of vasoconstriction of arterioles especially in the zone of increased airiness and grown connective tissue. Conclusion. The reduced capillary bed is of primary importance in increasing the calculated hydrodynamic resistance in the lung tissue during COVID-19. The growth in the average calculated hydrodynamic resistance in the lung tissue occurs to a greater extent during the proliferative phases (early and late) of COVID-19 infection. Keywords: COVID-19, SARS-CoV-2, lungs, vessels

EXCHANGE TRANSFUSION WITH VS -101: A NEW PEGYLATED-HB DESIGNED TO RESTORE PERFUSION AND INCREASE O 2 CARRYING CAPACITY.

Blood products are the current standard for resuscitation of hemorrhagic shock. However, logistical constraints of perishable blood limit availability and prehospital use, meaning alternatives that provide blood-like responses remain an area of active investigation and development. VS-101 is a new PEGylated human hemoglobin-based oxygen carrier that avoids the logistical hurdles of traditional blood transfusion. This study sought to determine the safety and ability of VS -101 to maintain circulatory function and capillary oxygen delivery in a severe (50%) exchange transfusion (ET) model. Anesthetized, male Sprague Dawley rats were prepared for cardiovascular monitoring and phosphorescence quenching microscopy of interstitial fluid oxygen tension (P ISFo2 ) in the spinotrapezius muscle. Fifty-percent isovolemic ET of estimated total blood volume with either lactated Ringer's solution (LRS, n = 8) or VS -101 (n = 8) at 1 mL/kg/min was performed, and animals were observed for 240 min. VS -101 maintained P ISFo2 at baseline with a transient 18 ± 4 mm Hg decrease ( P < 0.05) in mean arterial pressure (MAP). In contrast, ET with LRS decreased P ISFo2 by approximately 50% ( P < 0.05) and MAP by 74 ± 10 mm Hg ( P < 0.05). All VS -101 animals survived 240 min, the experimental endpoint, while 100% of LRS animals expired by 142 min. VS -101 animals maintained normal tissue oxygenation through 210 min, decreasing by 25% ( P < 0.05 vs. baseline) thereafter, likely from VS -101 vascular clearance. No arteriolar vasoconstriction was observed following VS -101 treatment. In this model of severe ET, VS -101 effectively maintained blood pressure, perfusion, and P ISFo2 with no vasoconstrictive effects. Further elucidation of these beneficial resuscitation effects of VS -101 is warranted to support future clinical trials.

Dopamine and noradrenaline activate spinal astrocyte endfeet via D1-like receptors.

Astrocytes, the most abundant glial cells in the central nervous system, respond to a wide variety of neurotransmitters binding to metabotropic receptors. Here, we investigated the intracellular calcium responses of spinal cord astrocytes to dopamine and noradrenaline, two catecholamines released by specific descending pathways. In a slice preparation from the spinal cord of neonatal mice, puff application of dopamine resulted in intracellular calcium responses that remained in the endfeet. Noradrenaline induced stronger responses that also started in the endfeet but spread to neighbouring compartments. The intracellular calcium responses were unaffected by blocking neuronal activity or inhibiting various neurotransmitter receptors, suggesting a direct effect of dopamine and noradrenaline on astrocytes. The intracellular calcium responses induced by noradrenaline and dopamine were inhibited by the D1 receptor antagonist SCH 23390. We assessed the functional consequences of these astrocytic responses by examining changes in arteriole diameter. Puff application of dopamine or noradrenaline resulted in vasoconstriction of spinal arterioles. However, blocking D1 receptors or manipulating astrocytic intracellular calcium levels did not abolish the vasoconstrictions, indicating that the observed intracellular calcium responses in astrocyte endfeet were not responsible for the vascular changes. Our findings demonstrate a compartmentalized response of spinal cord astrocytes to catecholamines and expand our understanding of astrocyte-neurotransmitter interactions and their potential roles in the physiology of the central nervous system.

Modeling the renoprotective mechanisms of SGLT2 inhibition in hypertensive chronic kidney disease.

Sodium-glucose cotransporter (SGLT)-2 inhibitors have recently been approved for chronic kidney disease (CKD) based on their ability to lower proteinuria and slow CKD progression independent of diabetes status. In diabetic renal disease, modulation of tubuloglomerular feedback (TGF) leading to lower intraglomerular pressure has been postulated as one of the mechanisms of renal protection with SGLT2 inhibition; however, this mechanism has not been sufficiently explored in non-diabetic CKD. We hypothesized that SGLT2 inhibition exerts renoprotection in CKD through increasing TGF despite normoglycemia. To test this hypothesis, we used an integrative mathematical model of human physiology, HumMod. Stage 3 CKD conditions were simulated by reducing nephron mass which was associated with hypertension, low glomerular filtration rate (GFR) (55 mL/min), hyperfiltration of remnant nephrons, elevated albuminuria (500 mg/day), and minimal levels of urinary glucose (0.02 mmol/L). SGLT2 inhibition was associated with acute reductions in GFR associated with afferent arteriolar vasoconstriction due to TGF. After 12 months, glomerular pressure, nephron damage, and chronic GFR decline were reduced with SGLT2 inhibition with additional SGLT1 inhibitory effects further enhancing these effects. This model supports the use of SGLT2 inhibitors to reduce hyperfiltration in CKD and mitigate renal disease progression, even in the absence of diabetes.

Inhibition of cystathionine-gamma lyase dampens vasoconstriction in mouse and human intracerebral arterioles.

In extracerebral vascular beds cystathionine-gamma lyase (CSE) activity plays a vasodilatory role but the role of this hydrogen sulfide (H2 S) producing enzyme in the intracerebral arterioles remain poorly understood. We hypothesized a similar function in the intracerebral arterioles. Intracerebral arterioles were isolated from wild type C57BL/6J mouse (9-12 months old) brains and from human brain biopsies. The function (contractility and secondary dilatation) of the intracerebral arterioles was tested ex vivo by pressure myography using a perfusion set-up. Reverse transcription polymerase chain reaction was used for detecting CSE expression. CSE is expressed in human and mouse intracerebral arterioles. CSE inhibition with L-propargylglycine (PAG) significantly dampened the K+ -induced vasoconstriction in intracerebral arterioles of both species (% of maximum contraction: in human control: 45.4 ± 2.7 versus PAG: 27 ± 5.2 and in mouse control: 50 ± 1.5 versus PAG: 33 ± 5.2) but did not affect the secondary dilatation. This effect of PAG was significantly reversed by the H2 S donor sodium hydrosulfide (NaSH) in human (PAG + NaSH: 38.8 ± 7.2) and mouse (PAG + NaSH: 41.7 ± 3.1) arterioles, respectively. The endothelial NO synthase (eNOS) inhibitor, Nω-Nitro-l-arginine methyl ester (L-NAME), and the inhibitor of soluble guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reversed the effect of PAG on the K+ -induced vasoconstriction in the mouse arterioles and attenuated the K+ -induced secondary dilatation significantly. CSE contributes to the K+ -induced vasoconstriction via a mechanism involving H2 S, eNOS, and sGC whereas the secondary dilatation is regulated by eNOS and sGC but not by CSE.

Nonatherosclerotic Renovascular Hypertension.

Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the renin-angiotensin-aldosterone system. Often, this occurs due to abnormally small, narrowed, or blocked blood vessels supplying one or both kidneys (ie: renal artery occlusive disease) and is correctable. Juxtaglomerular cells release renin in response to decreased pressure, which in turn catalyzes the cleavage of circulating angiotensinogen synthesized by the liver to the decapeptide angiotensin I. Angiotensin-converting enzyme then cleaves angiotensin I to form the octapeptide angiotensin II, a potent vasopressor and the primary effector of renin-induced hypertension. The effects of angiotensin II are mediated by signaling downstream of its receptors. Angiotensin receptor type 1 is a G-protein-coupled receptor that activates vasoconstrictor and mitogenic signaling pathways resulting in peripheral arteriolar vasoconstriction and increased renal tubular reabsorption of sodium and water which promotes intravascular volume expansion. Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion. Angiotensin II acts on glial cells and regions of the brain responsible for blood pressure regulation increasing renal sympathetic activation. Angiotensin II simulates the release of vasopressin from the pituitary which stimulates thirst and water reabsorption from the kidney to expand the intravascular volume and cause peripheral vasoconstriction (increased sympathetic tone). All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water.

Interaction of Angiotensin II AT1 Receptors with Purinergic P2X Receptors in Regulating Renal Afferent Arterioles in Angiotensin II-Dependent Hypertension.

In angiotensin II (Ang II)-dependent hypertension, Ang II activates angiotensin II type 1 receptors (AT1R) on renal vascular smooth muscle cells, leading to renal vasoconstriction with eventual glomerular and tubular injury and interstitial inflammation. While afferent arteriolar vasoconstriction is initiated by the increased intrarenal levels of Ang II activating AT1R, the progressive increases in arterial pressure stimulate the paracrine secretion of adenosine triphosphate (ATP), leading to the purinergic P2X receptor (P2XR)-mediated constriction of afferent arterioles. Thus, the afferent arteriolar tone is maintained by two powerful systems eliciting the co-existing activation of P2XR and AT1R. This raises the conundrum of how the AT1R and P2XR can both be responsible for most of the increased renal afferent vascular resistance existing in angiotensin-dependent hypertension. Its resolution implies that AT1R and P2XR share common receptor or post receptor signaling mechanisms which converge to maintain renal vasoconstriction in Ang II-dependent hypertension. In this review, we briefly discuss (1) the regulation of renal afferent arterioles in Ang II-dependent hypertension, (2) the interaction of AT1R and P2XR activation in regulating renal afferent arterioles in a setting of hypertension, (3) mechanisms regulating ATP release and effect of angiotensin II on ATP release, and (4) the possible intracellular pathways involved in AT1R and P2XR interactions. Emerging evidence supports the hypothesis that P2X1R, P2X7R, and AT1R actions converge at receptor or post-receptor signaling pathways but that P2XR exerts a dominant influence abrogating the actions of AT1R on renal afferent arterioles in Ang II-dependent hypertension. This finding raises clinical implications for the design of therapeutic interventions that will prevent the impairment of kidney function and subsequent tissue injury.

Postictal hypoxia involves reactive oxygen species and is ameliorated by chronic mitochondrial uncoupling

Prolonged severe hypoxia follows brief seizures and represents a mechanism underlying several negative postictal manifestations without interventions. Approximately 50% of the postictal hypoxia phenomenon can be accounted for by arteriole vasoconstriction. What accounts for the rest of the drop in unbound oxygen is unclear. Here, we determined the effect of pharmacological modulation of mitochondrial function on tissue oxygenation in the hippocampus of rats after repeatedly evoked seizures. Rats were treated with mitochondrial uncoupler 2,4 dinitrophenol (DNP) or antioxidants. Oxygen profiles were recorded using a chronically implanted oxygen-sensing probe, before, during, and after seizure induction. Mitochondrial function and redox tone were measured using in vitro mitochondrial assays and immunohistochemistry. Postictal cognitive impairment was assessed using the novel object recognition task. Mild mitochondrial uncoupling by DNP raised hippocampal oxygen tension and ameliorated postictal hypoxia. Chronic DNP also lowered mitochondrial oxygen-derived reactive species and oxidative stress in the hippocampus during postictal hypoxia. Uncoupling the mitochondria exerts therapeutic benefits on postictal cognitive dysfunction. Finally, antioxidants do not affect postictal hypoxia, but protect the brain from associated cognitive deficits. We provided evidence for a metabolic component of the prolonged oxygen deprivation that follow seizures and its pathological sequelae. Furthermore, we identified a molecular underpinning of this metabolic component, which involves excessive oxygen conversion into reactive species. Mild mitochondrial uncoupling may be a potential therapeutic strategy to treat the postictal state where seizure control is absent or poor.

Effects of pupil dilation with topical 0.5% tropicamide on retinal vascular parameters assessed by VAMPIRE® software in healthy cats

Our study investigates the effects of mydriasis obtained with topical 0.5% tropicamide on retinal vascular parameters evaluated in cats using the retinal imaging software: Vascular Assessment and Measurement Platform for Images of the Retina (VAMPIRE®). Forty client-owned healthy adult cats were included in the study. Topical 0.5% tropicamide was applied to dilate only the right pupil. The left eye was used as a control. Before dilation (T0), infrared pupillometry of both pupils was performed and fundus oculi images were taken from both eyes. Right eye fundus images were then captured 30 min after topical application of tropicamide (T30), when mydriasis was achieved. The retinal vessel widths (3 arteries and 3 veins) were measured with VAMPIRE® in four standard measurement areas (SMA) identified with the letters A, B, C, D. Average value of the 3 vessel widths was used. After normality assessment, the t-test was used to analyse the mean difference in vascular parameters of the left and right eyes at T0 and T30, with p set <0.05. The two eyes showed no statistical differences in pupil and vascular parameter measurements at T0. At T30, only one artery measurement of the right eye (SMA A-peripapillary area) showed a small but statistically significant mean vasoconstriction of approximately 4%. The results indicate that local application of 0.5% tropicamide seems to be associated with a small retinal arteriolar vasoconstriction as assessed by VAMPIRE® in cats. However, this change is minimal, and should not affect the interpretation of the results when VAMPIRE® is used.

Mitochondria and renal microvascular dysfunction following ischemia-reperfusion in rats

The pathophysiological mechanisms underlying ischemia-reperfusion (IR) induced acute kidney injury (AKI) remain poorly understood. Preglomerular microvessels (PGMV), specifically afferent arterioles, possess an intrinsic autoregulatory ability that is vital for ensuring stable renal hemodynamics. Our recent study indicates that renal autoregulation is impaired in IR rats due to reactive oxygen species (ROS) accumulation. We hypothesized that mitochondria-derived ROS (mtROS) in preglomerular microvessels contribute to renal autoregulatory impairment in IR rats. Blood-perfused juxtamedullary nephron experiments were performed on kidneys of male Sprague-Dawley rats 24 hours after IR induction (60-min, bilateral renal artery clamping). Afferent arteriolar autoregulation was assessed as perfusion pressure (PP) was increased from 65 to 170 mmHg in 15 mmHg increments. Afferent arterioles of sham-operated control rats (n=7) established pressure-mediated autoregulatory responses. Baseline diameter (100 mmHg) averaged 13.2±0.4 μm and increased to 114±4% of baseline when PP decreased from 100 to 65 mmHg. Diameter decreased to 65±3% of baseline when PP increased to 170 mmHg. In contrast, afferent arterioles from IR rats lost autoregulatory capability and remained between 90 and 100% of baseline diameter over 65-170 mmHg (n=8). Addition of Mito-Tempo (mitochondria-targeted antioxidant, 0.1 mM, n=3) to the perfusate restored autoregulation in IR rats at lower PP (65-125 mmHg, P&gt;0.05 vs sham) and partially restored it over 140-170 mmHg. Superfusion with oligomycin (ATP synthase inhibitor, 2.5 μM) in normal kidneys evoked vasodilation to 178±13% baseline and blunting of autoregulatory reactivity. Renal autoregulation is linked to ATP-sensitive P2X1-receptor signaling. Changes in ATP-induced intracellular calcium concentration ([Ca2+]i) were assessed in isolated PGMV myocytes using Fura-2 fluorescent dye. IR markedly attenuated [Ca2+]i responses to 10 and 100 μM ATP by 46±11% and 57±15%, respectively (P&lt;0.05, n=3-4 rats/group), and blunted ATP-induced afferent arteriolar vasoconstriction ( P&lt;0.05 vs. sham, n=3/group). IR markedly increased the fluorescence intensity of mitoROS (MitoSOX™ kit) in PGMV compared to sham rats. Mitochondrial respiratory function was assessed using High Resolution Respirometry in freshly isolated PGMV (n=3/group). IR significantly reduced basal respiration (20±4 vs. 58±9 pmol/s·ml in sham, P&lt;0.05) and oxidative phosphorylation capacity (51±10 vs. 219±37 pmol/s·ml in sham, P&lt;0.05). The percentage of ATP-linked respiration was also reduced in PGMV of IR (60±2% vs. 75±2% in sham, P&lt;0.05). In conclusion, mitochondria of PGMV are involved in regulating renal microvascular tone and autoregulation. IR leads to autoregulatory dysfunction by causing mitochondrial dysfunction in PGMV, increased mtROS production and suppression of ATP-dependent calcium signaling. This study is supported by grants R01DK106500. 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.

In vivo photoacoustic monitoring of vasoconstriction induced by acute hyperglycemia

Postprandial hyperglycemia, blood glucose spikes, induces endothelial dysfunction, increasing cardiovascular risks. Endothelial dysfunction leads to vasoconstriction, and observation of this phenomenon is important for understanding acute hyperglycemia. However, high-resolution imaging of microvessels during acute hyperglycemia has not been fully developed. Here, we demonstrate that photoacoustic microscopy can noninvasively monitor morphological changes in blood vessels of live animals’ extremities when blood glucose rises rapidly. As blood glucose level rose from 100 to 400 mg/dL following intraperitoneal glucose injection, heart/breath rate, and body temperature remained constant, but arterioles constricted by approximately –5.7 ± 1.1% within 20 min, and gradually recovered for another 40 min. In contrast, venular diameters remained within about 0.6 ± 1.5% during arteriolar constriction. Our results experimentally and statistically demonstrate that acute hyperglycemia produces transitory vasoconstriction in arterioles, with an opposite trend of change in blood glucose. These findings could help understanding vascular glucose homeostasis and the relationship between diabetes and cardiovascular diseases.

Renal blood flow during exercise: understanding its measurement with Doppler ultrasound.

The sympathetic nervous system (SNS) has a critical role in continuously coordinating responses to stimuli internal and external to the human body by appropriately modulating the activity of the organs it innervates. The SNS is activated in response to various physiological stressors, including exercise, which can involve a significant increase in SNS activity. An increase in SNS activity directed toward the kidneys causes vasoconstriction of afferent arterioles within the kidneys. This sympathetically mediated renal vasoconstriction decreases renal blood flow (RBF), causing significant blood flow redistribution toward active skeletal muscles during exercise. In research studies, different modes, intensities, and durations of exercise have been used to investigate the sympathetically mediated RBF response to exercise, and several methodological approaches have been used to quantify RBF. Doppler ultrasound provides noninvasive, continuous, real-time measurements of RBF and has emerged as a valid and reliable technique to quantify RBF during exercise. This innovative methodology has been applied in studies in which the RBF response to exercise has been examined in healthy young and older adults and patient populations such as those with heart failure and peripheral arterial disease. This valuable tool has enabled researchers to produce clinically relevant findings that have furthered our understanding of the effect of SNS activation on RBF in populations of health and disease. Therefore, the focus of this narrative review is to highlight the use of Doppler ultrasound in research studies that have provided important findings furthering our knowledge of the impact of SNS activation on RBF regulation in humans.

Alterations in Retinal Vessel Diameters in Patients with Retinal Vein Occlusion before and after Treatment with Intravitreal Ranibizumab

Purpose: To investigate the alterations of retinal vessel diameters in patients with macular edema secondary to retinal vein occlusion (RVO), before and after treatment with intravitreal ranibizumab. Methods: Digital retinal images were obtained from 16 patients and retinal vessel diameters were measured before and three months after treatment with intravitreal ranibizumab with validated software to determine central retinal arteriolar and venular equivalents, as well as arteriolar to venular ratio. Results: In 17 eyes of 16 patients with macular edema secondary to RVO (10 with branch RVO and 6 with central RVO) aged 67 ± 10.2 years, we found that diameters of both retinal arterioles and venules were significantly decreased after intravitreal ranibizumab treatment. Specifically, the central retinal arteriolar equivalent was 215.2 ± 11.2 μm at baseline and 201.2 ± 11.1 μm at month 3 after treatment (p < 0.001), while the central retinal venular equivalent was 233.8 ± 29.6 μm before treatment versus 207.6 ± 21.7 μm at month 3 after treatment (p < 0.001). Conclusions: A significant vasoconstriction in both retinal arterioles and venules in patients with RVO was found at month 3 after intravitreal ranibizumab treatment compared to baseline. This could be of clinical importance, since the degree of vasoconstriction might be an early marker of treatment efficacy, compatible with the idea that hypoxia is the major trigger of VEGF in RVO. Further studies should be conducted to confirm our findings.

Severe Raynaud in a young female with Mixed Connective Tissue Disorder (MCTD)

Raynaud phenomenon is clinically manifested by sharply demarcated colour changes of the skin of the digits due to abnormal vasoconstriction of digital arteries and cutaneous arterioles. Raynaud can be primary or secondary. Here we present a young female patient who presented with Raynaud, inflammatory type of small joint pain and proximal muscle weakness. She was diagnosed to have mixed connective tissue disease after extensive evaluation.

Comparability of childhood blood pressure measurements with two different devices.

Higher blood pressure levels are associated with vascular dysfunction as early as childhood. Here, we aim to compare two blood pressure devices for use in childhood populations within a school setting to screen for elevated blood pressure in children. Systolic and diastolic blood pressure, mean arteriolar pressure (MAP) as well as heart rate (HR) were measured with the validated Oscillomate 9002 and Mindray VS-900 in 82 randomly selected children between 10 and 12 years taking part in the EXAMIN YOUTH study in 2020. Measurements were performed after 5 min at rest in a sitting position in the school environment. Both devices showed strong correlations for systolic (r = 0.62, t[80] = 7, p < 0.001) and diastolic blood pressure (r = 0.73, t[80] = 9.52, p < 0.001), MAP (r = 0.75, t[80] = 10.22, p < 0.001) and HR (r = 0.89, t[79] = 17.77, p < 0.001). There was no evidence for a statistically significant difference of both devices for systolic (110 ± 9 mmHg vs. 111 ± 9 mmHg, p = 0.574), diastolic blood pressure (67 ± 9 mmHg vs. 66 ± 9 mmHg, p = 0.301) as well as MAP (81 ± 8 mmHg vs. 80 ± 8 mmHg, p = 0.400) and HR (83 ± 12 BPM vs. 83 ± 11 BPM, p = 0.994). Both devices, the older Oscillomate 9002 and the current Mindray VS-900 showed good agreement for the measurement of blood pressure in school children. It therefore appears to be feasible to measure childhood blood pressure with either device or replace one device with another in prospective long-term studies or screening programmes as long as both are validated for use in children.

Dual inhibition of SGLT2 and DPP-4 promotes natriuresis and improves glomerular hemodynamic abnormalities in KK/Ta-Ins2Akita mice with progressive diabetic kidney disease

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD.