Vasodilatory Effects Research Articles

The Effect of Environmental Factors on the Nitrate and Nitrite Metabolism of Oral Actinomyces and Schaalia Species.

Actinomyces naeslundii and Schaalia odontolytica belong to the most predominant nitrite-producing bacteria in the oral microbiome. Nitrite has antibacterial and vasodilatory effects that may contribute to maintaining oral and systemic health. We have previously elucidated the metabolic characteristics of the nitrite-producing activity of oral Veillonella species and the effects of oral environmental factors. However, this is still unknown for Actinomyces and Schaalia species. Furthermore, these bacteria are thought to degrade nitrite. Therefore, this study aimed to comprehensively elucidate the effects of environmental factors (pH, oxygen concentration, glucose, lactate, and the presence of nitrate/nitrite during growth) on nitrate and nitrite metabolism of these bacterial species using the type strains. Nitrite was quantified by Griess reagent, and final metabolites were analyzed by high-performance liquid chromatography (HPLC). The nitrite-producing activity of A. naeslundii and S. odontolytica was affected variously by environmental factors. Especially in A. naeslundii, under anaerobic conditions, the activity increased in a concentration-dependent manner with the addition of glucose or lactate and was higher at lower pH when lactate was added. The nitrite-degrading activity of both bacteria was lower than the nitrite-producing activity and was less affected by environmental factors. Metabolites from glucose by A. naeslundii were different with and without nitrate, suggesting that nitrate altered metabolic pathways. The growth was inhibited under anaerobic conditions but promoted under aerobic conditions. These results indicate that the nitrite-producing capacity of the oral microflora must take into account not only the composition and abundance of bacteria but also the variation in metabolic activity due to various environmental factors.

Impact of nitroglycerin-induced vasodilation on stroke volume and diuretic response in acute heart failure: A protocol for a mechanistic trial.

Acute heart failure is a clinical syndrome characterized by cardiac dysfunction and neurohumoral activation, encompassing complex underlying pathophysiology which may vary across phenotypes. Nitroglycerine is a nitrate donor with vasodilatory effects on both venous capacitance vessels and arterial resistance vessels in higher doses, typically used with the aim of reducing congestion, preload, and afterload. A limited number of studies have proposed that nitroglycerin could promote diuresis and natriuresis. However, the exact hemodynamic effects of nitroglycerin remain uncertain in the clinical setting of acute decompensated heart failure. We hypothesize that intravenous nitroglycerin induces a significant increase in stroke volume and urinary output while lowering cardiac filling pressures. This will be a prospective single-center interventional clinical study of 21 patients hospitalized with a diagnosis of AHF. Patients are examined before and after administration of intravenous nitroglycerin. To characterize hemodynamic phenotypes of AHF, continuous estimates of stroke volume will be obtained, and total blood volume estimated. Vital signs and estimates of peripheral perfusion will be recorded continuously. Measures of cardiac function, renal function, volume status, and autonomic function will be assessed sequentially. This study will assess the acute effects of vasodilation on stroke volume and urinary output in hospitalized patients with AHF. Furthermore, characterizing the hemodynamic profile of the patient prior to vasodilation may help explore which patients will benefit from vasodilation.

Inhibition of soluble epoxide hydrolase ameliorates cerebral blood flow autoregulation and cognition in alzheimer's disease and diabetes-related dementia rat models.

Alzheimer's Disease and Alzheimer's Disease-related dementias (AD/ADRD) pose major global healthcare challenges, with diabetes mellitus (DM) being a key risk factor. Both AD and DM-related ADRD are characterized by reduced cerebral blood flow, although the exact mechanisms remain unclear. We previously identified compromised cerebral hemodynamics as early signs in TgF344-AD and type 2 DM-ADRD (T2DN) rat models. Genome-wide studies have linked AD/ADRD to SNPs in soluble epoxide hydrolase (sEH). This study explored the effects of sEH inhibition with TPPU on cerebral vascular function and cognition in AD and DM-ADRD models. Chronic TPPU treatment improved cognition in both AD and DM-ADRD rats without affecting body weight. In DM-ADRD rats, TPPU reduced plasma glucose and HbA1c levels. Transcriptomic analysis of primary cerebral vascular smooth muscle cells from AD rats treated with TPPU revealed enhanced pathways related to cell contraction, alongside decreased oxidative stress and inflammation. Both AD and DM-ADRD rats exhibited impaired myogenic responses and autoregulation in the cerebral circulation, which were normalized with chronic sEH inhibition. Additionally, TPPU improved acetylcholine-induced vasodilation in the middle cerebral arteries (MCA) of DM-ADRD rats. Acute TPPU administration unexpectedly caused vasoconstriction in the MCA of DM-ADRD rats at lower doses. In contrast, higher doses or longer durations were required to induce effective vasodilation at physiological perfusion pressure in both control and ADRD rats. Additionally, TPPU decreased reactive oxygen species production in cerebral vessels of AD and DM-ADRD rats. These findings provide novel evidence that chronic sEH inhibition can reverse cerebrovascular dysfunction and cognitive impairments in AD/ADRD, offering a promising avenue for therapeutic development.

Endothelium-independent vasorelaxant effects of Curcuma phaeocaulis essential oil and its representative compound isocurcumenol.

The rhizomes of Curcuma phaeocaulis Val. are a Rhizoma curcumae source in Chinese pharmacopoeia, and this traditional Chinese medicine has been extensively used in China to promote blood circulation and remove blood stasis. However, little is known regarding the vasodilatory effects and underlying mechanisms. This study investigated the vasorelaxant effects and mechanisms of C. phaeocaulis essential oil (CPEO) and its representative compound, isocurcumenol. The effects of CPEO and isocurcumenol on the contractile tension of isolated rat thoracic aortic rings in a resting state and a KCl or phenylephrine (PHE) preincubation state in the tissue organ bath system were studied. The potential vasodilatory mechanisms of CPEO and isocurcumenol were investigated using a series of experiments that included endothelium removal, CPEO and isocurcumenol preincubation, extracellular Ca2+-induced contraction and intracellular Ca2+ release, and incubation with various blockers. Laser confocal microscopy was used to evaluate the effect of isocurcumenol on the intracellular Ca2+ fluorescence intensity in A7r5 cells. The influence of isocurcumenol on the myosin light chain (MLC) protein expression and phosphorylation was determined using a Western blot assay. Furthermore, the whole-cell patch clamp technique was used to investigate the effect of isocurcumenol on voltage-dependent K⁺channel (Kv) current cells. CPEO (0.25-25mg/L) and isocurcumenol (0.25-25μM) exhibited concentration-dependent vasodilatory effects on endothelial intact vascular rings that were pre-contracted using KCl or PHE. These vasodilatory effects did not significantly change after the endothelium was removed. Notably, the vasodilatory effects of the CPEO and isocurcumenol were attenuated when preincubation was performed using with 4-aminopyridine (4-AP, a Kv channel blocker) or verapamil hydrochloride (an L-type calcium channel blocker). In the cell experiments, isocurcumenol suppressed an increase in the Ca2+ fluorescence intensity and inhibited the phosphorylation of the MLC protein in A7r5 cells. The results of the whole-cell patch clamp assay indicated that 25μM of isocurcumenol enhanced Kv channel currents. In this study, we confirmed that CPEO and isocurcumenol had significant endothelium-independent vasorelaxant effects. The underlying mechanism was attributed to the activation Kv channels and the suppression of L-type calcium channels. This resulted in a Ca2+ influx decrease in vascular smooth muscle cells and subsequent vascular contraction inhibition.

Glucagon-Like Peptide-1 Links Ingestion, Homeostasis, and the Heart.

Glucagon-like peptide-1 (GLP-1), a hormone released from enteroendocrine cells in the distal small and large intestines in response to nutrients and other stimuli, not only controls eating and insulin release, but is also involved in drinking control as well as renal and cardiovascular functions. Moreover, GLP-1 functions as a central nervous system peptide transmitter, produced by preproglucagon (PPG) neurons in the hindbrain. Intestinal GLP-1 inhibits eating by activating vagal sensory neurons directly, via GLP-1 receptors (GLP-1Rs), but presumably also indirectly, by triggering the release of serotonin from enterochromaffin cells. GLP-1 enhances glucose-dependent insulin release via a vago-vagal reflex and by direct action on beta cells. Finally, intestinal GLP-1 acts on the kidneys to modulate electrolyte and water movements, and on the heart, where it provides numerous benefits, including anti-inflammatory, antiatherogenic, and vasodilatory effects, as well as protection against ischemia/reperfusion injury and arrhythmias. Hindbrain PPG neurons receive multiple inputs and project to many GLP-1R-expressing brain areas involved in reward, autonomic functions, and stress. PPG neuron-derived GLP-1 is involved in the termination of large meals and is implicated in the inhibition of water intake. This review details GLP-1's roles in these interconnected systems, highlighting recent findings and unresolved issues, and integrating them to discuss the physiological and pathological relevance of endogenous GLP-1 in coordinating these functions. As eating poses significant threats to metabolic, fluid, and immune homeostasis, the body needs mechanisms to mitigate these challenges while sustaining essential nutrient intake. Endogenous GLP-1 plays a crucial role in this "ingestive homeostasis."

Effect of Remote Ischemic Conditioning on the Form and Function of Red Blood Cells in Patients With Acute Ischemic Stroke.

Remote ischemic conditioning (RIC) is a simple and low-cost intervention that is thought to increase collateral blood flow through the vasodilatory effects of nitric oxide (NO) produced by the endothelium and red blood cells (RBCs). This study aims to investigate whether RIC affects RBC deformability and levels of NO and nitrite in patients with ischemic stroke. This is a predefined substudy to the RESIST (Remote Ischemic Conditioning in Patients With Acute Stroke Trial) randomized clinical trial conducted in Denmark. RIC was started in the ambulance and continued at the hospital for seven days. Blood samples were collected at different time points: prehospital in the ambulance, in-hospital upon arrival, 2 hours postadmission, and 24 hours postadmission. RBC deformability and erythrocyte aggregation rate were assessed using ektacytometry, NO using flowcytometry, and nitrite content using ozone chemiluminescence. Of 1500 prehospital randomized patients, 486 patients were included in this study between July 28, 2020, and November 11, 2023, and had blood samples taken. Of these, 249 (51%) had AIS, and here RIC treatment was not associated with increased RBC maximal deformability (RIC, 0.549; sham, 0.548; P=0.31), RBC NO (RIC, 35 301 median fluorescence intensity; sham, 34979 median fluorescence intensity; P=0.89), or nitrite (RIC, 0.036 µmol/L; sham, 0.034 µmol/L; P=0.38), but RIC treatment was associated with a significantly reduced aggregation pressure and a slower erythrocyte aggregation rate (RIC, 323.76 millipascal; sham, 352.74 millipascal; P=0.0113). Prehospital and in-hospital RIC significantly reduced erythrocyte aggregation rate in patients with acute ischemic stroke, while there was no change in RBC deformability, NO content, or whole blood nitrite levels. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03481777.

Inhibition of p75NTR/p53 axis by ambrisentan suppresses apoptosis and oxidative stress-mediated renal damage in a cisplatin AKI model.

Cisplatin (CP) is a potent antineoplastic agent that triggers nephrotoxicity as a major adverse effect which can cause treatment interruptions and limitations to its clinical use. Nephrotoxicity associated with CP involves inflammation, oxidative stress and apoptosis in kidney tubules. The objective of this work was to assess the effect of the blockade of endothelin-1 (ET-1) receptor with ambrisentan (Amb) on altered renal function induced by CP. Swiss albino mice were assigned into control, CP, CP/Amb-5 and CP/Amb-10 groups. Ambrisentan improved kidney function (serum creatinine and BUN) and histopathological changes in comparison to CP-treated group. Ambrisentan significantly reduced protein expression of p75NTR and JNK influencing renal apoptosis as evidenced by reducing p53, caspase-3 and Bax level and elevating Bcl-2 level (p<0.05 vs CP group). Moreover, vasodilatory effect of ambrisentan was indicated by significant increase in level of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) (p<0.05 vs CP group). Ambrisentan also significantly restored oxidative balance in renal tissues as evidenced by reduced malondialdehyde and increased total antioxidant capacity and superoxide dismutase activity, in addition to decreasing nitric oxide levels (p<0.05 vs CP group). This protective effect of ambrisentan might be mediated through the downregulation of death receptor, P75NTR that in turn restores renal blood flow and oxidative balance and regulates p53, VEGF/eNOS, NF-κB, and bcl-2/Bax/caspase-3 signaling.

The antioxidant property of CAPE depends on TRPV1 channel activation in microvascular endothelial cells.

Caffeic acid phenethyl ester (CAPE) is a hydrophobic phytochemical typically found in propolis that acts as an antioxidant, anti-inflammatory and cardiovascular protector, among several other properties. However, the molecular entity responsible for recognising CAPE is unknown, and whether that molecular interaction is involved in developing an antioxidant response in the target cells remains an unanswered question. Herein, we hypothesized that a subfamily of TRP ion channels works as the molecular entity that recognizes CAPE at the plasma membrane and allows a fast shift in the antioxidant capacity of intact endothelial cells (EC). By monitoring cytoplasmic Ca2+ in a microvascular EC model, we compared the calcium responses evoked by three structurally related compounds: caffeic acid phenethyl ester, neochlorogenic acid and caffeic acid. Only CAPE induced rapid and transient calcium responses at nanomolar concentrations together with a gradual increase in cytoplasmic sodium levels, suggesting the activation of a non-selective cationic permeation at the plasma membrane. Electrophysiological as well as pharmacological, and RNA silencing assays confirmed the involvement of TRPV1 in the recognition of CAPE by ECs. Finally, we demonstrated that Ca2+ influx by TRPV1 was necessary for recording CAPE-induced cytoplasmic redox changes, a phenomenon captured in real-time in ECs expressing the HyPer biosensor. Our data depict a molecular mechanism behind the antioxidant effect of CAPE in endothelial cells, connecting the activation of TRPV1 ion channels, cytoplasmic calcium increase, and a reduction of disulfide bonds on a redox biosensor. This phenomenon occurs within seconds to minutes and contributes to a better understanding of the mechanisms underlying the vasodilatory effect of CAPE and other compounds that interact with TRPV1 in the vascular bed.

Vasoactive properties of hydro-methanol pod powder extract of Acacia nilotica in porcine coronary artery: Role of Nitric Oxide (NO)

Background: Acacia nilotica is a plant used in traditional medicine in Senegal for treatment of high blood pressure. The aim of this study was to determine whether a hydro-methanolic pod powder extract of Acacia nilotica (MSAN01) can induce a relaxant effect in porcine coronary arteries and to elucidate the underlying mechanism. Methods: Porcine coronary artery rings were suspended in organ chambers to record changes in isometric forces. Rings with intact endothelium were incubated with or without L-Nitro Arginine (L-NA, 300 µM) to block NO synthase; 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL, 100 nM), an inhibitor of small-conductance calcium-activated potassium channels (SKCa); and Tram-34 (1 µM), an inhibitor of intermediate-conductance calcium-activated potassium channels (IKCa); or indomethacin (INDO, 10 µM), a cyclooxygenase inhibitor, before contraction with U46619 (1-60 nM), a thromboxane A2 analogue, and subsequent generation of a concentration-relaxation curve to hydro-methanolic pod powder extract of Acacia nilotica (MSAN01). In some experiments, the endothelium was removed before contraction with U46619 (1-60 nM) and concentration-relaxation with MSAN01. Bradykinin was used to verify the presence of functional endothelium. Results: Exposure The hydro-ethanolic pod powder extract of Acacia nilotica induces a vasodilatory effect in porcine coronary arteries pre-contracted with U46619. This effect is endothelium-dependent and mediated by nitric oxide (NO). Conclusion: It Acacia nilotica induces vascular relaxation, which may explain the beneficial effects of this plant in the treatment of high blood pressure in Africa.

Pipeline for development of acylated peptide based CGRP receptor antagonist with extended half-life for migraine treatment

Migraine is a debilitating headache disorder. The disease has neurovascular origin and migraine attacks can be elicited by vasodilative neuropeptides such as alpha calcitonin gene-related peptide (αCGRP). Antagonizing CGRP actions in migraine patients has proven clinically efficient. Here, we present a pipeline for development of a peptide-based hCGRP receptor antagonist with increased half-life capable of antagonising the vasodilatory effect of hαCGRP. A series of hαCGRP8-37 analogues carrying a C18-or C20-diacid lipidation was screened for their antagonism against the hCGRP receptor. hαCGRP8-37 analogues with a C20-diacid were 2-6 fold more potent than analogues conjugated with a C18-diacid. Half-life of hαCGRP8-37 analogues carrying a C20-diacid was estimated in mice in a pilot study (n = 1–2). Half-lives ranged from 7.3 to 13.7 h. An hαCGRP8-37 analogue conjugated with a C20 diacid at position 25 was subjected to an amino acid substitution scan to identify mutations that could further enhance hCGRP receptor antagonism. Substituting alanine with serine at position 36 resulted in a ~ 4 fold gain of potency. Vasodilative actions of hαCGRP were successfully antagonized by hαCGRP8-37 analogues carrying a C20 diacid at position 25. Our findings demonstrate that lipidation can improve hαCGRP8-37 pharmacokinetics while maintaining hαCGRP antagonism, thus demonstrating potential for a peptide-based migraine treatment strategy.

Effects of Intrauterine Isoproterenol Administration on Ovarian Follicular Development in Cows.

Isoproterenol (ISO) is a nonselective beta-adrenergic receptor agonist known for its vasodilatory effects. This experiment aims to investigate whether intrauterine ISO administration could alter vascular indices and follicular development in postpartum Holstein cows. The objectives are to evaluate the effects of intrauterine ISO administration on vascular changes and its impact on follicular development compared to placebo groups. This randomized controlled study was conducted on 36 Holstein cows selected based on their health status, including only those free from reproductive, metabolic and infectious disorders. The cows (n=36) were divided into two groups as control received distilled water alone (CON, n=18) and experiment received 4mg ISO in 40mL distilled water (ISO, n=18) and four subgroups as CON-I (n=9), CON-II (n=9), ISO-I (n=9) and ISO-II (n=9) according to days of intrauterine administration (I or II represents to 1 or 2days after ovulation, respectively). Uterine and ovarian artery blood flows were assessed before and after administration by Doppler ultrasonography. Blood samples were collected both before and after administration (on Day 1 or 2) and on Days 3, 6 and 9 post-ovulation for hormonal analysis. Antral follicle count (AFC) was recorded on the blood sampling days. Data were analysed via mixed model ANOVA. Intrauterine ISO administration significantly increased the pulse rate (PR) in the ovaries (89.4 vs. 65.5bpm, p<0.0001) and uterus (90.6 vs. 64.2bpm, p<0.0001). Early AFC (1-2.9mm) decreased, whereas small AFC (3-4.9mm) increased in the ISO groups. The weighted average antral follicle size (WAAFS) significantly increased in the ISO group but remained unchanged in the controls. Hormonal analysis revealed elevated levels of FSH (626 vs. 468mIU/mL), AMH (61.3 vs. 46.4ng/L), E2 (138 vs. 122ng/L), P4 (15.3 vs. 10.6ng/mL), IGF-1 (62.6 vs. 25.1ng/mL) and IGFBP-3 (28.4 vs. 16.5ng/mL) in the ISO groups (p<0.0001). The findings indicate that intrauterine administration of ISO on Day 1 post-ovulation could be a promising 'adjunct technique' for future research focussed on minimizing dependence on exogenous hormones or improving the sensitivity of follicles to endogenous hormonal signals, thereby potentially enhancing oocyte yield.

Comparison of desflurane and sevoflurane as maintenance inhalational anaesthetic agents for adult patients undergoing neurosurgeries: A systematic review and meta-analysis of randomised trials

Background and Aims: Despite its superior blood–gas partition coefficient compared to sevoflurane, use of desflurane in neurosurgery is limited due to concerns about cerebral vasodilation and potential adverse haemodynamic effects. This study aims to systematically evaluate the comparative efficacy and safety of desflurane and sevoflurane in neurosurgical procedures. Methods: A search was performed in the Cochrane Library, Scopus, Europe PMC and Medline databases for articles published until 5 November 2024 using a combination of pertinent keywords. This review includes randomised controlled trials (RCTs) that analyse the comparison between desflurane and sevoflurane in neurosurgery. The risk of bias from each RCT was assessed using the Risk of Bias version 2 tool from Cochrane Collaboration. We utilised random-effects models to evaluate the mean difference (MD) and odds ratio (OR) for the outcomes presented. Results: Fourteen trials, encompassing 904 patients, were included in the analysis. Our analysis revealed significantly faster recovery profiles with desflurane, including reduced emergence time [MD -2.26; 95% confidence interval (CI): -2.99, -1.52, P &lt; 0.00001, I 2 = 71%], extubation time (MD -3.02; 95% CI: -3.89, -2.15, P &lt; 0.00001, I 2 = 79%) and overall recovery time (MD -3.26; 95% CI: -5.01, -1.51, P = 0.0003, I 2 = 83%), compared to sevoflurane. Desflurane was associated with better postoperative cognitive function, as evidenced by higher short orientation memory concentration test scores – a measure of attention and memory – at 15 min (MD: 2.26; 95% CI: 0.13, 4.39, P = 0.04, I 2 = 91%) and 60 min (MD: 0.29; 95% CI: 0.09, 0.50, P = 0.005, I 2 = 0%) after extubation. We did not find any significant difference in the intra- and/or postoperative events, such as emergence agitation, nausea and vomiting, shivering, hypertension, hypotension, tachycardia, bradycardia, pain and convulsions, between the two groups of intervention. Conclusion: This study suggests that desflurane anaesthesia offers faster recovery with a similar safety profile to sevoflurane for neurosurgery.

Carob leaves: Phytochemistry, antioxidant properties, vasorelaxant effect and mechanism of action.

Ceratonia siliqua L., is a species of significant nutritional and industrial interest with extensive traditional uses. This fabaceae is renowned for its medicinal properties, including the treatment of high blood pressure. Due to its chemical composition, carob exhibits several valuable therapeutic functions such as antioxidant, antidiarrheal, antidiabetic, and antibacterial actions. This study investigates the chemical composition of Ceratonia siliqua L. leaves aqueous extract (CsAE) and explores the vasorelaxant effect and its underlying mechanisms. Acute toxicity and antioxidant activity of CsAE were also examined. The phytochemical profile was elucidated using TLC and UHPLC-MS. The vasorelaxant effect and mechanisms were studied on thoracic aortic rings from normotensive rats, using various antagonists. Acute toxicity was assessed by orally administering the extract to mice. Antioxidant activity was evaluated using β-carotene bleaching and DPPH. TLC analysis of CsAE reveals flavonoids and hydrolysable tannins. Gallic acid, myricitrin, quercitrin as well as galloylglucopyranoside derivatives were identified by UHPLC-MS. CsAE relaxed phenylephrine-precontracted aorta in a concentration-dependent manner. This response was reduced when the aorta was denuded or pretreated with L-NAME, hydroxocobalamin, ODQ, 4-AP, TEA, calmidazolium chloride, and thapsigargin. CsAE showed significant antioxidant activity with no observed toxicity in the experimental animals. CsAE has a significant vasodilatory effect, mediated through the CaM/eNOS/sGC pathway, activation of Kca and Kv, and intracellular calcium mobilization into SERCA. It also exhibits strong antioxidant activity, with no observed toxicity in the experimental animals. These findings represent the first evidence of the vasorelaxant effect of Ceratonia siliqua L. leaves from Eastern Morocco.

The SGLT2 inhibitor remogliflozin induces vasodilation in the femoral artery of rabbits via activation of a Kv channel, the SERCA pump, and the cGMP signaling pathway.

This study explored the vasodilatory mechanisms of the sodium-glucose cotransporter-2 inhibitor remogliflozin using femoral arteries of rabbits. Remogliflozin dilated femoral arterial rings pre-contracted with phenylephrine in a concentration-dependent manner. Pretreatment with the Ca2+-sensitive K+ channel inhibitor (paxilline), the ATP-sensitive K+ channel inhibitor (glibenclamide), or the inwardly rectifying K+ channel inhibitor (Ba2+) did not alter the vasodilatory effect. However, vasodilation was significantly reduced by pretreatment with the voltage-dependent K+ (Kv) channel inhibitor (4-AP) and with the Kv1.5 subtype inhibitor (DPO-1) but not with Kv2.1 or Kv7 subtype inhibitor. Neither endothelium removal nor the inhibition of nitric oxide production altered the vasodilatory effect of remogliflozin. However, pretreatment with the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin and cyclopiazonic acid effectively reduced the remogliflozin effect, as did pretreatment with cGMP/PKG-related but not cAMP/PKA-related signaling pathway inhibitors. These results indicate that remogliflozin-mediated dilation of the femoral artery occurs via the activation of Kv channels, mainly the Kv1.5 subtype, SERCA pump, and cGMP/PKG-related signaling pathways.

Retinoic Acid Improves Vascular Endothelial Dysfunction by Inhibiting PI3K/AKT/YAP-Mediated Ferroptosis in Diabetes Mellitus.

Vascular endothelial dysfunction is the initial factor involved in cardiovascular injury in patients with diabetes. Retinoic acid is involved in improving vascular complications in patients with diabetes, but its protective mechanism is still unclear. This study aimed to evaluate the effect and mechanism of All-Trans Retinoic Acid (ATRA) on endothelial dysfunction induced by diabetes. In the present study, streptozotocin (STZ)-induced diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs) were observed, and the effects of ATRA on HG-induced endothelial dysfunction and ferroptosis were evaluated. ATRA treatment improved impaired vasorelaxation in diabetic aortas in an endothelium-dependent manner, and this effect was accompanied by an increase in the NO concentration and eNOS expression. Ferroptosis, characterized by lipid peroxidation and iron overload induced by HG, was improved by ATRA administration, and a ferroptosis inhibitor (ferrostatin-1, Fer-1) improved endothelial function to a similar extent as ATRA. In addition, the inactivation of phosphoinositol-3-kinase (PI3K)/protein kinases B (AKT) and Yes-Associated Protein (YAP) nuclear localization induced by HG were reversed by ATRA administration. Vascular ring relaxation experiments showed that PI3K/AKT activation and YAP inhibition had similar effects on ferroptosis and endothelial function. However, the vasodilative effect of retinoic acid was affected by PI3K/AKT inhibition, and the inhibitory effects of ATRA on ferroptosis and the improvement of endothelial function were dependent on the retinoic acid receptor. ATRA could improve vascular endothelial dysfunction by inhibiting PI3K/AKT/YAP-mediated ferroptosis induced by HG, which provides a new idea for the treatment of vascular lesions in diabetes.

The Role of Minoxidil in Treatment of Alopecia Areata: A Systematic Review and Meta-Analysis.

Background/Objectives: Minoxidil, in addition to its vasodilatory effect, has also immunomodulatory properties that may be partially responsible for its efficacy in alopecia areata. The aim of the study was to evaluate the efficacy of monotherapy with topical or oral minoxidil in alopecia areata. Methods: A systematic review and meta-analysis of the efficacy of monotherapy with minoxidil in alopecia areata was conducted following the PRISMA guidelines. Efficacy of minoxidil in alopecia areata was evaluated separately for three groups of the patients: (1) treated with 5% topical minoxidil, (2) less than 5% topical minoxidil, and (3) oral minoxidil. Therapeutic response was defined as any regrowth of terminal hair. Results: Of 244 articles, 13 were considered eligible for the further analysis. The study included 372 patients with alopecia areata (338 using topical minoxidil and 34 taking oral minoxidil). The mean time of treatment ranged from 2 to 60 weeks (mean: 27 weeks). The response rate for 5% topical was 82% (95% CI 0.7-0.93) and 58% (95% Cl 0.5-0.67) for the less than 5% topical minoxidil group. For the group of patients treated orally, the response rate was 82%. Conclusions: Minoxidil, both topical and oral, may be beneficial in monotherapy in patients with alopecia areata. 5% topical minoxidil is characterized by significantly higher efficacy compared to minoxidil at a lower concentration. There are no sufficient data to recommend minoxidil as a first-line therapeutic option for alopecia areata.

Associations of Cumulative Adulthood, Childhood and Life-long Insulin with Adulthood Retinal Microvasculature.

Exogenous insulin is reported to have both vasodilatory and vasoconstrictive effects on the microvasculature. Little is known about the associations of long-term endogenous insulin exposure with microvasculature. To test the hypothesis that long-term exposure to high insulin levels in childhood and adulthood is associated with adverse changes in retinal microvasculature in adulthood in a population without diabetes. We analyzed data derived from the longitudinal Cardiovascular Risk in Young Finns Study (YFS). The first cross-sectional study was conducted in 1980, and participants were followed for 31 years from childhood to adulthood with frequent follow-up visits. Fundus photos were taken in 2011, and microvascular outcome measures were derived in participants at the age of 34-49 years (n=1684). After exclusion of individuals with diabetes or missing insulin measures, 1166 participants formed the population of the present study. Cumulative exposure as the area under the curve (AUC) for adulthood (10-year exposure between 2001 and 2011), and childhood (exposure between ages 6-18 years) insulin and other cardiovascular risk factors were determined. Additionally, adulthood and childhood cumulative AUCs were summarized to construct life-long AUCs. Higher adulthood, childhood and life-long exposure for cumulative insulin was associated with decreased retinal arteriolar diameter when adjusted for age and sex, and further for cumulative conventional cardiovascular risk factors. Cumulative childhood, adulthood and life-long insulin are associated with decreased retinal arteriolar diameter in adulthood in a population of participants without diabetes, independently of conventional cardiovascular risk factors.

Immunohistochemical Identification of Sensory Neuropeptides Calcitonin Gene-Related Peptide, Substance P, and Pituitary Adenylate Cyclase-Activating Polypeptide in Efferent Vestibular Nucleus Neurons

Introduction: The efferent vestibular system (EVS) originates in brainstem efferent vestibular nuclei (EVN) and modifies afferent vestibular signals at their source, in peripheral vestibular organs. Recent evidence suggests that EVS is also involved in the development of motion sickness symptoms, including vertigo and nausea, but the underlying mechanism is unknown. One possible link between EVN and motion sickness symptoms is through the neuropeptide calcitonin gene-related peptide (CGRP). CGRP often co-exists with substance P and pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides with similar vasodilatory effects. Collectively, these sensory neuropeptides have been associated with vestibular migraine pathophysiology and motion sickness. While CGRP and the fast EVS neurotransmitter, acetylcholine (ACh), have previously been identified in EVN neurons and their peripheral terminals, the presence of substance P and PACAP in the EVN has not yet been described. Methods: We used fluorescent immunohistochemistry combined with confocal microscopy to examine the distribution of these three neuropeptides in the mouse EVN. In transgenic choline acetyltransferase (ChAT)-gCaMP6f mice, EVN neurons were positively identified using the fluorescent expression of gCaMP6f. In wild-type C57/BL6 mice, EVN neurons were confirmed using ChAT immunolabelling. Results: Consistent with previous studies, CGRP was labelled in a subset of cholinergic EVN neurons. Additionally, we also show evidence for substance P and PACAP expression in EVN of transgenic and wild-type mice. Conclusion: The presence of CGRP, substance P, and PACAP in EVN neurons suggests a complex peptidergic modulation of cholinergic signalling, whose release into local blood vessels may contribute to motion sickness symptoms.

The New Nitric Oxide Donor, FOR 911B, Induces Relaxation in Isolated Rat Aorta Involving the NO/sGC/cGMP Pathway and K+ Channels

Background: Nitric oxide (NO) is a gaseous molecule considered to be a protagonist in the dilation of blood vessels, and its property and/or bioavailability are reduced in pathophysiological conditions such as cardiovascular diseases. Therefore, its exogenous administration becomes attractive, and new classes of compounds able to induce NO release have emerged to minimize the adverse effects found by existing NO donor drugs. Objective: Our aim was to investigate the vasorelaxant effect and mechanism of action induced by the ruthenium complex, which contains nitric oxide in its structure, [Ru(phen)2(TU)NO](PF6)3 (FOR 911B), in isolated rat aorta. Methods: The animals were euthanized, and the aorta artery was identified, removed, and immediately placed in modified Krebs–Henseleit solution. To verify tissue viability, a contraction was obtained with phenylephrine (Phe) (0.1 μM), and to assess endothelial integrity, acetylcholine (ACh) (1 μM) was added. Results: In the present study, we demonstrated, for the first time, that FOR 911B promotes vasorelaxation in a concentration-dependent manner in isolated rat aortic artery rings. After the removal of the vascular endothelium, the potency and efficacy of the relaxation were not altered. With pre-incubation with hydroxocobalamin, the relaxing response was abolished, and with the use of ODQ, the main NO receptor blocker, the vasorelaxant effect was attenuated with a shift of the curve to the right. To investigate the participation of K+ channels, the solution concentration was changed to KCl (20 and 60 mM), and it was pre-incubated with the non-selective K+ channels blocker (TEA). Under these conditions, relaxation was altered, demonstrating that K+ channels are activated by FOR 911B. By selectively blocking the different subtypes of K+ channels with specific blockers, we demonstrated that the subtypes KV, KIR, SKCa, and BKCa are involved in the vasodilator effect induced by FOR 911B. Conclusions: The results obtained demonstrated that FOR 911B promotes vascular relaxation in aortic artery rings in a concentration-dependent manner and independent of the vascular endothelium through the participation of the NO/sGC/cGMP pathway, as well as with the involvement of different K+ channels.

Changes in hemodynamic parameters with different anaesthesia induction agents in elderly patients with coronary heart disease

Background. Coronary heart disease (CHD) is one of the most common diseases in Ukraine and worldwide. Open myocardial revascularisation procedures require general anaesthesia with endotracheal intubation. Prevention of peri-intubation hypotension in elderly patients with CHD is relevant today. The purpose was to improve the safety of surgery in elderly CHD patients by determining the induction schedule for anaesthesia with minimal cardiodepressant and vasodilator effects. Materials and methods. A cohort prospective randomized study of 40 patients with ASA III–IV who underwent off-pump coronary artery bypass grafting. Their mean age was 67.00 ± 5.78 years. The participants were divided into 2 groups based on the type of induction agent: group 1 — propofol 1.5 mg/kg, fentanyl 2.0 μg/kg; group 2 — propofol 1.5 mg/kg, fentanyl 2.0 μg/kg, ketamine 0.5 mg/kg. Relaxation: pipecuronium bromide 0.1 mg/kg. Hemodynamic parameters were recorded at the following stages: 1) upon arrival to the operating room; 2) before it; 3) after intubation; 4) 25 minutes after intubation. Results. After the administration of induction drugs, a significant difference was observed only in mean arterial pressure (MAP): group 1 — 72.71 ± 4.76 %, group 2 — 81.29 ± 5.4 % of the baseline, p = 0.0001. At the third stage, a statistically significant difference between the groups was determined in three indicators: MAP (86.74 ± 8.82 %, 92.34 ± 7.26 %; p &lt; 0.05), stroke volume index (SVI) (99.91 ± 2.94 %, 109.63 ± 8.16 %, p &lt; 0.05), cardiac index (CI) (96.63 ± 11.77 %, 110.38 ± 12.37 %, p &lt; 0.05). At the fourth stage, a statistical difference between the groups was observed in MAP (74.87 ± 7.90 % in group 1 vs. 86.47 ± 6.07 % in group 2, p &lt; 0.05), SVI (87.09 ± 5.30 % in group 1 vs. 108.21 ± 8.32 % in group 2, p &lt; 0.05), ejection fraction (88.26 ± 3.58 % in group 1 vs. 106.89 ± 6.22 % in group 2, p &lt; 0.05), CI (79.59 ± 10.11 % in group 1 vs. 108.29 ± 9.95 % in group 2, p &lt; 0.05), systemic vascular resistance index (91.13 ± 9.34 % in group 1 vs. 77.86 ± 9.83 % in group 2, p &lt; 0.05). Conclusions. The addition of ketamine to the classic combination of propofol and fentanyl increases the effectiveness and reduces the percentage of possible potential complications by stabilizing hemodynamics during anaesthetic support for coronary artery bypass grafting in older patients with CHD.