Vasodilatory Effects Research Articles

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.

Vasodilator drugs and heart-related outcomes in systemic sclerosis: an exploratory analysis

Background and aimsSystemic sclerosis (SSc) is an autoimmune connective disease characterised by excessive extracellular matrix deposition and widespread skin and internal organ fibrosis including various cardiac manifestations. Heart involvement is...

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 < 0.05), stroke volume index (SVI) (99.91 ± 2.94 %, 109.63 ± 8.16 %, p < 0.05), cardiac index (CI) (96.63 ± 11.77 %, 110.38 ± 12.37 %, p < 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 < 0.05), SVI (87.09 ± 5.30 % in group 1 vs. 108.21 ± 8.32 % in group 2, p < 0.05), ejection fraction (88.26 ± 3.58 % in group 1 vs. 106.89 ± 6.22 % in group 2, p < 0.05), CI (79.59 ± 10.11 % in group 1 vs. 108.29 ± 9.95 % in group 2, p < 0.05), systemic vascular resistance index (91.13 ± 9.34 % in group 1 vs. 77.86 ± 9.83 % in group 2, p < 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.

Comparison of the Effect of Delay Phenomenon and Quercetin Application on the Viability of Dorsal Skin Island Flaps in Rats: An Experimental Study.

Surgical delay is any surgical intervention performed 7-14 days before flap elevation, separating part of flap from its vascular bed and aiming to decrease flap necrosis. However, delay surgery needs to be planned and performed as a separate surgical operation. Quercetin is a flavonoid with anti-inflammatory, and vasodilator effects. This study compares the effects of quercetin and surgical delay on flap survival. The study included 32 male Wistar rats divided into four groups: control group (group 1), surgical delay group (group 2), quercetin group (group 3), and both surgical delay and quercetin group (group 4). All dorsal skin island flaps were elevated based on deep circumflex iliac artery and 7 days were selected as waiting period after flap elevation, 50 mg/kg (0.5 mL) intraperitoneal quercetin administration period, and surgical delay period. Macroscopically flap necrosis rates were calculated and histopathological examination was performed to evaluate number of vessels, vessel lumen diameters, inflammation, epidermal damage, and dermal fibrosis scores. All rats were euthanized. Flap necrosis rates, inflammation, epidermal damage, and dermal fibrosis scores of group 3 and 4 were found to be lower than group 1 and 2 (P < 0.05). Vascular lumen diameter of group 2, 3, and 4 were found to be higher than group 1 (P < 0.05) but no statistically significant difference was found for this parameter between group 2, 3, and 4 (P > 0.05). The number of vessels were found to be higher in group 2, group 3, and group 4 compared with group 1, but this difference was not to be found statistically significant (P = 0.534). This study shows that quercetin application is more effective in reducing flap necrosis rates and anti-inflammatory effect than surgical delay and also has superior effect in terms of vasodilation.

The influence of yoga exercises with voluntary pulmonary ventilation changes on intracranial arterial blood flow

Introduction. Yoga breathing exercises that involve voluntary changes in pulmonary ventilation parameters can potentially influence cerebral circulation due to changes in CO2 content in arterial blood. Objective. To assess the effect of yoga breathing exercises with changes in pulmonary ventilation levels on blood flow parameters in the middle cerebral artery (MCA). Methods. The study included 21 participants, with an average age of 39.5±8.7 years, who were capable of performing yoga exercises at respiratory rates (RR) of 3–3.5/min and 1–1.5/min. For 5 minutes, participants underwent three stages: free breathing (stage 1), breathing with RR=3–3.5/min (stage 2), and breathing with RR=1–1.5/min (stage 3). During stages 2 and 3, the «full breathing» technique, which involves maximum deep inhalation and exhalation, was employed. Respiratory rate (RR), tidal volume (TI), minute ventilation (MV), end-tidal CO2 partial pressure (PetCO2), and oxygen fraction in exhaled air (FeO2) were recorded using spiro-gas analysis. Transcranial duplex scanning was used to measure peak systolic blood flow velocity (Vps), end-diastolic blood flow velocity (Vd), time-averaged maximum blood flow velocity (TAMAX), and resistance index (RI) in the right MCA. The velocity variation index (VVI) was calculated for each stage. Results. Compared to stage 1 (free breathing), stage 2 (RR = 3–3.5/min) showed an increase in MV and FeO2, a decrease in PetCO2, and reductions in Vps, Vd, and TAMAX, with an increase in RI. VVI decreased statistically insignificantly. In stage 3 (RR = 1–1.5/min), compared to stage 1, there was an increase in PetCO2, a decrease in MV and FeO2, and increases in Vps, Vd, and TAMAX, with a decrease in RI. VVI increased significantly. Conclusions. Yoga breathing exercises at respiratory rates of 3–3.5/min and 1–1.5/min result in multidirectional shifts in ventilation and gas exchange parameters, leading to changes in arterial cerebral blood flow (a decrease and increase in blood flow velocity with an increase and decrease in MV, respectively). VVI, reflecting fluctuations in blood flow velocity, increases significantly with reduced MV, likely due to the vasodilatory effect of CO2.

Investigating the stability of a cerebral vasodilator drug using chromatographic methods: Evaluation of methods’ practicality and environmental aspects

A vinca alkaloid; vinburnine (VNB) is utilized as an effective vasodilator. As a cyclic amide-containing drug, it is likely susceptible to hydrolytic degradation. This study examined the degradation profile of VNB, findings indicated that VNB undergoes degradation solely in the presence of alkali, generating a carboxylic acid derivative (DEG). The present study aimed to design and apply green TLC-densitometric and RP-HPLC assays for concurrently measuring VNB and its degradation product for the first time. TLC-densitometric assay was carried out on silica gel 60 F254 TLC plates and a developing system of ethyl acetate: methanol: triethylamine (6:4:0.05, by volume) and detection at 230 nm. RP-HPLC method depended on a C8 column and a mixture of methanol: water (95:5, v/v). The rate of flow was 1 mL/min and UV detection at 230 nm. The proposed assays were used for prediction of the degradation behavior of VNB under the mentioned conditions and then applied for quantitation of VNB in its commercially available capsules. Four distinct metric approaches; National Environmental Method Index (NEMI), Analytical Eco-Scale, Green Analytical Procedure Index (GAPI), and Blue Applicability Grade Index (BAGI) were utilized to assess the chromatographic method’s ecological effect. Findings obtained from the provided methodologies were contrasted statistically with the stated HPLC method using Student’s t and F-tests. The analysis revealed that there were no significant differences between them. The established methods were verified in accordance with the recommendations of the International Council for Harmonization (ICH), and all the outcomes were deemed to fall within the permissible limit.

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

Firsthand data acquisition for hypertension, its amelioration by extract of Bougainvillea spectabilis and formulation of nanoparticles

Hypertension is a widespread cardiovascular condition characterized by persistently elevated blood pressure, leading to serious health complications such as heart disease, stroke, and renal failure. This study investigates the antihypertensive properties of Bougainvillea spectabilis extract, focusing on its potential mechanisms of action and therapeutic efficacy. Using a controlled experimental design, hypertensive rats were treated with varying doses of Bougainvillea spectabilis extract. Blood pressure measurements were taken before and after treatment using a non-invasive tail-cuff method. Phytochemical analysis of the extract revealed a rich composition of bioactive compounds, including flavonoids, alkaloids, and tannins, known for their cardioprotective and vasodilatory effects. Results demonstrated a significant reduction in both systolic and diastolic blood pressure in treated subjects compared to the control group. Additionally, improvements in endothelial function were observed, indicated by increased nitric oxide levels and decreased oxidative stress markers. Histological analysis of vascular tissues showed enhanced integrity and reduced inflammation. These findings suggest that Bougainvillea spectabilis extract exerts a dual action: promoting vasodilation and improving endothelial health. The results support the potential of Bougainvillea spectabilis as a natural antihypertensive agent, highlighting the need for further research to elucidate its mechanisms and evaluate its clinical applicability in managing hypertension.

Effect of repeated hot and cold stimulation for the neck and shoulders on muscle fatigue recovery: a pilot study.

Increased use of electronic devices such as smartphones has led to an increase in neck and shoulder stiffness to the forefront of the public people. It is said that prolonged posture with the head tilted forward causes excessive muscle activity in the head and neck region, resulting in muscle fatigue symptoms such as stiff shoulders. Various bathing methods have been proposed as a means of recovering from muscle stiffness, and in particular, contrast water therapy (CWT) is said to be highly effective in recovering from muscle fatigue. In the present study, we examined the effect of CWT with hot and cold stimulation of the neck and shoulders (CWTNS) on muscle fatigue recovery. As the result, in the CWTNS condition, the effects of vasodilation and vasoconstriction were observed, and muscle hardness was significantly lower than that in the Control condition in 20 subjects (2 males, 18 females). Stress hormones were also decreased during and after bathing compared to those before bathing. These results motivate further exploration of the possibility that the effects of CWTNS could be muscle-recovery without high stress load.

Feasibility of controlled nitric oxide generation via ascorbate induced chemical reduction of nitrite ions.

Inhalable nitric oxide (iNO) is a lifesaving, FDA-approved drug to improve oxygenation in persistent pulmonary hypertension of the newborn. iNO also has many other applications in lung diseases owing to its vasodilatory and antimicrobial effects. However, its wider therapeutic application is often prohibited by the high cost and logistical barriers of traditional NO/N2 gas tanks. Development of low-cost, portable and tankless nitric oxide (NO) generators is a critical need to advance iNO therapy. Here, we describe the feasibility of NO generation by the controlled reduction of nitrite (NO2-) ions. This was accomplished by using ascorbate to reduce NO2- ions mediated by a copper(I/II) redox pair complexed by an azo-crown ether ligand ([Cu(II)L]2+/[Cu(I)L]+) in the solution phase. We found that oxalate, a decomposition product of ascorbate, interferes with the NO generation from the copper-ligand complex. This interference was mitigated, and the reaction was further optimized. NO generation through this method was found to be highly controllable via its proportionality to the flow rate of NO2- injected into a reaction chamber containing the reducing components. Hence, this simple approach adds to the current collection of innovative methods under development to obviate the use of NO tanks for iNO delivery.

Nitric Oxide and Small and Intermediate Calcium-Activated Potassium Channels Mediate the Vasodilation Induced by Apigenin in the Resistance Vessels of Hypertensive Rats.

Apigenin (4',5,7-trihydroxyflavone), a flavonoid with potential cardiovascular benefits, has unclear mechanisms of action. This study investigates its effects on vascular function in Spontaneously Hypertensive Rats (SHRs). Mesenteric vascular beds (MVBs) were isolated from SHRs and perfused with increasing doses of apigenin after pre-contraction with phenylephrine. To explore the mechanisms, different MVBs were pre-perfused with antagonists and inhibitors, including indomethacin, L-NAME, and potassium channel blockers (tetraethylammonium, a non-specific potassium channel blocker; glibenclamide, an ATP-sensitive potassium channel blocker; 4-aminopyridine, a voltage-gated potassium channel blocker; charybdotoxin a selective intermediate-conductance calcium-activated potassium channel blocker; and apamin, a selective small-conductance calcium-activated potassium channel blocker). Apigenin induced a dose-dependent reduction in perfusion pressure in MVBs with intact endothelium, an effect abolished by endothelium removal. L-NAME reduced apigenin-induced vasodilation by approximately 40%. The vasodilatory effect was blocked by potassium chloride and tetraethylammonium. The inhibition of small and intermediate calcium-activated potassium channels with charybdotoxin and apamin reduced apigenin-induced vasodilation by 50%, and a combination of these blockers with L-NAME completely inhibited the effect. Apigenin promotes vasodilation in resistance arteries through endothelial nitric oxide and calcium-activated potassium channels. These findings suggest that apigenin could have therapeutic potential in cardiovascular disease, warranting further clinical research.

The effectiveness of vasodilators on chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Chronic obstructive pulmonary disease (COPD) is a complex progressive disease. Some vasodilators have been reported with therapeutic potential to protect vascular function therefore may delay the progression of COPD. We searched PubMed, Embase, Cochrane Library, Web of Science, OVID and Clinicaltrials.gov database for eligible randomized controlled trials (RCTs) published before January 1, 2024. RCTs which treatment with vasodilators to COPD patients were included. Gas-blood exchange indicators were the primary outcomes, and ventilation function and quality of life indicators were the secondary outcomes. Mean differences with 95% confidence intervals were extracted. Subgroup analysis of vasodilator category and COPD complicated with or without pulmonary hypertension (PH) were performed. The risk of bias was assessed using Cochrane risk of bias tool, and the meta-analysis was conducted. Twenty studies with a total sample size of 986 were included. The results showed that the 2 types of drugs in vasodilators included PDE-5 inhibitors could improve DLCO (MD = 6.56 [95% CI (1.74, 11.39)], P = .008) and iNO could reduce PaCO2 (MD = -0.10 [95% CI (-0.17, -0.03)], P = .006). Vasodilators could reduce PaCO2 in COPD complicated with PH (COPD-PH) (MD = -0.10 [95% CI (-0.17, -0.03)], P = .006). There were no statistically significant differences in FEV1 (MD = 0.02 [95% CI (-0.11, 0.16)], P = .74), FEV1% predicted (MD = 0.07 [95% CI (-1.90, 2.05)], P = .94), FEV1/FVC (MD = 0.70 [95% CI (-4.02, 5.42)], P = .77) and VE/VCO2 (MD = -0.17 [95% CI (-2.39, 2.05)], P = .88) levels. The total SGRQ score was significantly lower in vasodilator groups (MD = -5.53 [95% CI (-9.81, -1.24)], P = .01). The therapeutic effects of vasodilators for COPD are controversial. In this meta-analysis, vasodilators have benefits in improving gas-blood exchange function and quality of life in COPD patients. However, vasodilators may have a limited capacity to improve pulmonary function.

Abstract 4137484: Clinical implications of combined midodrine and pulmonary vasodilator therapy in Portopulmonary Hypertension

Introduction: Portopulmonary hypertension (POPH) and associated pulmonary vascular resistance (PVR) elevation is seen in the context of underlying portal hypertension and liver disease. In the systemic circulation, liver cirrhosis can cause inappropriate splanchnic and systemic vasodilation with decreased systemic vascular resistance (SVR). Midodrine is used to maintain blood pressure in the setting of low SVR. Pulmonary vasodilators have systemic vasodilatory effects; the implications of combined midodrine and pulmonary vasodilator use in POPH are unanswered questions. Hypothesis: We hypothesized that SVR would decrease over time in patients with POPH started on pulmonary vasodilators, and that use of midodrine (as a surrogate for depressed SVR), may be associated with increased risk of mortality in patients with POPH starting pulmonary vasodilator therapy. Methods: Patients from the 3 Mayo Clinic sites (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) diagnosed with POPH from 1988-2020 were included in the database. Patients met hemodynamic criteria for POPH via right heart catheterization (RHC). Hemodynamics were obtained from echocardiography and RHC at initial and subsequent visits. The hazard ratio for risk of death was estimated using Cox proportional hazards method. SVR was calculated using mean arterial pressure and cardiac output. Results: Analysis included 147 POPH patients, 34 (23%) on midodrine and 113 (77%) not requiring midodrine. There were 116 patients with longitudinal SVR data. The mean initial SVR was 1224 Dyne sec cm-5 and decreased 251 Dyne sec cm-5 [95% CI -337 to -165 251 Dyne sec cm-5, p&lt;0.0001] with no difference between midodrine groups (p=0.57). Patients in the midodrine POPH group had an increased risk of mortality compared to those without midodrine use (HR 1.51, 95% CI: 1.02-2.21, p=0.0371). Conclusions: Patients with POPH starting pulmonary vasodilator have a reduction in SVR related to vasodilator therapy. Midodrine use with pulmonary vasodilator therapy is associated with increased mortality in the POPH population. Further study of the safety of combined midodrine and pulmonary vasodilator use in POPH is needed along with exploration of more selective pulmonary vasodilators.

Abstract 4140123: Real-time imaging of microvasculature obstruction and the vasculoprotection of nitric-oxide-donor nanoparticles during acute myocardial ischemia/reperfusion injury

Background/Introduction: Microvascular obstruction (MVO), due to damage to the coronary microvasculature, is a key determinant of infarct size, heart failure and poor outcomes following acute myocardial infarction, and there is currently no treatment for preventing MVO. Real-time in vivo imaging of MVO in the beating rodent heart is challenging due to the limited spatial and temporal resolution from movement artifacts. Here, we apply, for the first time, fiber-optic confocal laser endomicroscopy (CLM) for real-time imaging of the microvasculature in a beating murine heart with acute ischemia/reperfusion injury (IRI), and then monitoring the development of MVO. Methods: An in vivo murine acute myocardial IRI model (45 min ligation of left coronary artery (LCA) and 30 min reperfusion) was applied. At 10 min prior to ischaemia, 150 µl Dextran-FITC (150 kDa, 10 mg/ml) was injected retro-orbitally, and then CLM imaging with a flexible miniprobe (ProFlex S-1500 with CellVizio system) was applied to the epicardial surface at multiple sites at 5 min post-injection (baseline), 30 min post-ischemia and 30 min post-reperfusion. A nitric oxide donor(NO) nanoparticle (NONP) was synthesized and IV bolus injected into IRI mice 5min prior to reperfusion to prevent MVO. Results: We confirmed visualization of the macro- and microvasculature at various sites on the epicardial surface of the beating heart. Next, we observed reduced microvasculature blood flow below LCA ligature as evidenced by reduced or even totally absence of FITC within the vessels at 30min post-ischemia. The microvasculature at the non-ischemic myocardium was unaffected. Furthermore, at 30 min post-reperfusion, we visualised patchy areas of reduced FITC signal suggesting MVO, and damaged microvasculature as evidenced by leakage of FITC outside the vessel. Interestingly, NONP treatment preserved the microvascular network and prevented MVO at 30 min post-reperfusion with even greater FITC, suggesting increased microvascular blood flow and penetration into cardiac tissue because of the vasodilatory effect of NO in the ischemic area. Conclusion: With CellVizio CLM system, we have demonstrated the MVO development during IRI, and damage to the microvasculature with leakage of dye from vessels into cardiac interstitium, thereby providing a pre-clinical platform to test novel therapeutic agents for preventing MVO. Importantly, we have shown an effective MVO prevention with NO-donor nanoparticle following IRI in mice.

Abstract 4135357: Activation of prostaglandin E receptor 4 attenuates pulmonary vascular remodeling and pulmonary hypertension in monocrotaline-exposed rats via non-inflammatory pathway

Backgrounds: The prostacyclin pathway plays a pivotal role in the treatment of pulmonary arterial hypertension (PAH). Meanwhile, there is evidence that the expression of IP, the target of prostacyclin, is scant in PAH patients, whereas the prostaglandin E receptor 4 (EP 4 ) remains stable. EP 4 , similar to IP, exerts vasodilative effect via cAMP. In addition, an orally administrable selective EP 4 agonist, KAG-308, has shown to exert anti-inflammatory effect in patients with ulcerative colitis and the mouse with surgically induced osteoarthritis. However, the effect of KAG-308 on pulmonary vasculature of PAH remains unknown. Hypothesis: EP4 agonist ameliorates pulmonary vascular remodeling and pulmonary hypertension (PH). Methods and Results: We investigated the effects of KAG-308 on hemodynamics and pulmonary vascular remodeling in a monocrotaline (MCT)-exposed rat model of PH. Compared to normal rats, MCT-exposed rats had higher right ventricular systolic pressure (RVSP), total pulmonary vascular resistance index (TPRI) and RV hypertrophy, together with medial wall thickening and increased activation of nuclear factor kappa B (NFkB) and inflammatory cytokines in the lungs on day 21 after MCT injection. Chronic oral administration of KAG-308 (1 mg/kg, twice daily, by gavage, day 0 to 21) lowered RVSP (53.1 ± 9.3 vs 81.0±18.5 mmHg, p &lt;0.01), TPRI (112.0 ± 16.6 vs 161.4 ± 37.0 mmHg/mL/min/g, p &lt;0.05) and RV hypertrophy (0.47 ± 0.04 vs 0.57±0.10, p &lt;0.05). Elastica van Gieson staining showed attenuation of medical wall thickening. Furthermore, KAG-308 significantly reduced NFkB activation and inflammatory cytokines such as Il6 , Mcp1 and Il1b in the lungs. In addition, chronic KAG-308 administration didn’t alter the level of cAMP in the lung, suggesting that the reduction of TPRI wasn’t the results of vasodilation. Interestingly, in human pulmonary artery smooth muscle cells (PASMCs) stimulated by TNFα 10ng/ml, pretreatment with KAG-308 significantly upregulated mRNA level of Il6 (5.9±0.1vs 1.0±0.1, p &lt;0.05), whereas downregulated Ki67 (0.4±0.1 vs 1.0±0.2, p &lt;0.05), suggesting anti-proliferative effect via non-inflammatory pathway. Conclusions: KAG-308 ameliorated pulmonary vascular remodeling and PH in MCT-exposed rat, whereas it didn’t show anti-inflammatory effect but anti-proliferative effect in human PASMCs. Although EP 4 agonist KAG-308 could be a potential therapeutic agent for the treatment of PAH, the mechanism of anti-proliferation remains to be elucidated.

In silico prediction of the pharmacological potential of new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine

The development of new drug-like molecules based on 7-R-8-hydrazine derivatives of 1,3-dimethylxanthine is promising in view of the known pharmacological effect of theophylline and functional hydrazine derivatives. In silico methods make it possible to rationalize the synthesis and reduce the number of chemical compounds at the stage of virtual screening by eliminating potentially ineffective molecules. The aim of the work was to carry out а virtual design and predictive evaluation of pharmacological activity of new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine by in silico methods. Materials and methods. To perform in silico prediction of the pharmacological potential of several new 7-alkyl-8-hydrazine derivatives of 1,3-dimethylxanthine, we used the online services. As 12 model compounds, we chose 12 derivatives of 5-(2-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)hydrazine)-5-phenylpentanoic acid with linear and branched alkyl substituents at the 7th position of the basic heterocycle: methyl-, ethyl-, n-propyl-, n-butyl, i-butyl, n-amyl, i-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl. The use of the freely available web tool SwissADME made it possible to calculate physicochemical parameters and to determine the drug-likeness properties of molecules. And other Internet platforms allowed to predict the spectrum of biological activity of the target compounds. Results. In silico analysis of the pharmacological potential of model compounds was performed. Three biological actions (peripheral vasodilator, kidney function stimulant, lipoprotein lipase inhibitor) with high Pa values are predicted for all derivatives of the series. The ADME parameters of the molecules were evaluated and their potential drug-like properties were determined. Conclusions. It was established that the extension of the alkyl substituent at the 7th position of the basic heterocycle should lead to a deterioration of the ADME parameters of the molecules, potentially reduce their oral bioavailability, but should not radically affect their biological activity profile. Compounds 1–3 and 5 are predicted to be orally bioavailable. They should be characterized by a wide spectrum of biological activity with the highest probability of vasodilator effect on peripheral vessels. In the future, it is advisable to carry out targeted synthesis of hit compounds and thorough in vitro, in vivo studies, and for compounds with violated physicochemical criteria – structural optimization of molecules in order to find a lead compound.

Biological activities of quercetin and other flavonols: A mini-review

There are countless benefits arising from the consumption of vegetables, which can present significant levels of compounds with bioactive properties, effectively acting in the promotion of human health. Bioactive compounds that play an antioxidant role have been widely studied since most of the diseases that affect humans can be derived from the presence of free radicals in the body, leading to a series of metabolic disorders. Quercetin has several pharmacological activities and antioxidant, anti-inflammatory, vasodilator, and anticancer effects. Despite the efficacy and safety of its consumption, the limited bioavailability of this phenol continues to be highlighted as a main concern, where factors such as solubility, absorption, and metabolism have a direct influence on this process and its beneficial effects. Among the compounds with antioxidant activity are flavonoids, such as quercetin, which have shown great effectiveness and are even associated with very positive responses against some types of tumor cells. Quercetin is shown to be a powerful ally in promoting health and a better quality of life. However, further studies are needed to be able to accurately state the benefits resulting from the consumption of this compound.

Preliminary Characterization of the Vasorelaxant Effect of Thymus atlanticus (Ball) Roussine Using Optical Methods.

Thymus atlanticus (Ball) Roussine is a Moroccan endemic thyme species that is traditionally used as an aromatic and medicinal plant. Several studies have demonstrated its pharmacological significance and therapeutic value. The current study aimed to assess the vasorelaxant effect of the aqueous extract of this species. The contractility of isolated rat aortas was investigated using the multi-well organ bath technique. This method was adapted and validated in our experimental conditions using epinephrine and hydralazine as vasoconstrictive and vasodilator agents, respectively. The application of 10 μM epinephrine induced a clear vasoconstriction of the aorta rings (Lumen reduction = 31.8±0.4%). However, hydralazine induced a dose-dependent relaxation with an EC50 value of 6.1±1.2 mM. For the aqueous extract of T. atlanticus, the aortic rings were precontracted with epinephrine, and then increasing concentrations (0.125-1 mg/mL) of this extract were added cumulatively. The results have indicated T. atlanticus extract to have a significant vasodilatory effect in a dose-dependent manner (EC50 = 0.52±0.03 mg/mL). The findings provide preliminary evidence of the vasorelaxant effect of the aqueous extract of T. atlanticus using a low-cost optical approach. However, the cellular and molecular mechanisms underlying this effect have yet to be revealed.

Benefits of Tadalafil and Sildenafil on Mortality, Cardiovascular Disease, and Dementia

BackgroundErectile dysfunction and lower urinary tract symptoms, from benign prostatic hyperplasia and bladder neck obstructions, are prevalent in men and associated with an increased risk of cardiovascular diseases. Phosphodiesterase-5 (PDE-5) inhibitors, such as tadalafil and sildenafil, are used to treat erectile dysfunction and may also offer cardiovascular benefits due to their vasodilatory effects. This study evaluates the impact of these PDE-5 inhibitors on all-cause mortality, cardiovascular disease, and dementia in middle-aged men with erectile dysfunction and lower urinary tract symptoms over a 3 year follow-up period. MethodsThis longitudinal study analyzed data from 50 million US men using the TriNetX database. Men at least 40 years of age prescribed tadalafil or sildenafil after an erectile dysfunction diagnosis, or tadalafil after lower urinary tract symptom diagnoses, from 2004 to 2021 were included. Three-year outcomes assessed included all-cause mortality, cardiovascular disease, and dementia, comparing men on PDE-5 inhibitors to those not on these medications. Propensity matching was performed for demographics and eight pre-existing conditions. ResultsThe final cohort included 509,788 men with erectile dysfunction and 1,075,908 with lower urinary tract symptoms. Tadalafil and sildenafil were associated with significantly reduced risks of all-cause mortality (RR 0.66/0.76), myocardial infarction (0.73/0.83), stroke (0.66/0.78), venous thromboembolism (0.79/0.80), and dementia (0.68/0.75) in erectile dysfunction patients, with tadalafil showing more significant benefits. In lower urinary tract symptom patients, tadalafil was similarly associated with reduced mortality, cardiovascular disease, and dementia. ConclusionsIn conclusion, tadalafil and sildenafil use in erectile dysfunction patients reduced mortality, cardiovascular disease, and dementia risks, with tadalafil providing more benefits. Tadalafil also conferred similar benefits to patients with lower urinary tract symptoms.

Low-dose oral minoxidil does not significantly affect blood pressure: A systematic review and meta-analysis

IntroductionMinoxidil, traditionally used as an anti-hypertensive, is now widely used for treating various forms of alopecia due to its vasodilatory effects. While topical minoxidil has been the standard treatment, low-dose oral minoxidil (LDOM) is emerging as an effective alternative. This study investigates LDOM’s potential hypotensive effects. MethodsStudies were selected based on criteria such as the use of LDOM (≤5 mg/day) and reporting on blood pressure changes. Mean differences (MD) were calculated for mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR). ResultsLDOM did not significantly alter SBP (MD: -0.13, 95% CI: -2.67-2.41) or DBP (MD: -1.25, 95% CI: -3.21-0.71). Though MAP was not significantly altered, there was a strong tendency towards decreased MAP (MD: -1.92, 95% CI: -4.00-0.17). There was a significant increase in HR (MD: 2.67, 95% CI: 0.34-5.01). Hypotensive symptoms were reported in 119 patients (5.0%), but no hypotensive episodes were observed. Hypertrichosis was the most frequent side effect, leading to 34.6% of discontinuations. LimitationsStudies lacked control groups and showed variability in dosing regimens and blood pressure monitoring. ConclusionLDOM appears to be a safe treatment for alopecia with no significant impact on blood pressure.