Vasoconstrictor Activity Research Articles

Antihypertensive Effects of Lindera erythrocarpa Makino via NO/cGMP Pathway and Ca2+ and K+ Channels.

Studies have demonstrated the therapeutic effects of Lindera plants. This study was undertaken to reveal the antihypertensive properties of Lindera erythrocarpa leaf ethanolic extract (LEL). Aorta segments of Sprague-Dawley rats were used to study the vasodilatory effect of LEL, and the mechanisms involved were evaluated by treating specific inhibitors or activators that affect the contractility of blood vessels. Our results revealed that LEL promotes a vasorelaxant effect through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, blocking the Ca2+ channels, opening the K+ channels, and inhibiting the vasoconstrictive action of angiotensin II. In addition, the effects of LEL on blood pressure were investigated in spontaneously hypertensive rats by the tail-cuff method. LEL (300 or 1000 mg/kg) was orally administered to the rats, and 1000 mg/kg of LEL significantly lowered the blood pressure. Systolic blood pressure decreased by -20.06 ± 4.87%, and diastolic blood pressure also lowered by -30.58 ± 5.92% at 4 h in the 1000 mg/kg LEL group. Overall, our results suggest that LEL may be useful to treat hypertensive diseases, considering its vasorelaxing and hypotensive effects.

Abstract 54: The kidney-OVLT axis in renovascular hypertension: Individual and combined effects of afferent renal denervation and OVLT lesion in 2K1C rats.

We have recently reported that afferent renal denervation (ARDN) markedly attenuates the pathogenesis of hypertension in the 2 kidney 1 clip (2K1C) model in the rat. This was associated with a reduction in neurogenic pressor activity (NPA). We have also recently shown that lesion of the organum vasculosum of the lamina terminalis (OVLT), a forebrain circumventricular organ, had nearly identical effects in 2K1C rats as ARDN. Together these findings suggest that a neural pathway from the kidney to the OVLT plays an important role in 2K1C hypertension. Based on these findings we hypothesized that the combined effect of ARDN and lesion of the OVLT (OVLTx) on arterial pressure in 2K1C rats would not be greater than the individual treatments. Male Sprague-Dawley rats were randomly selected to receive either OVLT lesion (x) or sham-OVLTx. One week later, rats were instrumented with telemeters to measure mean arterial pressure (MAP). One week later, renal artery stenosis was created by placing a clip on the left renal artery and then, rats were subjected to ARDN by periaxonal capsaicin or sham treatment of the clipped kidney creating 4 experimental groups: sham+sham (n=6), sham+ARDN (n=6), OVLTx+sham (n=5), OVLTx+ARDN (n=5). MAP was measured daily for 28 days, and at the end of the protocol, NPA was assessed by measuring the peak MAP response to ganglionic blockade. MAP was similar in all 4 groups at the beginning of the study averaging 108±3 mmHg. MAP increased to 180±10 mmHg in the sham+sham group compared to 130±13mmHg in sham+ARDN, 142±18mmHg in OVLTx+sham rats and 158±14mmHg in OVLTx+ARDN rats (p<0.001). NPA in Sham+sham rats was significantly higher (-44 ± 8 mmHg) compared to sham+ARDN (-18 ± 3 mmHg), OVLTx+sham (-21 ± 2 mmHg) and OVLTx+ARDN (-19 ± 4 mmHg) rats (p<0.05). Notably, the combined effects of OVLTx+ARDN on MAP and NPA were not significantly different from either OVLTx (p=1.00 and p=0.819) or ARDN (p=0.113 and p= 0.878) alone. In summary, ARDN and OVLTx attenuated hypertension and NPA similarly in 2K1C-HTN rats but the combination of these treatments did not produce any additional effect on MAP or NPA. These findings are consistent with the hypothesis that afferent renal nerves and the OVLT are linked in a common neural pathway required for the development of hypertension following renal artery stenosis.

The Enigma of Norbormide, a Rattus-Selective Toxicant.

Norbormide (NRB) is a Rattus-selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to non-Rattus species. However, due to inconsistent efficacy and the emergence of second-generation anticoagulants, its usage declined, with registration lapsing in 2003. NRBs' lethal action in rats entails irreversible vasoconstriction of peripheral arteries, likely inducing cardiac damage: however, the precise chain of events leading to fatality and the target organs involved remain elusive. This unique contractile effect is exclusive to rat arteries and is induced solely by the endo isomers of NRB, hinting at a specific receptor involvement. Understanding NRB's mechanism of action is crucial for developing species-selective toxicants as alternatives to the broad-spectrum ones currently in use. Recent research efforts have focused on elucidating its cellular mechanisms and sites of action using novel NRB derivatives. The key findings are as follows: NRB selectively opens the rat mitochondrial permeability transition pore, which may be a factor that contributes to its lethal effect; it inhibits rat vascular KATP channels, which potentially controls its Rattus-selective vasoconstricting activity; and it possesses intracellular binding sites in both sensitive and insensitive cells, as revealed by fluorescent derivatives. These studies have led to the development of a prodrug with enhanced pharmacokinetic and toxicological profiles, which is currently undergoing registration as a novel efficacious eco-sustainable Rattus-selective toxicant. The NRB-fluorescent derivatives also show promise as non-toxic probes for intracellular organelle labelling. This review documents in more detail these developments and their implications.

β-Adrenergic Receptor Blockade Augments Sympathetically Mediated Vasoconstriction during Hypoxia in Healthy Young Adults

Objective: Vascular tone is dictated by the net balance of vasodilatory and vasoconstrictor influences. During hypoxia, systemic sympathetic vasoconstrictor activity is increased but peripheral vasodilation prevails — suggesting vasodilatory factors outweigh sympathetically-mediated vasoconstrictor influences in the healthy state. Given vascular β-adrenergic receptors contribute to hypoxic vasodilation, we hypothesized pharmacological blockade of β-adrenergic receptors would augment the vasoconstrictor response to acute sympathetic activation during hypoxia. Methods: Thirteen young healthy participants (5F/8M, 27±7 yr, 25±3 kg/m2) completed two study visits randomized and blinded to oral placebo or propranolol (1mg/kg, NCT05256069). On each visit, participants completed two trials: 1) 10-min normoxia (0.21 FiO2, 98±0% SpO2) followed by sympathetic activation via a 2-min normoxic cold pressor test (CPT); 2) 5-min steady-state hypoxia (0.10±0.01 FiO2, 81±1% SpO2) followed by a 2-min hypoxic CPT. Forearm blood flow (FBF, venous occlusion plethysmography) and blood pressure (BP, finger photoplethysmography) were assessed. FBF was normalized for mean BP (forearm vascular conductance, FVC). A change in FVC from steady-state to the last 1-min of CPT was calculated (ΔFVC = CPT − steady-state) and expressed as a percent change (%FVC = ΔFVC/steady-state x 100). Results: The vascular response to sympathetic activation (CPT) was unaffected by hypoxia under placebo conditions (normoxia: -34±21%; hypoxia: -29±32%, p=0.33). In contrast, following β-adrenergic blockade with oral propranolol, sympathetically-mediated vasoconstriction was augmented during hypoxia (normoxia: -29±30%; hypoxia: -40±27%, p=0.04). Conclusion: β-adrenergic receptor blockade augments the vasoconstrictor response to acute sympathetic activation during hypoxia in a mixed-sex cohort. These preliminary data indicate functional β-adrenergic receptors are required to restrain sympathetically-mediated vasoconstriction during hypoxia. Based on data supporting sex-related differences in adrenergic control of vascular tone, future work will seek to stratify results by sex. Funding: AHA 909014 (DWJ), APS-SURF (BJB), HL153523 (JKL). 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.

Blood-Pressure-Lowering and Endothelium-Dependent Vasorelaxant Effects of Nutgall Tree in Rats.

Hypertension is the crucial modifiable risk factor for cardiovascular diseases, and efforts to identify functional foods that are effective for hypertension control are increasing. The nutgall tree (NT, Rhus chinensis Mill.) is used in traditional medicine and food because of its medicinal value. However, the role of NT in hypertension has not been investigated. Therefore, the hypotensive effect of NT leaf ethanol extract (NTE) was investigated in spontaneously hypertensive rats (SHRs). SHRs were allocated to three groups (control, 300, or 1000 mg/kg NTE), and blood pressure was measured before and after oral administration. Systolic and diastolic blood pressure significantly decreased in the NTE 1000 mg/kg group and was the lowest at 2 h after administration (-26.4 ± 10.3, -33.5 ± 9.8%, respectively). Daily NTE administration for five days also resulted in a similar effect. Further, the vasorelaxant effects and related mechanisms were investigated in the aortas of Sprague Dawley rats. NTE showed the dose-dependent blood-vessel-relaxing effect, and its mechanism involves the NO-sGC-cGMP pathway, activation of K+ channels, and reduction in the vasoconstrictive action of angiotensin II. Therefore, our study provides basic data indicating the potential use of NTE as a functional food for high blood pressure.

A Narrative Review on Managing Retinopathy of Prematurity: Insights Into Pathogenesis, Screening, and Treatment Strategies.

Retinopathy of prematurity (ROP) is a rare proliferative ocular condition that can happen in premature babies (born preterm<36 weeks)or who weigh <1.5 kgat birth (low birth weight babies). ROP is a major cause of childhood blindness. It is a premature diseasesince retina vascularization is completed only by 40 weeks of life. The survivability for preterm infants has increased owing to recent improvements in neonatal care during the past decade. As a result, the prevalence of ROP has risen concurrently. The abnormal development of blood vessels in the retina is the cause of this illness. It occurs in two phases, phases 1 and 2. Most preterm infants weighing <1.5 kg need supplemental oxygen for respiratory support at birth. This leads to the initiation of phase 1 (vasoconstrictive phase). Phase 1 is characterized by loss of maternal-fetal connection and hyperoxia due to supplemental oxygen therapy.Oxygen's vasoconstrictive and obliterative action is primarily observed in developing retinal vessels. The inhibition of vascular endothelial growth factorfollows from this.Phase 2 (vasoproliferative phase) showsthe dilatation and tortuosity of the bigger existing vessels together with neovascularization and proliferation of new vessels into the vitreous when the baby is shifted from respiratory support to room air. Now, the retina gets hypoxic, where the retina becomes more metabolically active but is yetminimally vascularized, leading to VEGF-induced vasoproliferation, which might result in retinal detachment. Patients with ROP face the danger of loss of vision. If correct and quick treatment is not provided, they might land into permanent blindness. Yet, ROP remains one of themost preventablecauses of childhoodblindnessworldwide. Blindness caused by ROP can only be avoided if screening programs are readily available, pertinent, and appropriate.The initial stage in the therapy of ROP is the screening ofpremature neonates. Timely screening and management for ROP is important to avoidthis irreversible loss of vision. The treatment is based on the severity of the disease. Management may include pharmacological interventions like intravitrealand anti-vascular endothelial growth factor and non-pharmacological interventions like laser surgery, vitrectomy, and scleral buckling. We conducted athorough literature search of studies onpathogenesis, risk factors, classification, and various treatment options for retinopathy of prematurity in infants, using a mixture of pertinent keywords.Only those studies published in peer-reviewed journals between 2010 and 2023 and written in English were included.Duplicate studies, unavailable in full-text for free, or studies unrelated to our subject matter were excluded. After thoroughly evaluating the selected studies, the results were synthesized and presented narratively. This article sheds light on the pathogenesis of ROP, particularly its relation to oxygen use, screening, and potential therapeutic management of ROP. Today advances in screening techniques have improved the outcomes for infants with ROP. Still, ongoingresearch is needed to optimize management strategies and reduce the burden of this condition.

Nocturnal Autonomic and Vasoconstriction Parameters By Wearable Wrist Photoplethysmography Predict Intensity of Imminent Pain in Subjects with Sickle Cell Disease

Introduction: Sudden and unpredictable onset of pain is one of the biggest contributors to the morbidity of sickle cell disease (SCD), thought to occur due to obstruction of microvascular blood flow by rigid sickle-shaped red blood cells. Autonomic mediated vasoconstriction in the peripheral vasculature, with resulting decrease in tissue perfusion, is likely a triggering mechanism for the onset of vaso-occlusive pain, while the autonomic nervous system is also implicated in the pathogenesis of chronic neuropathic pain. Our analysis of 212 polysomnograms in SCD subjects showed that greater magnitude of nocturnal vasoconstriction (Mvasoc) is predictive of increased frequency of hospitalizations for vaso-occlusive pain crises (VOC) in the subsequent years (Chalacheva et al., Am J Hematol, 2020). In order to further develop this finding into a biomarker of more imminent pain, we monitored nocturnal photoplethysmography (PPG) at home with a wearable wristband device to measure vasoconstriction activity and heart rate variability, along with a daily electronic pain survey. Methods: 10 subjects with SCD were consented and underwent autonomic monitoring with a wristband device (Biostrap Inc) that uses an optical sensor to measure continuous PPG during sleep, with the raw PPG waveforms available from a cloud-based server. A unique biomarker (Mvasoc) was used to quantify the magnitude of vasoconstriction from the raw PPG signal, considering the frequency, magnitude, and duration of autonomic mediated spontaneous vasoconstrictions each night. Heart rate variability was derived from the pulse-to-pulse interval (PPI) of the PPG signal. Spectral indices of the PPI represent parasympathetic activity (high frequency power; HFP) and sympatho-vagal balance (Low to high Ratio; LHR = low frequency power(LFP)/HFP). Subjects concurrently documented daily pain incidence using an electronic text-based REDCap survey, with pain intensity measured on a scale of 1-10 if experiencing pain. Daily stress levels were also recorded on a scale of 1-10. Multivariate regression analysis was performed. Results: The subjects had a mean age of 25 years (range 14- 40 years) with an average hemoglobin of 8.8 g/dl . A total of 68 usable nocturnal PPG recordings were made (3-16 nights per subject). Therewere 25 incidents of pain on the day following autonomic monitoring with Biostrap, with the pain intensity ranging from 3-8. Multivariate analysis of nocturnal autonomic and vasoconstriction parameters revealed that a lower HFP ( p =0.0002) and a higher Mvasoc ( p=0.02) both preceded a higher intensity of pain the following day (Table 1). These results are consistent with a greater parasympathetic withdrawal and a higher magnitude of peripheral vasoconstriction predicting higher intensity of imminent pain. Age, gender, hemoglobin, stress levels and LHR were not predictive of pain the following day. Conclusion: Augmented nocturnal vasoconstriction and parasympathetic withdrawal noted prior to high intensity of pain imply that dysautonomia, with attendant changes in peripheral perfusion, has a significant role in pathogenesis of pain in SCD. Furthermore, autonomic vasoreactivity parameters were not significantly altered on the night after pain onset suggesting that the dysautonomia precedes pain. These results support the possibility of employing indices of nocturnal autonomic vasoreactivity as a predictive biomarker for imminent pain in SCD and provides a potential window for therapeutic intervention. This pilot study demonstrates the successful use of a wearable device PPG to remotely monitor nocturnal autonomic vasoreactivity and the ability to objectively quantify peripheral vasoconstriction responses. These findings will need to be applied in a larger cohort of SCD subjects with longer term monitoring for further validation and development of autonomic vasoreactivity as a predictive tool for pain in SCD.

20-HETE As an Emerging Target to Improve Renal Health in Sickle Cell Disease

The kidney is one of the most severely affected organs in sickle cell disease (SCD), with glomerular hyperfiltration and microalbuminuria beginning in childhood, and progressing to chronic kidney disease (CKD) in majority of adults. Sickle individuals also suffer from acute kidney injury (AKI) often during characteristic vaso-occlusive crisis. Renal pathology in sickle cell nephropathy includes extensive microvascular congestions and thrombotic microangiopathy. The hypercoagulable and vasoconstrictive environment of SCD, in conjunction with medullary hypoperfusion and cortical hyperperfusion contributes to vaso-occlusive injury and deregulates intrarenal hemostasis leading to CKD development. Ischemic injury increases arachidonic acid hydroxylation producing 20-hydroxyeicosatetraenoic acid (20-HETE), which in turn triggers thrombosis and promotes vasoconstriction in the kidney. However, the role of 20-HETE in regulating renal hemostasis in SCD nephropathy has never been reported. We found that plasma 20-HETE is significantly elevated in SCD patients (n=9-11; p&amp;lt;0.01) compared to normal individuals. Similarly, transgenic SCD mice (SS), homozygous for human hemoglobin S, have increased plasma 20-HETE compared to control mice (AA), homozygous for human hemoglobin A (n=6; p&amp;lt;0.01). We have previously shown that elevated circulating heme mimicking hemolytic crisis triggers clinically relevant acute kidney injury (AKI) in SS mice (Blood (2020) 135(13): 1044-1048). We postulated that hemolytic stress may exacerbate 20-HETE production which in turn aggravates renal microvascular occlusion and vasoconstriction, leading to renal damage in SCD. Immunohistochemistry and biochemical experiments showed that the expression of CYP4A12a, a cytochrome 450-dependent enzyme responsible 20-HETE production in mice, is substantially elevated in the kidneys of SS mice compared to AA mice, associated with increased vascular congestion and renal thrombogenesis. Renal CYP4A12a and plasma 20-HETE were increased substantially following heme-induced AKI in SS mice, associated with a heightened expression of renal angiotensin II receptor 1 (ATIIR1), thus indicating induced vasoconstrictive activity. In vitro, we found that 20-HETE induced ATIIR1 expression in human renal glomerular endothelial cells (hRGEC), which was further exacerbated by low-concentration of heme challenge (5 mM for 24 hour). Nitro-oleic acid (NO 2-OA) is a nitrated fatty acid that binds ATIIR1 and inhibits angiotensin II induced vasoconstriction. Pretreatment with NO 2-OA reduced 20-HETE-dependent ATIIR1 expression in hRGEC, while NO 2-OA prophylaxis during hemin-induced AKI inhibited albuminuria, normalized plasma creatinine levels, and lowered the expression of ATIIR1 in SS mice kidneys. Overall, our data show that elevated 20-HETE levels during hemolytic stress may aggravate renal injury in SCD which can be prevented by NO 2-OA prophylaxis. Ongoing experiments will determine the direct effect of elevated 20-HETE in renal hemostasis and CKD development in SCD.

Priority choice of topical antibacterial drugs in the commonly accepted paradigm of acute rhinosinusitis treatment

Introduction. In the complex therapy of acute rhinosinusitis, topical drugs with different mechanisms of action and influence on the main links in the pathogenesis of acute infectious lesions of the mucous membrane of the paranasal sinuses are widely used. Local drugs with antibacterial, as well as mucolytic and vasoconstrictor effects do not inhibit mucociliary clearance, have a convenient release form and ensure dosing accuracy with each use.Aim. Evaluation of the clinical effectiveness of the use in complex therapy of a topical antibiotic of the aminoglycoside group in combination with a drug having vasoconstrictive and mucolytic effects of domestic production in the treatment of acute bacterial rhinosinusitis.Materials and methods. The study involved 30 patients with a verified diagnosis of acute bacterial rhinosinusitis of moderate severity aged 18 to 68 years, who were divided into two groups. Patients of the first group (n = 15), in addition to complex treatment (antibacterial, antihistamine and unloading therapy, anti-inflammatory and puncture treatment), used a drug with a bactericidal effect from the group of aminoglycosides (Tramicent). Patients of the second group (n = 15) supplemented the same treatment with a drug with mucolytic and vasoconstrictive action (Rhinostein®). The effectiveness of therapy was evaluated based on the results of three visits to the doctor within two weeks.Results. The positive dynamics of the subjective and objective status of patients in both study groups was noted. By the 3rd visit (10–14 days), the severity of clinical manifestations in patients who used two drugs Tramicent and Rhinostein® as additional therapy was 2 times lower than at the first visit compared with the group of patients who used only Tramicent as additional therapy. The absence of complaints after treatment in the 2nd group was noted by 15% of the examined, in the 1st – 10%.Conclusions. Topical drug from the group of aminoglycosides containing the active substance framycetin sulfate (Tramicent) in the form of a spray is a safe and effective remedy in the complex therapy of bacterial rhinosinusitis, and its use in combination with the drug mucolytic and vasoconstrictive action (Rhinostein®) significantly reduces the duration of treatment and improves the quality of life of patients.

Study of quality indicators of sour cream products enriched with extracts of tea drinks

The decline in household income against the backdrop of rising food prices has led to a decrease in their demand. Among fermented milk products, the smallest deviation in purchasing demand can be noted for sour cream. It is possible to reduce the cost of this product line by producing sour cream products. The use of herbal prescription components in sour cream products allows you to expand their range, adjust properties, and give a functional focus. Tea extracts are used as natural dyes and flavors, structure-forming additives. Biologically active substances of tea raw materials and products of its processing exhibit various types of physiological activity: antioxidant, anti-inflammatory, antiseptic, antispasmodic, vasoconstrictive action, etc. To give sour cream products a pleasant color and improved taste properties, it is of interest to use extracts of green tea and hibiscus tea drink. Studies of the obtained sour cream products have been carried out. The mass fraction of the introduced extracts was determined by evaluating the total significance coefficient for the following indicators: harmony of taste; consistency; color. The optimal dosage of green tea extracts and hibiscus tea drink is 10%. Flavor components (a mixture of cinnamon and sugar), a stabilizer were additionally added to the composition of sour cream products. The products were stored at a temperature of 4±2 ºС, the organoleptic, physicochemical and microbiological parameters of the latter were studied. Viscosity studies were carried out in the control and test samples. It has been established that the samples of sour cream products have a high viscosity index, well restore the structure after mixing. Sour cream products with extracts of tea drinks can be consumed as an independent product, as well as a prescription ingredient for baked goods.

Abstract P220: Angiotensin II Dependent And Independent Pressor Effect Of Ang-(1-12)

Background: Ang-(1-12) serves as a functional substrate for the formation of Ang II in the blood and tissues. It remains unknown whether the hypertensive effect of Ang-(1-12) is solely caused by Ang II formation or whether the peptide itself exerts a pressor effect by binding to the AT1-receptor or a yet-to-be-identified receptor subtype. Here we examined the possibility of Ang II independent pressor effects of Ang-(1-12). Methods: Anesthetized male c57bl6 mice were injected with Ang II or Ang-(1-12) (0.2 μg/g BW) and the systolic blood pressure (SBP) was measured continuously for 15 minutes. To evaluate whether Ang-(1–12) vasoconstrictor activity is due to its processing into Ang II, mice were preinjected with Telmisartan or Lisinopril before Ang-(1-12) injection. We further assessed the effect of recombinant (r) ACE2 as a way to augment Ang II metabolism and therefore unravel Ang II independent pressor effects of Ang-(1-12). Results: Ang-(1-12) infusion led to a peak increase in SBP almost as high as Ang II (145 ±24 mmHg vs. 160±26 mmHg, respectively). The pressor effect of Ang-(1-12) was completely abolished by either Telmisartan or Lisinopril (103±11 mmHg and 98±12 mmHg, respectively). rACE2 prevented the sustained rise in SBP induced by Ang II (Fig. 1), but it did not affect the pressor effect of Ang-(1-12) (Fig. 1). Conclusions: Ang-(1–12) hypertensive effect is blocked by RAS blockade consistent with an action dependent on Ang II formation and coupling to AT-1 receptors. In contrast, Ang-(1–12) pressor activity is not modified when Ang II is rapidly metabolized by rACE2. These data suggest a vasoactive action of Ang-(1–12) that is, in part, independent of its conversion into Ang II.

A single high-fat Western meal modulates vascular responsiveness to sympathetic activation at rest and during exercise in humans: a randomized controlled trial.

A single high-fat Western meal transiently reduces endothelium-dependent vasodilation at rest but the interaction with sympathetic vasoconstrictor activity during exercise remains unknown. Herein, we tested the hypothesis that a single high-fat Western meal would impair the ability of contracting skeletal muscle to offset vascular responsiveness to sympathetic activation during exercise, termed functional sympatholysis. In 18 (10F/8M) healthy young adults, forearm blood flow (Doppler ultrasound) and beat-to-beat arterial pressure (photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) applied at rest and simultaneously during low- (15% maximum contraction) and moderate-intensity (30% maximum contraction) rhythmic handgrip. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes in forearm vascular conductance (FVC) between handgrip and rest. Experiments were performed preprandial and 1h, 2h, and 3h after a high- or low-fat meal. In the preprandial state, LBNP decreased resting FVC (∆-54±10%), and these responses were attenuated during low- (∆-17±7%) and moderate-intensity handgrip (∆-8±6%). Following a high-fat meal, LBNP induced attenuated decreases in resting FVC (3h postprandial: ∆-47±10%, P=0.002 vs. preprandial), and blunted attenuation of FVC during low- (3h postprandial: ∆-23±8%, P=0.001 vs. preprandial) and moderate-intensity handgrip (3h postprandial: ∆-16±6%, P<0.001 vs. preprandial). The high-fat meal attenuated the magnitude of sympatholysis during low- (preprandial: 38±7% vs. 3h postprandial: 23±8%, P<0.001) and moderate-intensity handgrip (preprandial: 46±11% vs. 3h postprandial: 31±10%, P<0.001). The low-fat meal had no impact on these responses. In conclusion, a single high-fat Western meal modulates sympathetic vasoconstriction at rest and during low- and moderate-intensity handgrip exercise in young healthy adults.

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.

Renal and hypothalamic inflammation in renovascular hypertension: role of afferent renal nerves.

Renal denervation (RDN) is a potential therapy for drug-resistant hypertension. However, whether its effects are mediated by ablation of efferent or afferent renal nerves is not clear. Previous studies have implicated that renal inflammation and the sympathetic nervous system are driven by the activation of afferent and efferent renal nerves. RDN attenuated the renal inflammation and sympathetic activity in some animal models of hypertension. In the 2 kidney,1 clip (2K1C) model of renovascular hypertension, RDN also decreased sympathetic activity; however, mechanisms underlying renal and central inflammation are still unclear. We tested the hypothesis that the mechanisms by which total RDN (TRDN; efferent + afferent) and afferent-specific RDN (ARDN) reduce arterial pressure in 2K1C rats are the same. Male Sprague-Dawley rats were instrumented with telemeters to measure mean arterial pressure (MAP), and after 7 days, a clip was placed on the left renal artery. Rats underwent TRDN, ARDN, or sham surgery of the clipped kidney and MAP was measured for 6 wk. Weekly measurements of water intake (WI), urine output (UO), and urinary copeptin were conducted, and urine was analyzed for cytokines/chemokines. Neurogenic pressor activity (NPA) was assessed at the end of the protocol calculated by the depressor response after intraperitoneal injection of hexamethonium. Rats were euthanized and the hypothalamus and kidneys removed for measurement of cytokine content. MAP, NPA, WI, and urinary copeptin were significantly increased in 2K1C-sham rats, and these responses were abolished by both TRDN and ARDN. 2K1C-sham rats presented with renal and hypothalamic inflammation and these responses were largely mitigated by TRDN and ARDN. We conclude that RDN attenuates 2K1C hypertension primarily by ablation of afferent renal nerves which disrupts bidirectional renal neural-immune pathways.NEW & NOTEWORTHY Hypertension resulting from reduced perfusion of the kidney is dependent on renal sensory nerves, which are linked to inflammation in the kidney and hypothalamus. Afferent renal nerves are required for chronic increases in both water intake and vasopressin release observed following renal artery stenosis. Findings from this study suggest an important role of renal sensory nerves that has previously been underestimated in the pathogenesis of 2K1C hypertension.

O100 The effect of acidosis on contractility induced in porcine splanchnic arteries by clonidine or noradrenaline

Abstract Introduction Clonidine, through its agonist action on central α2-adrenoceptors, is increasingly being used to induce sedation in critically ill patients with persistent acidosis and impaired renal function. Since it is also known to exert cardiovascular effects via peripheral α2-adrenoceptors, we compared its vasoconstrictor activity in porcine isolated arteries at different pH, to that produced by noradrenaline. Methods Isometric tension recordings of porcine isolated mesenteric, splenic and renal arteries (2mm internal diameter) were conducted in modified Krebs-Henseleit solution containing 105mM chloride ions maintained at pH 7.2 and 7.4 (modification of bicarbonate and chloride ions with gluconate ions). The potency of clonidine and noradrenaline was assessed by the pD2 (logarithm of concentration causing 50% of maximum response). Results Clonidine elicited concentration-dependent contractions in the renal artery (pD2 - 7.25±0.09 and 7.10±0.10, n=9) and splenic artery (pD2 - 6.81±0.09 and 7.02±0.06, n=8) that were not altered by a reduction in pH from 7.4 to 7.2 (p &amp;gt;0.05 paired Student's t-test). Clonidine failed to elicit consistent responses in the mesenteric artery (&amp;lt; 10% 60mM KCl). In contrast, the maximum response and potency to noradrenaline in the mesenteric artery (226.6±24.6% and pD2 5.43±0.11, n=6) was significantly reduced (p &amp;lt;0.05) by pH 7.2 (174.4±13.3% and pD2 5.13±0.11, n=6). Responses to noradrenaline in the renal and splenic artery were not affected by changes in pH. Conclusion Acidosis impairs the peripheral vascular actions of the non-selective α-adrenoceptor agonist noradrenaline more than those elicited by the selective α2-adrenoceptor agonist clonidine.

Current possibilities of using silver proteinate in the treatment of inflammatory diseases of the nose and paranasal sinuses

The article evaluates the possibility of using silver proteinate to treat acute inflammatory diseases of the nasal cavity and paranasal sinus mucosa, as well as their complications. Acute rhinitis and rhinosinusitis are among the most common upper respiratory diseases. Viral pathogens are the main agents that trigger the pathological process. At the same time, the bacterial superinfection in some cases may develop due to viral infection, which promotes further development of lingering clinical symptoms up to a complicated course of the disease. The course of rhinosinusitis with underlying COVID-19 infection can be complicated by fungal superinfection and postnasal drip. For these reasons, topical drugs that could be used in the early stages of these conditions should have a number of properties, such as activity against most respiratory viruses and aetiologically significant bacterial pathogens; lack of opportunity to evolute and implement rapid resistance mechanisms in microorganisms; additive effects with other antibacterial drugs; acceleration of regeneration of the nasal cavity and paranasal sinus mucosa with underlying infectious alteration; vasoconstrictive and anti-inflammatory action, without causing an addictive effect, which enables repeated use of the drug in chronic diseases, as well as the absence of local and systemic toxic effects. Sialor (silver proteinate) has all the specified characteristics that were proved in various studies, and consistently demonstrated high clinical efficacy for many years.

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors

Scleroderma renal crisis is a rare complication of systemic sclerosis characterized by a rapid decline in kidney function due to acute renal vascular injury. Recently, activating autoantibodies targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor have been implicated in the pathophysiology of scleroderma renal crisis by sensitizing the angiotensin II type 1 receptor and endothelin-1 type A receptor in renal resistance arteries to their natural ligands. Here, we describe a cohort of 10 patients with scleroderma renal crisis refractory to standard treatment, including blockade of the renin-angiotensin system. Multimodal therapy was initiated, targeting at the removal of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies by plasma exchange and the reduction of vasoconstrictive activity. Further treatment options included angiotensin II type 1 receptor and endothelin-1 type A receptor blockade, iloprost, intravenous immunoglobulins, and immunosuppression. Six patients were hypertensive. On kidney biopsy, concentric intimal sclerosis was present in all patients, whereas acute vascular injury was evident in eight. Levels of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies were significantly reduced by multimodal treatment. Kidney function improved in three patients with histological signs of severe acute renal vascular damage. This report demonstrates that intensive multimodal therapy taking account of potentially pathogenic anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies in concert with other vasodilatory interventions provides a salvage option for patients with refractory scleroderma renal crisis.

New Entries into the Migraine Market: 2018-2021

Migraine is a chronic condition of recurring headaches, often severe and disabling, not in the least because of the associated gastrointestinal symptoms. The focus of its treatment is pharmacological, which we traditionally divide into abortive or acute and preventive or prophylactic. In the 4-year period, 2018-2021, the United States (US) Food and Drug Administration (FDA) approved twelve new entries into the migraine market, six for abortive treatment and six for preventive treatment, including one for both. Three of them are reformulations of already marketed medications, four are CGRP antibodies, three are small-molecule CGRP-receptor antagonists or gepants, and one is a serotonin-1F receptor agonist or ditan. In this paper, we review the twelve new migraine entries in light of the abortive and preventive migraine medications marketed prior to 2018. We present the efficacy of four of the new entries for migraine abortion – the FDA approved the remaining two based on comparable bioavailability – and of all six of the new entries for migraine prevention, focusing on 2-hour pain-free and 50%-responder rates, respectively. We conclude that preventively we have made progress if only because of the (much) better tolerability of the CGRP antibodies and gepants, in comparison to the traditional oral preventive migraine medications. In terms of efficacy, we probably have made progress as well although supported by only one randomized, double-blinded, head-to-head comparative trial. Abortively, the three new chemical entities in the classes of gepants and ditans lack vasoconstrictor activity and, hence, we can prescribe them where the ergots and triptans are contraindicated. This is a step ahead in safety while tolerability and efficacy seem similar to that of the triptans, the mainstay in abortive migraine treatment.

Sex Differences in Age-Related Changes in Functional Activity and Expression of the Main Regulatory Proteins of the Renin-Angiotensin System in the Aorta and Myocardium of Rats

The sex differences of age-related changes in the functional activity and expression of receptor and regulatory proteins of the renin-angiotensin system (RAS) in the aorta and myocardium of rats is evaluated. It was found that with age in females, the sensitivity of the aorta to the vasoconstriction action of angiotensin II increases, while in older males it remains unchanged. In the aorta of old females, a decrease in the mRNA levels of ACE, MasR and ACE2 was revealed by 1.6, 1.8 and 4.4 times, respectively. It has been shown that during aging in the left ventricle of females, the level of MasR and ACE2 mRNA decreases, in males, on the contrary, the level of ACE and MasR mRNA increases. The results obtained indicate the sexual characteristics of age-related changes in RAS activity in the vessels and heart of rats.

Angiotensin-Converting Enzyme 2 Expression and Severity of SARS-CoV-2 Infection.

Angiotensin-converting enzyme 2 (ACE2), first discovered in 2000, serves as an important counterregulatory enzyme to the angiotensin II-mediated vasoconstrictive, pro-inflammatory, and pro-fibrotic actions of the renin-angiotensin system (RAS). Conversion of angiotensin II to the peptide angiotensin 1-7 (ANG 1-7) exerts protective vasodilatory, anti-inflammatory, and anti-fibrotic actions through interaction with the MasR receptor. There are many important considerations when noting the role of ACE2 in the pathogenesis and sequelae of COVID-19 infection. ACE2, in the role of COVID-19 infection, was recognized early in 2020 at the beginning of the pandemic as a cell membrane-bound and soluble binding site for the viral spike protein facilitating entering into tissue cells expressing ACE2, such as the lungs, heart, gut, and kidneys. Mechanisms exist that alter the magnitude of circulating and membrane-bound ACE2 (e.g., SARS-CoV-2 infection, viral variants, patient characteristics, chronic disease states, and the degree of cell surface expression of ACE2) and the influence these mechanisms have on the severity of disease and associated complications (e.g., respiratory failure, systemic inflammatory response syndrome, acute myocarditis, acute kidney injury). Several medications alter the ACE2 receptor expression, but whether these medications can influence the course of the disease and improve outcomes is unclear. In this review, we will discuss what is known about the interrelation of SARS-CoV-2, ACE2 and the factors that may contribute to the variability of its expression and potential contributors to the severity of COVID-19 infection.