Vasodilatory Effects Research Articles

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<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.

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.

Role of Glutamine Synthetase on Vascular Permeability in Gliomas.

This study aimed to investigate the effect and underlying mechanism of inhibiting glutamine synthetase (GS) on the vascular permeability of gliomas. C6 glioma rat models were randomly divided into control and L-methionine sulfoximine (MSO) treatment groups. MSO was intraperitoneally injected once every other day for a total of three injections in the MSO group. We assessed the effect of MSO on tumor vascular permeability by tail vein injection of Evans blue dye. GS activity, glutamate (Glu) concentration, glutamine (Gln) concentration, and arginine concentration in tumor tissues were measured using the corresponding kits. qPCR experiments were then conducted to examine the effect of glutamate concentration on N-methyl-D-aspartate (NMDA) receptor expression. Finally, the nitric oxide synthase (NOS) assay kit and the nitric oxide (NO) assay kit were employed to detect NOS activity and NO concentration changes, respectively. Increased glioma tumor vascular permeability was observed after intraperitoneal injection of MSO; MSO acted as an inhibitor of GS, leading to a decrease in GS activity; increased glutamate levels caused activation of NMDA receptors and further activation of NOS; additionally, elevated NO levels were detected in association with an increase in arginine and NOS. Inhibiting GS results in increased vascular permeability in gliomas, which is associated with elevated NO levels and the vasodilatory effects of NO.

Expression of soluble guanylate cyclase (sGC) and its ability to form a functional heterodimer are crucial for reviving the NO-sGC signaling in PAH

In order to determine the underpinnings of a dysfunctional NO-sGC signal pathway which occurs in pulmonary arterial hypertension (PAH), we investigated pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients. We found low expression of sGC, a poor sGCα1β1 heterodimer and this correlated with low expression of its facilitator chaperon, hsp90. Treating PASMCs overnight (16 h) with low micromolar doses of a slow release NO donor DETANONOate, reinstated the sGCα1β1 heterodimer and restored its NO-heme dependent activity. Transwell co-culture of HEK cells stably expressing eNOS with PAH PASMCs also restored the sGC heterodimer and its heme-dependent activity with sGC stimulator, BAY 41–2272. To determine whether the dysfunctionality in the NO-sGC pathway stems from a dysfunctional eNOS producing negligible NO, we did transwell co-cultures of pulmonary arterial endothelial cells (PAECs) with PASMCs. Our results indicated that PAECs from both control and PAH samples when activated for eNOS restored both sGC heterodimer and its heme-dependent sGC activity in the corresponding PASMCs, suggesting that PAECs from PAH can also generate NO. In line with these results expression of eNOS, its support chaperon hsp90, its specific kinase Akt, p-Akt or post-translational modifications (PTMs) like OGlcNAc or phospho-tyrosine were unchanged in PAH relative to controls. Additionally there was uniform expression of Hbα/β and Mb in PASMCs or PAECs in PAH or controls and these globins can effectively scavenge the eNOS generated NO, as there was evidence of strong eNOS-Hb/Mb interactions. Our studies suggest that factors such as globin NO scavenging along with vascular remodeling in PAH can cause hampered vasodilation which in the face of poor NO levels as occurs in PAH are additional impediments for effective vasodilation. However importantly our studies suggests that future therapies can use low doses of NO along with sGC stimulators as a potential drug for PAH subjects.

The safety and efficacy of treprostinil for the treatment of pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Pulmonary arterial hypertension (PAH) is a severe and life-threatening condition characterized by increased pulmonary vascular resistance and elevated mean pulmonary artery pressure. Treprostinil, a prostacyclin analog, has vasodilatory and anti-remodeling effects on pulmonary arterial smooth muscle cells, indicating promising benefits in enhancing exercise capacity, improving hemodynamics, and reducing morbidity in patients with PAH. Aim The primary objective of this systematic review and Meta-analysis is to assess the efficacy and safety of Treprostinil in patients with PAH. Methods We systematically searched PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov from inception until July 2023. Randomized controlled trials comparing Treprostinil with Placebo were selected. We used the mean values to compare continuous data and odds ratio (OR) for dichotomous outcomes with their 95% confidence interval (CI). Results We included 7 studies with a total of 2,447 patients. The Treprostinil group was favored over the control group in terms of 6-minute walk distance (6MWD) (Mean difference (MD), meters (m)) (MD = 15.16 m, 95% confidence interval (CI) (10.42 – 19.90 )). Subgroup analysis based on the route of administration revealed a 6MWD of (MD = 13.55 m (95% CI (7.82 – 19.28)) for oral administration and (MD = 17.49 m, 95% CI (6.01 – 28.89)) for intravenous (IV)/subcutaneous (SC) administration, indicating enhanced exercise capacity. When evaluating the efficacy of Treprostinil for oral administration, there was a slight but non-significant trend toward functional improvement (Odds Ratio (OR): 1.36; 95% CI: 0.95 to 1.93) and no significant change in maintaining functional status (OR: 0.94; 95% CI: 0.59 to 1.51). In terms of functional deterioration, the risk was also not significantly reduced (OR: 0.84; 95% CI: 0.36 to 1.98). Safety assessment of the drug was based on clinical, mortality, and adverse events outcomes. Clinically, Treprostinil demonstrated a protective effect against disease progression, evidenced by a reduced risk of clinical worsening (OR: 0.69; 95% CI: 0.52 to 0.91). Mortality rates were not significantly impacted by Treprostinil addition (OR: 0.95; 95% CI: 0.57 to 1.58 for oral, 0.80; 95% CI: 0.32 to 1.98 for IV/SC). However, the incidence of adverse events was notably higher among Treprostinil-treated patients, particularly with oral administration. Conclusion The addition of Treprostinil therapy for patients with PAH significantly improved exercise capacity, as evidenced by an increase in the 6MWD compared to control groups and demonstrated a reduced risk of clinical worsening. The incidence of adverse events was higher among Treprostinil-treated patients, especially with oral administration, potentially impacting quality of life.Forest plot of the 6MWD

A Comparison of Remimazolam versus Propofol on Blood Pressure Changes During Therapeutic Endoscopic Retrograde Cholangiopancreatography: A Randomized Controlled Trial.

Intraoperative hypotension is the most common adverse event in endoscopic retrograde cholangiopancreatography (ERCP) and is usually attributed to the vasodilatory effect of the anesthetic. The aim of this randomized controlled trial was to evaluate the impact of remimazolam versus propofol on blood pressure changes during the therapeutic ERCP procedure. Adult patients scheduled for elective therapeutic ERCP were randomized to receive either remimazolam or propofol anesthesia (40 patients in each group). The primary outcomes included the change in mean arterial pressure (MAP) during induction and the area under the baseline (AUB), calculated as the blood pressure below baseline multiplied by the duration, throughout the procedure. These measures, respectively, indicated the severity of blood pressure decrease during anesthesia induction and the overall impact of blood pressure changes throughout the procedure. Any incidences of hypotension, defined as MAP <65 mm Hg for at least 1 minute, were recorded. The recovery time and any adverse events were also reported. The change in MAP after induction was smaller in the remimazolam group compared to the propofol group (-7.5 [-14.0 to 0] mm Hg vs -25.0 [-33.8 to -14.3] mm Hg), with a median difference of 17.0 mm Hg (95% confidence interval [CI], 12.0-22.0; P <.001). The AUB in the remimazolam group was less than in the propofol group (-373 [-82 to -854] mm Hg·min vs -705 [-272 to -1100] mm Hg·min), with a median difference of 255 mm Hg·min (95% CI, 29-477; P =.021). The incidence of hypotension was significantly lower for remimazolam than propofol (5% vs 30%; P =.006). There were no serious adverse events in either group. Remimazolam may be considered as an alternative to propofol for general anesthesia during therapeutic ERCP procedures, with the potential advantage of stable hemodynamics.

Effect of 5β-dihydrotestosterone on vasodilator function and on cell proliferation.

Aging is one of the main factors associated with cardiovascular diseases. Androgens exert beneficial effects on the cardiovascular system and testosterone (TES) replacement therapy improves cardiometabolic risk factors. However, TES is contraindicated in patients with prostate cancer due to its proliferative effects on prostatic tumor cells. Additionally, TES and its reduced metabolites 5α- and 5β-dihydrotestosterone (5α-DHT and 5β-DHT) exert vasodilatory effects. Since androgen levels decrease during aging and 5β-DHT lacks genomic effects, this study is focused on analyzing its effect on vasodilator function and the proliferation rate of prostatic tumor and vascular smooth muscle cells. To study the vascular function, mesenteric arteries from aged-orchidectomized Sprague-Dawley rats were used. Mesenteric segments were divided into one control (without treatment) and three groups with the androgens (10 nM, 30 min) to analyze: acetylcholine- and sodium nitroprusside-induced responses and nitric oxide and superoxide anion production. To analyze cell proliferation, the effect of androgens on cell viability was determined. The results showed that 5β-DHT improves vasodilator function in arteries from aged-orchidectomized rats and induces antioxidant action, while the proliferation rate of the androgen-dependent prostatic tumor cells remains unaltered. These results make 5β-DHT a promising therapeutic agent for the treatment of cardiovascular pathologies.

Effects of Papaverine on Experimentally Induced Myringosclerosis.

This study aims to investigate the effects of papaverine on experimentally induced myringosclerosis (MS). MS is characterized by hyaline degeneration and calcification of the lamina propria of the tympanic membrane and can adversely affect hearing function if left untreated. The study examined the potential effects of both systemic and topical applications of papaverine on this process. In the study, 20 Wistar albino rats were used. The rats were divided into 4 groups and different treatment methods were applied in each group. In group 1, myringotomy was performed, but no additional intervention was performed. In group 2, saline-impregnated gelfoam was applied after myringotomy. In groups 3 and 4, topical and systemic applications of papaverine hydrochloride were performed. Tympanic membranes were examined under a microscope after 21 days, and the severity of MS and histopathologic changes were evaluated. The papaverine-treated groups observed a significant increase in otomicroscopic sclerosis, the degree of inflammation, and tympanic membrane thickness. The degree of fibrosis was higher in group 3 compared with the other groups. The results showed that papaverine administration increased the occurrence of MS. This study suggests that papaverine may increase MS through its vasodilating effect. Vasodilation is thought to cause an increase in oxygen-derived free radicals, which may contribute to the pathogenesis of MS. The results suggest that the effects of papaverine on MS should be carefully evaluated.

Effects of inhaled nitric oxide on endothelial function in patients with ischemic stroke

BACKGROUND: A crucial pathogenetic link in the development of stroke is the deterioration of endothelial function, which is a pathological condition characterized by an imbalance between endothelium-dependent relaxing and constricting factors. An example of an endothelium-dependent relaxing factor is nitric oxide, a substance synthesized by the body’s cells that has a vasodilating, antithrombogenic, anti-inflammatory, and antiproliferative effect. Studies have shown the neuroprotective function of inhaled nitric oxide after ischemia; however, determining the minimum effective dose of inhaled nitric oxide in patients who have suffered an acute cerebrovascular accident remains challenging. AIM: To analyze the protective effect of exogenous nitric oxide using the TIANOX device on the vascular endothelium in patients who have had an ischemic stroke in the early and late recovery period during medical rehabilitation. MATERIALS AND METHODS: The study involved 21 patients (10 people in the main group, 56.9±8.9 years old, 11 people in the control group, 57.2±8.8 years old) in the early or late recovery period after an ischemic stroke. Patients in the main group underwent an individual medical rehabilitation program and a course of 8–10 inhalations of a gas mixture with nitric oxide at 20 ppm for 20 minutes. Those in the control group underwent an individual rehabilitation course without nitric oxide therapy. Flow-dependent vasodilation of the brachial artery was evaluated to assess endothelial function. RESULTS: In the main group, a statistically insignificant (p 0.05) increase was found in the diameter of the brachial artery (3.68±0.64 mm), whereas in the control group, this indicator at rest during repeated diagnostics was less than the initial one (3.09±0.87 mm). During repeated diagnostics, the average endothelial shear velocity in patients of the control group increased from 141.53±52.62 to 159.3±82 versus from 143.17±43.53 to 143.48±46.37 in the main group; however, the results were not statistically significant (p=0.753). CONCLUSION: The increase in the diameter of the brachial artery during flow-dependent vasodilation in patients in the main group may indicate a prosthetic effect of the exogenous form of nitric oxide when using the Tianox device on the vascular endothelium, owing to the possibility of depositing nitric oxide in the body. To confirm the obtained data, a larger sample size of patients is critical in order to further divide the groups of patients into early and late recovery periods after ischemic stroke.

Monocrotaline-induced pulmonary arterial hypertension: the benefic effects of magnesium sulfate, Rosuvastatin and Sildenafil.

Pulmonary arterial hypertension (PAH) is characterized by several maladaptive mechanisms: endothelial dysfunction, oxidative stress, inflammation, pathological remodeling of the pulmonary arterioles, and cellular hypoxia. These mechanisms all favor progressive pulmonary vasculopathy and progressive right ventricle (RV) dysfunction. This study aims to characterize the experimental model of monocrotaline-induced PAH in rats. Subsequently, by administering Sildenafil, Rosuvastatin, and Magnesium sulfate, we assessed the animals via ultrasonography and assayed biochemical parameters to evaluate the efficacy of the treatment. 42 male Wistar rats were randomly allocated into six equal groups (n=7) and received a single subcutaneous MCT injection (60 mg/kg dose). Drug therapy with Sildenafil, Rosuvastatin, and Magnesium sulfate in different combinations was initiated 14 days after MCT injection. Fulton Index, RV anterior wall thickness, RV internal diameter, and pulmonary arterial acceleration time/ejection time (PAAT/PAET) were measured. The following biochemical parameters were also measured: endothelin 1(ET1), brain natriuretic peptide (BNP), nitric oxide (NO) metabolites, vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS). MCT-PAH was a successful experimental model that has fulfilled anatomical, pressure, and biochemical characteristics supporting this fact. Sildenafil monotherapy does not provide any substantial benefit in reducing MCT-PAH. The additive effects of Rosuvastatin + Sildenafil or Sildenafil + Magnesium sulfate significantly reduced the degree of RV hypertrophy and improved RV systolic pressures. However, there were also modest decreases in biochemical parameters compared to Sildenafil alone. The triple drug combination Sildenafil + Rosuvastatin + Magnesium sulfate shows significant results (p<0,001) compared to the previously described drug combinations. The lowest biochemical parameters were recorded: RV anterior wall thickness, RV internal diameter values, and a significant PAAT/PAET ratio improvement. Thanks to their benefits on vascular pathological remodeling, triple drug combinations implicitly reduce ET1, VEGF, NO metabolites, and iNOS values with statistical significance. The beneficial pleiotropic effects of Rosuvastatin combined with Magnesium sulfate (thanks to its potent vasodilator and antioxidant effects) demonstrated its efficacy in this study by improving RV systolic pressures, RV hypertrophy, oxidative stress, and myocardial dysfunction biomarkers.

Evaluation of the effect of carvedilol orodispersible tablets on ischemia-reperfusion injury and flap viability in rats: An in vivo study.

Flap surgery is an integral part of plastic surgery, and ischemia-reperfusion (I/R) injury significantly affects the viability of the flap. Carvedilol (CRV), a nonselective beta-blocker with alpha-1 blocking and antioxidant properties, and known for its potential in reducing I/R damage, was chosen as the active substance for our study. The aim of this study was to investigate the vasodilator and antioxidant effects of CRV on rat inferior epigastric artery skin flap using orally disintegrating tablets (ODTs). The optimized ODT formulation was subjected to in vivo experiments using Sprague-Dawley female rats (n = 24) divided into three groups: Group I (control, I/R), Group II (treatment, I/R + CRV), and Group III (treatment, I/R), I/R + CRV ODT). Reperfusion was then observed following the release of the microclamp from the pedicle, and the flap was then re-adapted to its original position. Control rats were given oral isotonic solution via gavage and were subjected to 8 h of ischemia and 12 h of reperfusion. Group II was given 2 mg/kg CRV oral tablets for 7 days before and after surgery. Group III was given 2 mg/kg/day CRV ODT for the same period. Biopsies were taken from the flap and histopathological and biochemical analyses including superoxide dismutase, glutathionenitric oxide, malondialdehyde, paraoxonase 1, total oxidant, and total antioxidant capacities were performed. This study demonstrates that CRV ODTs significantly increased flap viability by approximately 25% compared to the control group, highlighting their promising therapeutic potential.

The delapril-indapamide combination in treatment of arterial hypertension: practical implications in light of the new guidelines.

The recent guidelines issued by the European Society of Hypertension reaffirmed that the degree of control of hypertension remains suboptimal worldwide. In order to increase the proportion of well-controlled patients, in addition to nonpharmacological measures, it is necessary to improve the implementation of drug therapy in the clinical practice as much as possible. Initial therapy should almost always be based on the combination, free or fixed, between ACE inhibitor drugs, or direct angiotensin II inhibitors ('sartans') and diuretics (thiazide or thiazide-like) or calcium channel blockers at the maximum recommended and well-tolerated dose. The combination of the thiazide-like diuretic indapamide with the ACE inhibitor delapril has shown, based on numerous clinical trials and meta-analyses, very good results in terms of antihypertensive efficacy, tolerability, and prevention or regression of organ damage. Indapamide is a thiazide-like diuretic also endowed with direct vasodilator effect and long duration of action. A meta-analysis of 19 randomized clinical trials demonstrated a greater reduction in the incidence of cardiac events, stroke and heart failure with thiazide-like diuretics than with thiazide diuretics. Delapril is a non-sulfhydryl ACE-inhibitor with high affinity for converting enzyme at the cardiac, pulmonary, and peripheral vascular levels. Being strongly lipophilic, delapril inhibits the ACE enzyme at the tissue level more potently than other ACE inhibitors. A peculiar feature of delapril is its weak bradykinin-enhancing effect due to its higher affinity for the C site than the N site of ACE, resulting in a lower incidence of cough and angioneurotic edema compared with other ACE inhibitors. In some meta-analyses, the pressor reduction was statistically, greater with the delapril-indapamide combination than with combinations between hydrochlorothiazide and ACE inhibitors. The combination consists of divisible tablets containing 30 mg delapril and 2.5 mg indapamide, and its pharmacological and clinical properties are not affected by simultaneous food intake. The antihypertensive efficacy of the combination, as well as its components, persists for the entire 24 hours. The recent alarming reports on the incidence of skin cancer during treatment with hydrochlorothiazide should also be a guide in clinical practice toward the preferential choice of a thiazide-like diuretic such as chlorthalidone or indapamide to replace hydrochlorothiazide.

Maternal AMPK pathway activation with uterine artery blood flow and fetal growth maintenance during hypoxia.

High-altitude (HA) hypoxia lowers uterine artery (UtA) blood flow during pregnancy and birth weight. Adenosine monophosphate kinase (AMPK) activation has selective, uteroplacental vasodilator effects that lessen hypoxia-associated birth weight reductions. In this study, we determined the relationship between AMPK-pathway gene expression and metabolites in the maternal circulation during HA pregnancy as well as with the maintenance of UtA blood flow and birth weight at HA. Residents at HA (2,793 m) versus low altitude (LA; 1,640 m) had smaller UtA diameters at weeks 20 and 34, lower UtA blood flow at week 20, and lower birth weight babies. At week 34, women residing at HA versus women residing at LA had decreased expression of upstream and downstream AMPK-pathway genes. Expression of the α1-AMPK catalytic subunit, PRKAA1, correlated positively with UtA diameter and blood flow at weeks 20 (HA) and 34 (LA). Downstream AMPK-pathway gene expression positively correlated with week 20 fetal biometry at both altitudes and with UtA diameter and birth weight at LA. Reduced gene expression of AMPK activators and downstream targets in women residing at HA versus women residing at LA, together with positive correlations between PRKAA1 gene expression, UtA diameter, and blood flow suggest that greater sensitivity to AMPK activation at midgestation at HA may help offset later depressant effects of hypoxia on fetal growth.NEW & NOTEWORTHY Fetal growth restriction (FGR) is increased and uterine artery (UtA) blood flow is lower at high altitudes (HA) but not all HA pregnancies have FGR. Here we show that greater UtA diameter and blood flow at week 20 are positively correlated with higher expression of the gene encoding the α1-catalytic subunit of AMP protein kinase, PRKAA1, suggesting that increased AMPK activation may help to prevent the detrimental effects of chronic hypoxia on fetal growth.

Biphasic effects of single-dose intravenous injection of uridine adenosine tetraphosphate on blood pressure in mice

PurposeTo explore the effects of a single dose of uridine adenosine tetraphosphate (Up4A) administered through the tail vein, on the blood pressure of mice.MethodsThe mice were separated into three groups: the Up4A group, the norepinephrine (NA) group, and the α, β-methylene adenosine triphosphate (α, β-meATP) group. Each group of mice were injected drugs through the tail vein at 1, 3, 10, and 30 nmol/kg doses in an ascending order. Additionally, six mice were injected Up4A through the tail vein at 20, 40, 60, and 80 nmol/kg doses in an ascending order. The administration intervals for each dose were 20 min.ResultsMice in these groups experienced a rapid increase in blood pressure, reaching its peak within 10 s after drug administration. It took approximately 120 s for the blood pressure to return to baseline levels after the administration of the drugs in both the NA and α, β-meATP groups. After higher doses of Up4A were administered to the mice, their blood pressure exhibited biphasic changes. Initially, blood pressure of the mice rapidly dropped to a minimum within 10 s, then rose rapidly to a peak within 30 s. Subsequently, it gradually declined, taking around 10 min to return to the levels before the drug administration.ConclusionCompared to NA and α, β-meATP, Up4A, which contains purine and pyrimidine components, displayed a weaker blood pressure-elevating potency. Through its corresponding structure, Up4A exerted vasodilatory and vasoconstrictive effects throughout the entire experiment resulting in biphasic changes in blood pressure.

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.