Vasorelaxant Effect Research Articles

Cardioprotective effect of 2-methoxy phenol derivatives against oxidative stress-induced vascular complications: An integrated in vitro, in silico, and in vivo investigation

BackgroundOxidative stress and inflammation play crucial roles in macro/microvascular complications. Phenolic compounds and their derivatives show promise as therapeutic agents for diseases like cancer, metabolic disorders, and cardiovascular diseases. With their antioxidant and anti-inflammatory properties, these compounds hold potential for mitigating vascular complications and improving overall health. MethodologyThis study aimed to assess the therapeutic potential of five 2-methoxy phenol derivatives (T2, T5, T6, T7, and T8) as antioxidants, anti-inflammatory agents, and vasorelaxants using in vitro, in silico, and in vivo approaches. ResultsAmong all, T2 exhibited substantial antioxidant potential against 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals with IC50 (27.97 µg/mL), nitric oxide (NO) radicals (IC50 = 34.36 µg/mL), hydroxyl (OH) radicals (IC50 = 34.83 µg/mL) and Iron chelation (IC50 = 24.32 µg/mL). Molecular docking analysis confirms that all derivatives, particularly T2, exhibit favorable binding energies with the target proteins, ACE (−7.7 Kcal/mol), ECE-1 (−7.9 Kcal/mol), and COX-1 (−7.8 Kcal/mol). All of the compounds demonstrated satisfactory physicochemical and pharmacokinetic characteristics, and showed minimal to no toxicity during in silico, in vitro, and in vivo assessments. In isolated aortic rings from Sprague Dawley rats, pre-contracted with high K+ (80 mM), T2 induced vasorelaxation in dose dependent manner and shifted calcium response curves to the right as compared to verapamil. T2 also showed substantial platelet aggregation inhibition in a dose dependent manner with IC50 21.29 µM. All derivatives except T7 exhibited significant conservation of endogenous antioxidants i.e. catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) and significantly suppressed serum levels of inflammatory markers i.e. nitric oxide (NO), peroxides (TBARS), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2). ConclusionThe study concludes that T2 has significant antioxidant potential and vasorelaxant effects with adequate pharmacokinetics, making it a promising lead compound for further molecular investigation in cardiovascular disorders.

Dapagliflozin prevents oxidative stress-induced endothelial dysfunction via sirtuin 1 activation

Recent studies have demonstrated that dapagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, prevents endothelial dysfunction; however, direct effects of dapagliflozin on the endothelium under oxidative stress and the underlying mechanism of action are not completely understood. This study aimed to define the role and related mechanisms of dapagliflozin in hydrogen peroxide (H2O2)-induced endothelial dysfunction. The endothelium-dependent vasorelaxation effect of dapagliflozin was assessed in an organ bath study. Endothelial dysfunction was assessed using protein expression level and phosphorylation of endothelial nitric oxide synthase (eNOS), nitric oxide (NO), reactive oxygen species (ROS), senescence-associated beta-galactosidase (SA-β-gal) activity, and senescence marker proteins (p21, p53). Co-immunoprecipitation and protein acetylation were performed to detect protein interactions. Dapagliflozin exerted a direct vasorelaxant effect in the aortic rings of C57BL/6 J mice. Furthermore, there was a significant improvement in endothelium-dependent vasorelaxation in dapagliflozin-treated diabetic mice compared to vehicle controls. Moreover, intracellular ROS levels and ONOO- levels, increased by H2O2, were reduced by dapagliflozin. Importantly, dapagliflozin inhibited H2O2-induced senescence in the human umbilical vein endothelial cells (HUVECs), as indicated by reduced SA‐β‐gal, p21, and p53. Mechanistically, dapagliflozin reversed the H2O2-mediated inhibition of eNOS serine phosphorylation and sirtuin 1 (SIRT1) expression in endothelial cells. In particular, SIRT1-mediated eNOS deacetylation is reportedly involved in dapagliflozin-enhanced eNOS activity. These findings indicate that dapagliflozin ameliorates endothelial dysfunction by restoring eNOS activity, restoring NO bioavailability, and reducing ROS generation via SIRT1 activation in oxidative stress-stimulated endothelial cells.

Vasorelaxant effect of Alpinia zerumbet's essential oil on rat resistance artery involves blocking of calcium mobilization

Alpinia zerumbet is a plant from the Zingiberaceae family, popularly used for hypertension treatment. Several studies have demonstrated Alpinia zerumbet vasodilator effect on conductance vessels but not on resistance vessels. Thereby, the aim of this study was to verify the vasodilator effect of the essential oil of Alpinia zerumbet (EOAz) on isolated rat resistance arteries and characterize its mechanism of action. Therefore, the effect of EOAz (3 to 3000 μg/mL) was verified in second-order branches of the mesenteric artery (SOBMA) pre-contracted by KCl and U46619. To study the mechanism of action, the influence of several inhibitors (TEA, 4-AP, Glibenclamide, Atropine, L-NAME, ODQ and indomethacin) on the vasodilator effect of EOAz was evaluated. Some protocols were also performed aiming to study the effect of EOAz on Ca2+ influx and release from intracellular storage. Furthermore, the binding energy of the main constituents with calcium channels were evaluated by molecular docking. Results showed an endothelium-independent vasorelaxant effect of EOAz on SOBMA, and only ODQ and L-NAME produced significant alteration on its pEC50. Regarding the calcium assays, contraction reduction caused by incubation with EOAz was observed in all three protocols. Hence, our results suggest that EOAz has a vasodilator effect mediated by inhibition of Ca2+ influx and release from intracellular storage, as well as an activation of the NOS/sGC pathway.

Rosuvastatin relaxes rat thoracic aorta, pulmonary artery, and trachea via nitric oxide, prostanoids, and potassium channels

Purpose: This study aimed to determine the functional effects and mechanisms of the action of rosuvastatin on vascular and tracheal smooth muscle tissues. 
 Materials and Methods: Vascular and tracheal rings (2-3 mm) isolated from the thoracic aortas, pulmonary arteries, and tracheas of Wistar Albino male rats (250-300 g) were placed in chambers in the isolated tissue bath system. As the resting tension, 1 g was selected. Vascular rings contracted with 10-6 M phenylephrine after a 90-minute equilibration period. Tracheal rings contracted with 10-5 M acetylcholine. After the contraction was steady, rosuvastatin (10-8-10-4 M) was cumulatively applied to the vascular and tracheal rings. The defined experimental methodology was repeated following the incubation of selective inhibitors of signaling pathways and K+ channel blockers to ascertain rosuvastatin's functional effect mechanisms. 
 Results: In the precontracted rat vascular and tracheal rings, rosuvastatin induced concentration-dependent relaxation. The maximal relaxation level in vessel samples was 96%. On the other hand, the maximal relaxation level in tracheal samples was found to be 75%. The vasorelaxant effects of rosuvastatin were dramatically attenuated by endothelium removal, L-NAME treatment, and indomethacin incubation (up to 27%). With the incubation of tetraethylammonium, glyburide, 4-Aminopyridine, and anandamide, rosuvastatin-mediated vascular smooth muscle relaxation levels were significantly decreased (up to 38%). Moreover, With the incubation of tetraethylammonium, glyburide, and 4-Aminopyridine rosuvastatin-mediated tracheal smooth muscle relaxation levels were significantly decreased (up to 30%). 
 Conclusion: Rosuvastatin has a noticeable relaxing effect on the vascular and tracheal smooth muscles. The vasorelaxant effect of rosuvastatin involves intact endothelium, nitric oxide, prostanoids, and K+ channels (BKCa, KV, and KATP channels). Furthermore, nitric oxide, prostanoids, BKCa channels, KV channels, and KATP channels play a role in rosuvastatin-induced tracheal smooth muscle relaxation

Study of the Antihypertensive and Vasorelaxant Activities of Haloxylon scoparium in Rats.

The work aimed to study the antihypertensive ability of Haloxylon scoparium. Haloxylon scoparium Pomel is used to treat various diseases, including hypertension. This study aimed to evaluate the antihypertensive effect of Haloxylon scoparium (H. scoparium) in hypertensive rats, and to evaluate its probable vasorelaxant activity. The aqueous extract of Haloxylon scoparium (AEHS) was prepared and used to investigate its antihypertensive ability in L-NAME(Nω-L-arginine methyl ester)-induced hypertensive rats, and its vasorelaxant activity was studied on the isolated thoracic aorta of rats. The acute and subchronic effects of (AEHS) on blood pressure parameters were evaluated after oral administration of AEHS (60 and 100 mg/kg body weight) for 6 h for the acute experiment and for 7 days for the subchronic test. The results indicated that AEHS decreased blood pressure parameters (systolic, mean, and diastolic blood pressure) after repeated oral administration in hypertensive rats without affecting normal rats. In addition, AEHS (375-1250 μg/mL) revealed a vasorelaxant effect in thoracic aortic rings precontracted with norepinephrine (NE) (10 μM) or KCl (80 mM). This effect was partially decreased in the presence of nifedipine by inhibition of the vascular calcium channel pathway in isolated rat thoracic aorta. The study demonstrates the beneficial effect of Haloxylon scoparium as an antihypertensive agent. Moreover, this plant exerts vasorelaxant activity via the blockade of Ca2+ channels.

The Phthalic Selenoanhydride Decreases Rat Blood Pressure and Tension of Isolated Mesenteric, Femoral and Renal Arteries.

Phthalic selenoanhydride (R-Se) solved in physiological buffer releases various reactive selenium species including H2Se. It is a potential compound for Se supplementation which exerts several biological effects, but its effect on the cardiovascular system is still unknown. Therefore, herein we aimed to study how R-Se affects rat hemodynamic parameters and vasoactive properties in isolated arteries. The right jugular vein of anesthetized Wistar male rats was cannulated for IV administration of R-Se. The arterial pulse waveform (APW) was detected by cannulation of the left carotid artery, enabling the evaluation of 35 parameters. R-Se (1-2 µmol kg-1), but not phthalic anhydride or phthalic thioanhydride, transiently modulated most of the APW parameters including a decrease in systolic and diastolic blood pressure, heart rate, dP/dtmax relative level, or anacrotic/dicrotic notches, whereas systolic area, dP/dtmin delay, dP/dtd delay, anacrotic notch relative level or its delay increased. R-Se (~10-100 µmol L-1) significantly decreased the tension of precontracted mesenteric, femoral, and renal arteries, whereas it showed a moderate vasorelaxation effect on thoracic aorta isolated from normotensive Wistar rats. The results imply that R-Se acts on vascular smooth muscle cells, which might underlie the effects of R-Se on the rat hemodynamic parameters.

The new quinazoline derivative (N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats

During the screening of new N2,N4-disubstituted quinazoline 2,4-diamines as phosphodiesterase-5 inhibitors and pulmonary artery vasodilators, one N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine (compound 8) presented a greater selectivity for systemic than pulmonary vasculature. The present study aimed to characterize its vasorelaxant and hypotensive effects in Wistar rats. Vasorelaxant effects of compound 8 and underlying mechanisms were evaluated on isolated mesenteric arteries. Acute hypotensive effect was evaluated in anesthetized rats. Additionally, cell viability and cytochrome P450 (CYP) activities were studied in rat isolated hepatocytes. Nifedipine was used as a comparator. Compound 8 induced a strong vasorelaxant effect, similar to nifedipine. This was unaffected by endothelium removal but was decreased by inhibitors of guanylate cyclase (ODQ) and KCa channel (iberiotoxin). Compound 8 enhanced sodium nitroprusside-induced relaxation, but inhibited vasoconstriction evoked by α1-adrenergic receptor activation and extracellular Ca2+ influx via receptor-operated Ca2+ channels. Acute intravenous infusion of compound 8 (0.05 and 0.1 mg/kg) produced hypotension. It showed similar potency to nifedipine for lowering diastolic and mean arterial blood pressure, but less so for the effect on systolic blood pressure. Compound 8 had no effect on hepatocyte viability and CYP activities except at high concentration (10 μM) at which a weak inhibitory effect on CYP1A and 3A was observed. In conclusion, this study identified a N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine with a potent vasodilator effect on resistance vessels, leading to an acute hypotensive effect and a low risk of liver toxicity or drug-drug interactions. These vascular effects were mediated mainly through sGC/cGMP pathway, opening of KCa channels, and inhibition of calcium entry.

Atorvastatin and Fluvastatin Potentiate Blood Pressure Lowering Effect of Amlodipine through Vasorelaxant Phenomenon.

Background and Objectives: We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin and fluvastatin on blood vessels for a possible vasorelaxant effect. We also studied the possible additional vasorelaxant effect of atorvastatin and fluvastatin, in the presence of amlodipine, to quantify its effects on the systolic blood pressure of experimental animals. Materials and Methods: Atorvastatin and fluvastatin were tested in isolated rabbits' aortic strip preparations using 80mM Potassium Chloride (KCl) induced contractions and 1 micro molar Norepinephrine (NE) induced contractions. A positive relaxing effect on 80 mM KCl induced contractions were further confirmed in the absence and presence of atorvastatin and fluvastatin by constructing calcium concentration response curves (CCRCs) while using verapamil as a standard calcium channel blocker. In another series of experiments, hypertension was induced in Wistar rats and different test concentrations of atorvastatin and fluvastatin were administered in their respective EC50 values to the test animals. A fall in their systolic blood pressure was noted using amlodipine as a standard vasorelaxant drug. Results: The results show that fluvastatin is more potent than amlodipine as it relaxed NE induced contractions where the amplitude reached 10% of its control in denuded aortae. Atorvastatin relaxed KCL induced contractions with an amplitude reaching 34.4% of control response as compared to the amlodipine response, i.e., 39.1%. A right shift in the EC50 (Log Ca++ M) of Calcium Concentration Response Curves (CCRCs) implies that statins have calcium channel blocking activity. A right shift in the EC50 of fluvastatin with relatively less EC50 value (-2.8 Log Ca++ M) in the presence of test concentration (1.2 × 10-7 M) of fluvastatin implies that fluvastatin is more potent than atorvastatin. The shift in EC50 resembles the shift of Verapamil, a standard calcium channel blocker (-1.41 Log Ca++ M). Conclusions: Atorvastatin and fluvastatin relax the aortic strip preparations predominantly through the inhibition of voltage gated calcium channels in high molar KCL induced contractions. These statins also inhibit the effects of NE induced contractions. The study also confirms that atorvastatin and fluvastatin potentiate blood pressure lowering effects in hypertensive rats.

A New Lignan from Annona squamosa L. (Annonaceae) Demonstrates Vasorelaxant Effects In Vitro.

Esquamosan, a new furofuran lignan, has been isolated by bio-guided assays from the methanolic extract of the leaves of Annona squamosa L., and its structure was elucidated by spectroscopic methods. Esquamosan inhibited the rat aortic ring contraction evoked by phenylephrine in a concentration-dependent manner and showed an inhibitory effect on vasocontraction of the depolarized aorta with high-concentration potassium. The vasorelaxant effect by esquamosan could be attributed mainly to the inhibition of calcium influx from extracellular space through voltage-dependent calcium channels or receptor-operated Ca2+ channels and also partly mediated through the increased release of NO from endothelial cells. The ability of esquamosan to modify the vascular reactivity of rat aortic rings incubated with high glucose (D-glucose 55 mM) was then evaluated, and this furofuran lignan reverted the endothelium-dependent impairment effect of high glucose in rat aortic rings. The antioxidant capacity of esquamosan was assessed using DPPH and FRAP assays. Esquamosan exhibited a similar antioxidant capacity compared to ascorbic acid, which was used as a positive control. In conclusion, this lignan showed a vasorelaxant effect, free radical scavenging capacity, and potential reductive power, suggesting its potential beneficial use to treat complex cardiometabolic diseases due to free radical-mediated diseases and its calcium antagonist effect.

Cannabidiol alleviates right ventricular fibrosis by inhibiting the transforming growth factor β pathway in monocrotaline-induced pulmonary hypertension in rats

Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death. There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats. Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin. Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.

Suxiao Jiuxin Pill attenuates acute myocardial ischemia via regulation of coronary artery tone.

Suxiao Jiuxin Pill (SJP) is a well-known traditional Chinese medicine drug used to manage heart diseases. This study aimed at determining the pharmacological effects of SJP in acute myocardial infarction (AMI), and the molecular pathways its active compounds target to induce coronary artery vasorelaxation. Using the AMI rat model, SJP improved cardiac function and elevated ST segment. LC-MS and GC-MS detected twenty-eight non-volatile compounds and eleven volatile compounds in sera from SJP-treated rats. Network pharmacology analysis revealed eNOS and PTGS2 as the key drug targets. Indeed, SJP induced coronary artery relaxation via activation of the eNOS-NO pathway. Several of SJP's main compounds, like senkyunolide A, scopoletin, and borneol, caused concentration-dependent coronary artery relaxation. Senkyunolide A and scopoletin increased eNOS and Akt phosphorylation in human umbilical vein endothelial cells (HUVECs). Molecular docking and surface plasmon resonance (SPR) revealed an interaction between senkynolide A/scopoletin and Akt. Vasodilation caused by senkyunolide A and scopoletin was inhibited by uprosertib (Akt inhibitor) and eNOS/sGC/PKG axis inhibitors. This suggests that senkyunolide A and scopoletin relax coronary arteries through the Akt-eNOS-NO pathway. In addition, borneol induced endothelium-independent vasorelaxation of the coronary artery. The Kv channel inhibitor 4-AP, KCa2+ inhibitor TEA, and Kir inhibitor BaCl2 significantly inhibited the vasorelaxant effect of borneol in the coronary artery. In conclusion, the results show that Suxiao Jiuxin Pill protects the heart against acute myocardial infarction.

Enhancement of Sphingomyelinase-Induced Endothelial Nitric Oxide Synthase-Mediated Vasorelaxation in a Murine Model of Type 2 Diabetes.

Sphingolipids are important biological mediators both in health and disease. We investigated the vascular effects of enhanced sphingomyelinase (SMase) activity in a mouse model of type 2 diabetes mellitus (T2DM) to gain an understanding of the signaling pathways involved. Myography was used to measure changes in the tone of the thoracic aorta after administration of 0.2 U/mL neutral SMase in the presence or absence of the thromboxane prostanoid (TP) receptor antagonist SQ 29,548 and the nitric oxide synthase (NOS) inhibitor L-NAME. In precontracted aortic segments of non-diabetic mice, SMase induced transient contraction and subsequent weak relaxation, whereas vessels of diabetic (Leprdb/Leprdb, referred to as db/db) mice showed marked relaxation. In the presence of the TP receptor antagonist, SMase induced enhanced relaxation in both groups, which was 3-fold stronger in the vessels of db/db mice as compared to controls and could not be abolished by ceramidase or sphingosine-kinase inhibitors. Co-administration of the NOS inhibitor L-NAME abolished vasorelaxation in both groups. Our results indicate dual vasoactive effects of SMase: TP-mediated vasoconstriction and NO-mediated vasorelaxation. Surprisingly, in spite of the general endothelial dysfunction in T2DM, the endothelial NOS-mediated vasorelaxant effect of SMase was markedly enhanced.

Vasorelaxant property of 2-phenyl ethyl alcohol isolated from the spent floral distillate of damask rose (Rosa damascena Mill.) and its possible mechanism

Ethnobotanical relevanceRosa damascena Mill. (Rosaceae), commonly known as damask rose, is an ancient medicinal and perfumery plant used in Traditional Unani Medicine due to various therapeutic effects, including cardiovascular benefits. Aim of the studyThis study aimed to evaluate the vasorelaxant effect of the 2-phenyl ethyl alcohol (PEA) isolated from the spent flowers of R. damascena which remain after the extraction of essential oil. Materials and methodsThe freshly collected flowers of R. damascena were hydro-distilled in a Clevenger's type apparatus to extract the rose essential oil (REO). After removing the REO, the spent-flower hydro-distillate was collected and extracted with organic solvents to yield a spent-flower hydro-distillate extract (SFHE), which was further purified by column chromatography. The SFHE and its isolate were characterized by gas chromatography (GC-FID), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) techniques. The PEA, isolated from SFHE, was evaluated for vasorelaxation response in conduit blood vessels like rat aorta and resistant vessels like mesenteric artery. The preliminary screening of PEA was done in aortic preparation pre-constricted with phenylephrine/U46619. Further, a concentration-dependent relaxation response to PEA has been elicited in both endothelium-intact and endothelium-denuded arterial rings, and the mode of action was explored. ResultsThe SFHE revealed the presence of PEA as the main constituent (89.36%), which was further purified by column chromatography to a purity of 95.0%. The PEA exhibited potent vasorelaxation response both in conduit vessels like the rat aorta and resistance vessels like the mesenteric artery. The relaxation response is mediated without any involvement of vascular endothelium. Further, TEA sensitive BKCa channel was found to be the major target for PEA-induced relaxation response in these blood vessels. ConclusionsThe spent flowers of R. damascena, which remain after the extraction of REO, could be used to extract PEA. The PEA possessed marked vasorelaxation properties in both aorta and mesenteric artery and showed promise for development into an herbal product against hypertension.

Vasorelaxing effect of Garcinia cowa leaf extract in rat thoracic aorta and its underlying mechanisms.

The leaves of Garcinia cowa (G. cowa) are used in Thai traditional medicine to improve blood circulation. However, there is no scientific evidence to confirm this therapeutic claim. Here, we investigated the vasorelaxing effect and its underlying mechanisms of an aqueous extract of G.cowa leaves in rat thoracic aortic rings. Dried leaves of G.cowa were extracted with water, followed by phytochemical analysis. Vascular reactivity experiments were performed in isolated rat thoracic aortic rings using an organ bath system. The results were recorded using the data acquisition system Power Lab. Phytochemical analysis showed that the leaves of G.cowa are rich in polyphenols and flavonoids, especially kaempferol, vitexin, and isovitexin. The G.cowa leaf extract caused a concentration-dependent relaxation of aortic rings. This effect was attenuated by denudation of the endothelium, or by pre-treatment of the aortic rings with l-NAME, ODQ, indomethacin, or glibenclamide, but not with TEA. This study indicates that G.cowa leaf extract induces vasorelaxation through both endothelium-dependent and endothelium-independent manners. Its mechanism of action mainly involves the production of nitric oxide and prostanoids, as well as opening ATP-sensitive K+ channels. The vasorelaxing effect of G.cowa leaf extract is probable promoted by the action of flavonoids.

The endocannabinoidome in human placenta: Possible contribution to the pathogenesis of preeclampsia.

Preeclampsia (PE) was first reported thousands of years ago, yet there is still a shortage of biomarkers to determine the severity and type of PE. The importance of the expanded endocannabinoid system, or endocannabinoidome (eCBome), has emerged recently in placental physiology and pathology, though the potential alterations of the eCBome in PE have not been fully explored. Analysis by qRT-PCR using placental samples of normotensive and PE women demonstrate for the first time the presence of ABHD4, GDE1, and DAGLβ in both normotensive and PE placental tissues. Interestingly, NAPE-PLD, FAAH-1, DAGLα, MAGL, and ABHD6 mRNA levels were increased in the placental tissues of PE patients. Quantification in plasma and placental tissues showed a decrease for anandamide (AEA), N-oleoylethanolamine (OEA), and N-docosahexaenoylethanolamine (DHEA) in the placenta, accompanied only by a decrease in plasma levels of AEA. In addition, a strong negative correlation was obtained between OEA and the biomarker of PE, soluble fms-like tyrosine kinase-1. Given the inflammatory nature of PE and the anti-inflammatory role of OEA and DHEA, the decrease in the local levels of these mediators may underlie the inflammatory component of this pathology. Additionally, lower AEA levels in both placenta and plasma may contribute to the atypical alterations of the spiral arteries in PE due to the vasorelaxation effects of AEA. These results add new information to the role of the eCBome members in placental development, while also pointing to a potential role as biomarkers of PE.

The Effects of Endogenous Cannabinoids on the Mammalian Respiratory System: A Scoping Review of Cyclooxygenase-Dependent Pathways.

Introduction: The endogenous cannabinoid (endocannabinoid) system is an emerging target for the treatment of chronic inflammatory disease with the potential to advance treatment for many respiratory illnesses. The varied effects of endocannabinoids across tissue types makes it imperative that we explore their physiologic impact within unique tissue targets. The aim of this scoping review is to explore the impact of endocannabinoid activity on eicosanoid production as a measure of human airway inflammation. Methods: A scoping literature review was conducted according to PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) guidelines. Search strategies using MeSH terms related to cannabinoids, eicosanoids, cyclooxygenase (COX), and the respiratory system were used to query Medline, Embase, Cochrane, CINAHL, Web of Science, and Biosis Previews in December 2021. Only studies that investigated the relationship between endocannabinoids and the eicosanoid system in mammalian respiratory tissue after 1992 were included. Results: Sixteen studies were incorporated in the final qualitative review. Endocannabinoid activation increases COX-2 expression, potentially through ceramide-dependent or p38 and p42/44 Mitogen-Activated Protein Kinase pathways and is associated with a concentration-dependent increase in prostaglandin (PG)E2. Inhibitors of endocannabinoid hydrolysis found either an increase or no change in levels of PGE2 and PGD2 and decreased levels of leukotriene (LT)B4, PGI2, and thromboxane A2 (TXA2). Endocannabinoids increase bronchial epithelial cell permeability and have vasorelaxant effects in human pulmonary arteries and cause contraction of bronchi and decreased gas trapping in guinea pigs. Inhibitors of endocannabinoid hydrolysis were found to have anti-inflammatory effects on pulmonary tissue and are primarily mediated by COX-2 and activation of eicosanoid receptors. Direct agonism of endocannabinoid receptors appears to play a minor role. Conclusion: The endocannabinoid system has diverse effects on the mammalian airway. While endocannabinoid-derived PGs can have anti-inflammatory effects, endocannabinoids also produce proinflammatory conditions, such as increased epithelial permeability and bronchial contraction. These conflicting findings suggest that endocannabinoids produce a variety of effects depending on their local metabolism and receptor agonism. Elucidation of the complex interplay between the endocannabinoid and eicosanoid pathways is key to leveraging the endocannabinoid system as a potential therapeutic target for human airway disease.

Elabela relaxes rat pulmonary artery and trachea via BKCa, KV, and KATP channels

ObjectiveElabela is a newly discovered peptide hormone. This study aimed to determine the functional effects and mechanisms of action of elabela in rat pulmonary artery and trachea. Materials and methodsVascular rings isolated from the pulmonary arteries of male Wistar Albino rats were placed in chambers in the isolated tissue bath system. The resting tension was set to 1 g. After the equilibration period, the pulmonary artery rings were contracted with 10-6 M phenylephrine. Once a stable contraction was achieved, elabela was applied cumulatively (10-10-10-6 M) to the vascular rings. To determine the vasoactive effect mechanisms of elabela, the specified experimental protocol was repeated after the incubation of signaling pathway inhibitors and potassium channel blockers. The effect and mechanisms of action of elabela on tracheal smooth muscle were also determined by a similar protocol. ResultsElabela exhibited a concentration-dependent relaxation in the precontracted rat pulmonary artery rings (p < .001). Maximal relaxation level was 83% (pEC50: 7.947 CI95(7.824–8.069)). Removal of the endothelium, indomethacin incubation, and dideoxyadenosine incubation significantly decreased the vasorelaxant effect levels of elabela (p < .001). Elabela-induced vasorelaxation levels were significantly reduced after iberiotoxin, glyburide, and 4-Aminopyridine administrations (p < .001). L-NAME, methylene blue, apamin, TRAM-34, anandamide, and BaCl2 administrations did not cause a significant change in the vasorelaxant effect level of elabela (p = 1.000). Elabela showed a relaxing effect on precontracted tracheal rings (p < .001). Maximal relaxation level was 73% (pEC50: 6.978 CI95(6.791–7.153)). The relaxant effect of elabela on tracheal smooth muscle was decreased significantly after indomethacin, dideoxyadenosine, iberiotoxin, glyburide, and 4-Aminopyridine incubations (p < .001). ConclusionsElabela exerted a prominent relaxant effect in the rat pulmonary artery and trachea. Intact endothelium, prostaglandins, cAMP signaling pathway, and potassium channels (BKCa, KV, and KATP channels) are involved in the vasorelaxant effect of elabela. Prostaglandins, cAMP signaling pathway, BKCa channels, KV channels, and KATP channels also contribute to elabela-induced tracheal smooth muscle relaxant effect.

New insights on mode of action of vasorelaxant activity of simvastatin.

Simvastatin is a semisynthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used extensively to treat atherosclerotic cardiovascular disease. Apart from the lipid-lowering effect, simvastatin has been documented to offer impressive vasorelaxant activity. However, the mechanism associated with this vasorelaxant activity has yet not been substantially explored. Thus, the present study has aimed to elucidate the mechanism(s) associated with simvastatin-induced vasorelaxation using an established rat aortic ring model. The results from the study depicted that simvastatin caused significant relaxation in aortic rings pre-contracted with phenylephrine and potassium chloride (KCl). The vasorelaxant effect of simvastatin was attenuated by methylene blue (sGC-dependent cyclic guanosine monophosphate (cGMP) inhibitor), NG-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor), 4-aminopyridine (Kv blocker), glibenclamide (KATP blocker), and barium chloride (Kir blocker). In addition, the vasorelaxant effect of simvastatin was slightly reduced by PD123319 (angiotensin II type 2 receptor (AT2R) antagonist). However, indomethacin (COX inhibitor), 1H-[1,2,4]Ox adiazolol [4,3-α]quinoxalin-1-one (ODQ; selective soluble guanylate cyclase (sGC) inhibitor), losartan (angiotensin II type 1 receptor (AT1R) antagonist), atropine (muscarinic receptor blocker), and tetraethyl ammonium (TEA; KCa blocker) did not affect the vasorelaxant effect of simvastatin. Furthermore, simvastatin was found to attenuate the release of calcium (Ca2+) from intracellular stores in the presence of ruthenium red (ryanodine receptor, RyR inhibitor) and extracellular stores via nifedipine (voltage-operated Ca2+ channels, VOCC blocker) and SK&F96365 (receptor-operated Ca2+ channel, ROCC blocker). Thus, it can be concluded that the vasorelaxant effect of simvastatin involves NO/cGMP pathways, AT2R receptors, Ca2+ channels, and K+ channels.

Anti-Inflammatory and Vasorelaxant Effects Induced by an Aqueous Aged Black Garlic Extract Supplemented with Vitamins D, C, and B12 on Cardiovascular System.

Multiple studies demonstrated biological activities of aged black garlic, including anti-inflammatory, antioxidant, and cardioprotective effects. We aimed to investigate the protective effects of an aged black garlic water extract (ABGE) alone or in association with multivitamins consisting of combined Vitamins D, C, and B12, on mouse heart specimens exposed to E. coli lipopolysaccharide (LPS). Moreover, we studied the hydrogen sulphide (H2S) releasing properties and the membrane hyperpolarization effect of the Formulation composed by ABGE and multivitamins, using Human Aortic Smooth Muscle Cells (HASMCs). ABGE, vitamins D and C, and the Formulation suppressed LPS-induced gene expression of cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, interleukin (IL)-6, nuclear factor-kB (NF-kB), and inducible nitric oxide synthase (iNOS) on mouse heart specimens. The beneficial effects induced by the extract could be related to the pattern of polyphenolic composition, with particular regard to gallic acid and catechin. The Formulation also increased fluorescence values compared to the vehicle, and it caused a significant membrane hyperpolarization of HASMCs compared to ABGE. To conclude, our present findings showed that ABGE, alone and in association with multivitamins, exhibited protective effects on mouse heart. Moreover, the Formulation increased intracellular H2S formation, further suggesting its potential use on cardiovascular disease.

Antioxidant and Vasorelaxant Properties of Phaseolus vulgaris Linn (Fabaceae) Immature Pods Extract on the Thoracic Aorta of NMRI Mice

Introduction: Oxidative stress, through the increased bioavailability of reactive oxygen species (ROS), is a major cause of hypertension. The resulting endothelial remodeling promotes the production of vasoconstrictor substances leading to an increase in blood pressure. This study aimed to evaluate the antioxidant and vasorelaxant properties of the decoction (PAD), ethyl acetate (EAP), and residual aqueous (ARP) fractions of immature Phaseolus vulgaris pods on NMRI mice thoracic aorta rings. Methods: Phytochemical screening was performed by high-performance thin-layer chromatography. Folin-Ciocalteu and aluminum trichloride colorimetric methods were used to quantify total polyphenol compounds (TPC) and total flavonoids (TFC), respectively. Antioxidant activities of the extracts were determined by 2,29-azinobis-3-ethylbenzothiazoline-6-sulfonic (ABTS●), 2,2-Diphenyl-1-picrylhydrazyl (DPPH●), and ferric ion (FRAP) radical reduction methods. The DMT 620M ADInstruments myograph technique was used to evaluate the ex-vivo vasodilatory effects of Phaseolus vulgaris extracts on aortic rings. Results: Chromatographic fingerprints showed the presence of flavonoids, coumarins, tannins, steroids, triterpenes, and saponins in the extracts studied. The TPC (61.07±0.04 mgGAE/g) and TFC (6.16±0.03 mgQE/g) of EAP were statistically significant compared to that of PAD and ARP (p&lt;0.001). The antioxidant power of Trolox was statistically significant compared to all studied extracts (p&lt;0.05). It should be noted that among these extracts, EAP showed the better antiradical capacities for ABTS (IC50=71.87±0.30 µg/mL) and DPPH (IC50=9.93±0.00 µg/mL). However, for FRAP activity, it was the PAD extract (T=170.68±0.11 µgAAE/g) that obtained the best score. In terms of vasorelaxant activity, all extracts induced concentration-dependent relaxation of aortic rings precontracted with U46619. Pharmacodynamic parameters were significantly in favor of EAP [EAP(E+)=(Emax=100.06±0.00%; pD2=1.24±0.01) and EAP(E-)=(Emax=101.01±0.00%; pD2=0.84±0.02)] followed by PAD and then ARP. Conclusion: Phaseolus vulgaris immature pod extracts possess concentration-dependent vasorelaxant effects on isolated mouse aorta. These preliminaries results were scientific evidence to support the use of this plant in traditional and complementary medicine for the treatment of hypertension.