Vasodilator Activity Research Articles

Age-dependent Role of Cilostazol on Cold Restraint Stress-induced Gastric Ulceration in Female Rats

Introduction: Cilostazol (CIL), a phosphodiesterase III inhibitor, is a potent antiplatelet drug which possesses vasodilator and anti-inflammatory activity that making it an effective drug in gastric ulcer protection. Objectives: This study investigated the influence of age on the effects of CIL against cold restraint stress (CRS) - induced gastric ulcer in rats. Methods: CIL (10 mg/kg/day) was administered orally for 2 weeks to adult and aged female rats before CRS-induced gastric ulcer. Results: This syudy showed that CIL exhibited gastroprotective effects in both adult and aged rats as evidenced by significant decrease in ulcer index, gastric mucosal malondialdehyde level, myeloperoxidase activity and tumor necrosis factor-α protein expression with concomitant increase in gastric mucosal reduced glutathione level and glutathione peroxidase activity, nitric oxide, prostaglandin E2 level, cyclooxygenase-1 and 2 protein expression and gastric juice mucin concentration compared to adult and aged CRS rats, respectively. Additionally, the histopathological examination results came to confirm the protection afforded by CIL in CRS - induced gastric ulcer. Conclusion: The possible protective effect of CIL against CRS-induced gastric ulceration in both adult and aged rat’s may be explained via its antioxidant and antiinflammatory properties and by enhancement of gastric mucus secretion. It could be recommended that CIL is considered as a more proper antiplatelet drug for adult and elderly patients who are at risk of gastric ulceration.

A Review of Endothelium-Dependent and -Independent Vasodilation Induced by Phytochemicals in Isolated Rat Aorta.

This review discusses the contribution of the use of the isolated rat aorta (IRA) as a model for the evaluation of extracts and metabolites produced by plants with a vasodilator effect in animals. This model continues to be a valuable approach for the search and development of new phytochemicals consumed as medicinal plants or foods. In most cases, the sources of phytochemicals have been used in folk medicine to treat ailments that include hypertension. In this model, the endothelium is emphasized as a key component that modulates the vessel contractility, and therefore the basal tone and blood pressure. Based on the functional nature of the model, we focused on studies that determined the endothelium-dependent and -independent vasodilatory activity of phytochemicals. We describe the mechanisms that account for aorta contraction and relaxation, and subsequently show the vasoactive effect of a series of phytochemicals acting as vasodilators and its endothelium dependence. We highlight information regarding the cardiovascular benefits of phytochemicals, especially their potential antihypertensive effect. On this basis, we discuss the advantages of the IRA as a predictive model to support the research and development of new drugs that may be of help in the prevention and treatment of cardiovascular diseases, the number one cause of death worldwide.

Paraoxonase 1 and atherosclerosis-related diseases.

A direct and an indirect relationship between paraoxonase 1 (PON1) and atherosclerosis exists. Given PON1's physical location within high-density lipoprotein (HDL) particles and its recognized enzyme activity, it is certainly reasonable to suggest that PON1 facilitates the antiatherogenic nature of HDL particles. PON1 also plays a role in regulating reverse cholesterol transport, antioxidative, anti-inflammatory, antiapoptotic, vasodilative, and antithrombotic activities and several endothelial cell functions. HDL dysfunctionality is a more recent issue and seems to be centered on pathological conditions affecting HDL structure and size profiles. This review is focused on the role of PON1 status in different atherosclerosis-related diseases that we have studied over the last twenty years (coronary heart disease, acute ischemic stroke, diabetes mellitus type 2, end-stage renal disease, chronic obstructive pulmonary disease, and sarcoidosis) with the aim to determine the true value of PON1 as a biomarker. The role of PON1 in cancer is also covered, as risk factors and mechanisms underlying both atherosclerosis and cancer share common features.

8-methoxysmyrindiol from Gerbera piloselloides (L.) Cass. and its vasodilation effects on isolated rat mesenteric arteries

Gerbera piloselloides (L.) Cass. (Compositae) possesses various biological effects. It is used as an oriental remedy for relieving cough and resolving phlegm. The present study is to investigate the vasodilation effects of Gerbera piloselloides on isolated rat mesenteric arteries (MAs) and the potential mechanism. Different organic extracts of Gerbera piloselloides were tested, and an HPLC-UV-FD-based analytical method was established to identify the active constituents. The principal components, namely, 8-MOP (8-methoxypsoralan) and 8-MSD (8-methoxysmyrindiol), were found to be predominant in the extracts of petroleum ether and dichloroform, which showed stronger vasodilation activities. 8-MSD was isolated from Gerbera piloselloides by silica gel column chromatography coupled with a Waters 2545 high throughput autopurification system, and its vasodilation effects were explored by an assay of tension on rat MA rings. The results suggest that 8-MSD induces vascular relaxation in rat MAs via an endothelium-dependent mechanism involving the Kir channel, which enables Ca2+ entry in the cell and activates production of NO. The present research indicates that 8-MSD may be therapeutically useful as an anti-hypertension agent and to potentially treat cardiovascular and gastrointestinal diseases.

Bloqueadores beta: perspectiva histórica y mecanismos de acción

Beta-blockers are widely used molecules that are able to antagonize β-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon β-AR stimulation, numerous intracellular cascades are activated, ultimately leading to cardiac contraction or vascular dilation, depending on the relevant subtype and their location. Three subtypes have been described that are differentially expressed in the body (β1-, β2- and β3-ARs), β1 being the most abundant subtype in the heart. Since their discovery, β-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, β-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective β-blockers, cardioselective β-blockers (selective β1-antagonists), and a third generation of these drugs able to block β1 together with extra vasodilation activity (also called vasodilating β-blockers) either by blocking α1- or by activating β3-AR. More than 50 years after propranolol was introduced to the market due to its ability to reduce heart rate and consequently myocardial oxygen demand in the event of an angina attack, β-blockers are still widely used in clinics.

Gastroprotective effect of cilostazol against ethanol- and pylorus ligation-induced gastric lesions in rats.

Despite the availability of effective antiulcer medications, their suboptimal safety profile ignites the search for alternative/complementary treatments. Drug repositioning is an attractive, efficient, and low-risk strategy. Cilostazol, a clinically used phosphodiesterase 3 inhibitor, has pronounced anti-inflammatory and vasodilatory effects suggesting antiulcer activity. Using ethanol-induced and pyloric ligation-induced gastric ulcer models, we investigated the gastroprotective effect of cilostazol (5 or 10mg/kg, p.o.) in comparison with the standard antiulcer ranitidine (50mg/kg, p.o.) in rats. Gastric mucosa was examined macroscopically, histologically, and biochemically for ulcer severity, markers of oxidative stress, proinflammatory cytokines, apoptotic, and cytoprotective mediators. Gastric acidic output, peptic activity, and mucin content were measured in gastric fluids. Pretreatment with cilostazol reduced ulcer number and severity, ameliorated redox status (reduced glutathione and malonaldehyde content), and decreased levels of IL-1β, IL-6, and TNF-훼 in gastric mucosa, in parallel with increases in mucosal defensive factors nitric oxide (NO), prostaglandin E2 (PGE2), and heat-shock protein 70 (HSP70) promoting mucus secretion, tissue perfusion, and regeneration. Histological examination confirmed the beneficial effects of cilostazol in terms of reducing focal necrosis and infiltration of inflammatory cells, as well as increasing mucopolysaccharide content. These beneficial effects are likely secondary to an increase in cAMP and decrease in apoptosis regulator Bcl-2-associated X protein (BAX). Cilostazol, in a dose-dependent effect, exhibited vasodilatory, anti-inflammatory, and antiapoptotic actions in the gastric mucosa resulting in significant antiulcer activity comparable with the standard drug, ranitidine, but devoid of antisecretory activity. Therefore, its use should be dose and ulcer-inducer dependent.

A REVIEW ON ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF CALCIUM CHANNEL BLOCKERS AND ANGIOTENSIN- CONVERTING ENZYME INHIBITORS IN BULK AND PHARMACETICAL FORMULATION

A simple, economical and rapid by UV detector and PDA Detector was used for Estimation of Trandolapril and Verapamil in combination and other drugs in various Pharmaceutical formulation. Calcium channel blockers(CCBs) and angiotensin- converting enzyme (ACE) inhibitors has been developed and fully validated by High performance liquid Chromatographic Methods. Calcium channel blockers (CCBs) or Calcium antagonists are among the most widely used drugs in cardiovascular medicine and hypertension also in angina. CCBs promote vasodilator activity by reducing calcium influx into vascular smooth muscle cells by interfering with calcium channels in the cell membrane. Trandolapril is a potent nonsulfhydryl and dicarboxyl containing Angiotensin converting inhibitor (ACE). Trandolapril used to treatment of hypertension appears to result the inhibition of tissue ACE activity and to improve survival myocardial infarction thereby reduce angiotensin II formation.
 It includes drugs like Trandolapril, Norverapamil, Nifedipine, Verapamil. This Review enlists different method Developed, Validated and determination of Calcium channel blockers and angiotensin- converting enzyme inhibitors Like, RP-HPLC, LC-MS/MS and HPLC UV- Spectophotometric method. This method was also validated for various validation terms indicates that precise, accurate, linearly, and limit of Detection and limit of Quantitation as per ICH guidelines.
 Keywords: HPLC Chromatography, Calcium Channel blocker, angiotensin- converting enzyme (ACE) inhibitors, Hypertension, Validation etc.

Effect of pH increasing of Wuluh star fruit (Averrhoa bilimbi L.) juice on vasodilatation activity

Wuluh star fruit (Averrhoa bilimbi L.) is Oxadiliaceae family which can be used as an antihypertensive drug by ethnomedicine. A. bilimbi fruit juice is proven to lower blood pressure in preclinical testing and limited phase 1 clinical trials, where the mechanism of action is through vasodilatation of blood vessels. The taste of juice fruit is very sour, but there is no information about the effect of pH increasing of juice on vasodilatation activity in blood vessels. In this research, A. bilimbi fruits were made into juice, filtered, centrifuged to get the supernatant. The pH of juice was increased by NaOH and KOH addition. Vasodilatation activity of juice was tested on isolated organs of the aortic ring endothelium. The control that used was Kreb’s-Henselheit solution with a pH approaching the tested juice solution. The result showed that an increase in the pH of A. bilimbi fruit juice caused a decrease in vasodilatation activity. The type of solution to increase the pH of juice also affected the changes in vasodilatation activity. It can be concluded that the pH increasing on juice of A. bilimbi fruit can decrease vasodilatation activity on isolated organs of the aortic ring endothelium.

The vascular protective role of oestradiol: a focus on postmenopausal oestradiol deficiency and aneurysmal subarachnoid haemorrhage

The steroid hormone, oestradiol, has pleiotropic functions. The protective effects of oestradiol are attributed to its anti-inflammatory, antioxidant, anti-atherogenic, anti-apoptotic, vasodilatory activities and regulation of micro RNA. Oestradiol upregulates endothelial nitric oxide synthase gene expression and increases the production of nitric oxide, an important vasodilator. It suppresses the renin-angiotensin system and monitors haemodynamic stress. The hormone maintains the integrity of blood vessels by reducing oxidative stress while upregulating the expression of antioxidant enzymes and prevents vascular inflammation by regulating pro- and anti-inflammatory cytokines. Aneurysmal subarachnoid haemorrhage (aSAH) occurring as a consequence of the rupture of an intracranial aneurysm is a devastating cerebrovascular event, representing 5-7% of all strokes. Postmenopausal women are more susceptible to aSAH compared to men in the same age group. This gender disparity has been attributed to reduced levels of the vascular protective hormone oestradiol following menopause. This review is focused on the protective role of oestradiol on vasculature and how the drop in oestradiol levels after menopause dramatically increases the incidence of aSAH in women. During menopause, oestradiol deficiency may affect vascular integrity causing dysregulation of vascular homeostasis by affecting the renin-angiotensin-aldosterone system (RAAS) and inflammatory and apoptotic cascades, resulting in the weakening of the cerebral arterial wall and potentially to development of an aneurysm and its rupture. In view of the role of oestradiol in maintaining vascular integrity, treatments involving hormone replacement could be a promising approach in postmenopausal women who are at risk of developing or rupturing an intracranial aneurysm.

Propofol Relaxes Isolated Rat Aorta through BKCa Activation

Propofol is an intravenous anesthetic that can be used for the induction and maintenance of anesthesia. In the present study, it was aimed to investigate the mechanism of vasodilator action of propofol in the rat aorta (RA). The RA rings were suspended in isolated organ baths and tension was recorded isometrically. First, potassium chloride (KCl) and phenylephrine (PE) were added to organ baths to form precontraction. When the precontractions were stable, propofol (1, 10, and 100μM) was added cumulatively to the baths. The antagonistic effect of propofol on KCl (45mM), PE (1μM), 5-hydroxytryptamine (5-HT) (30μM), and calcium chloride (CaCl2) (10μM to 10mM) induced contractions in the vascular rings were investigated. Propofol-induced relaxations were alsotested in the presence of the K+ channel inhibitors tetraethylammonium (TEA, 1mM), glibenclamide (GLI, 10μM), 4-aminopyridine (4-AP, 1mM), and barium chloride (BaCl2, 30μM). Preincubation with propofol (1, 10, and 100μM) did not affect the basal tone but inhibited the contraction induced by KCl, PE, 5-HT, and CaCl2-induced contractions. Propofol-induced relaxation was not effected by 4-AP, GLI, and BaCl2. However, TEA inhibited propofol-induced relaxations significantly. The propofol induces relaxation in contracted RA and inhibits KCl, PE, 5-HT, andCaCl2-induced contractions. The results demonstrate that the mechanism of action of propofol-induced vasodilation in the RA may be related to large conductance Ca2+-activated K+ channel activation.

Beta-blockers: Historical Perspective and Mechanisms of Action

Beta-blockers are widely used molecules that are able to antagonize β-adrenergic receptors (ARs), which belong to the G protein-coupled receptor family and receive their stimulus from endogenous catecholamines. Upon β-AR stimulation, numerous intracellular cascades are activated, ultimately leading to cardiac contraction or vascular dilation, depending on the relevant subtype and their location. Three subtypes have been described that are differentially expressed in the body (β1-, β2- and β3-ARs), β1 being the most abundant subtype in the heart. Since their discovery, β-ARs have become an important target to fight cardiovascular disease. In fact, since their discovery by James Black in the late 1950s, β-blockers have revolutionized the field of cardiovascular therapies. To date, 3 generations of drugs have been released: nonselective β-blockers, cardioselective β-blockers (selective β1-antagonists), and a third generation of these drugs able to block β1 together with extra vasodilation activity (also called vasodilating β-blockers) either by blocking α1- or by activating β3-AR. More than 50 years after propranolol was introduced to the market due to its ability to reduce heart rate and consequently myocardial oxygen demand in the event of an angina attack, β-blockers are still widely used in clinics.

1933-P: Acute Hyperglycemia + Hyperinsulinemia Increases Carotid-Femoral Arterial Stiffness and Perfusion of Skeletal Muscle in Healthy Subjects

Introduction: Chronic hyperglycemia injures both micro-and microvasculature. Conversely, insulin stimulates vascular nitric oxide production and acts as a vasodilator. Whether acute hyperglycemia (AH) inhibits insulin’s vasodilator action in healthy vasculature is unknown. Here we tested whether AH interfered with insulin’s action to recruit microvasculature, enhance endothelial function, or diminish vascular stiffness. Methods: Nine healthy, fasting subjects (ages 18-35 years; BMI 18-25 kg/m2) twice received a 1 mU/kg/minute 2-hour insulin clamp. On one occasion, subjects were euglycemic (EH); and on the second, were hyperglycemic (∼200 mg/dL) (HH) for 2 hours before and throughout the clamp. Octreotide infusion blocked endogenous insulin in both studies. We assessed endothelial function by flow-mediated dilation (FMD) and arterial stiffness with pulse wave velocity (PWV) and augmentation index (AI). We used contrast-enhanced ultrasound to measure insulin-mediated capillary recruitment in skeletal and cardiac muscle. Linear mixed model was used for statistical analysis, with Bonferroni correction for comparison between studies. Results: Insulin increased carotid-femoral PWV (p=0.02 for Δ PWV) but decreased AI (p= 0.02) during HH, with AI significantly reduced in HH compared to EH (p=0.04). Insulin recruited microvasculature (p<0.05) with either EH or HH, and microvascular blood volume (p=0.03) and blood flow (p=0.04) significantly increased in skeletal muscle after HH. No changes were observed in FMD or cardiac microvascular perfusion with either condition. Discussion: This study provides evidence that 4 hours of AH evokes insulin-induced increases of carotid-femoral arterial stiffness in healthy subjects. Insulin’s ability to recruit microvasculature is preserved during AH. Disclosure W.B. Horton: None. L. Jahn: None. L. Hartline: None. J.T. Patrie: None. E. Barrett: Research Support; Self; AstraZeneca. Funding National Institutes of Health (F32HL142304-01)

Effects of oxidation and browning of macerated white wine on its antioxidant and direct vasodilatory activity

Abstract Although naturally produced macerated white wines are increasingly popular, their biological effects are rarely studied. As wines containing no preservatives, they are highly susceptible to oxidation after bottle opening. Our aims were therefore: (1) to compare the antioxidant and direct vasodilatory activity of standard (W) and polyphenols-rich macerated white wine (PW); (2) to examine effects of oxidation and browning of PW, associated with its exposure to air for 24 (24 h-OxPW) and 48 h (48 h-OxPW), on measured biological activities. Total phenolics content, direct vasodilatory and antioxidant activity of PW were much higher than those of W. Overall effects of up to 48 h-exposure to air on levels and composition of examined phenolics were minor. Similarly, exposure to air and associated browning did not affect maximal vasodilatory and antioxidant activity of PW. Vasodilatory potency, however, increasingly weakened with exposure to air as oxidized samples had higher half maximal effective concentrations than intact PW.

Insulin exposure mitigates the increase of arterial stiffness in patients with type 2 diabetes and albuminuria: an exploratory analysis

AimsInsulin possesses both vasodilatory and sympathomimetic activities. The aim was to examine the relationship between changes in insulin exposure and arterial stiffness in type 2 diabetes (T2D).MethodsPatients with T2D with (n = 22) or without (n = 24) albuminuria, and non-diabetic controls (n = 25) were randomized to a crossover study having a breakfast with or without pre-meal rapid-acting insulin. Pulse wave velocity (PWV) was measured at 30 min before and at 60-min intervals up to 240 min after the breakfast.ResultsAt baseline, both postprandial aortic (p = 0.022) and brachial (p = 0.011) PWV were higher in individuals with T2D than in healthy controls irrespective of the presence of albuminuria. In patients with albuminuria, weight-adjusted insulin dose correlated inversely with the excursion of the aortic (r = − 0.412, p = 0.006) and brachial (r = − 0.372; p = 0.014) PWV. Similarly, circulating endogenous insulin concentrations correlated inversely with the aortic (r = − 0.347, p = 0.026) and brachial (r = − 0.622, p = <0.001) PWV. No correlations between insulin and PWV were observed in patients without albuminuria or in healthy controls.ConclusionsThe inverse correlation between insulin and PWV in T2D with albuminuria may reflect a vasorelaxing effect of insulin.Clinical trial registration numberThe study was registered (clinicaltrials.gov) with the identifier of NCT01159938.

Furanoeremophilanes from Euryops arabicus alleviate metabolic syndrome-associated exaggerated vasoconstriction via direct vasodilatation

• Euryops arabicus alleviated MetS associated exaggerated vasoconstriction. • The chloroform fraction yielded eight furanoeremophilane derivatives. • All isolated compounds showed significant vasodilation activity. • Vasodilation activity may involve calcium channel blocking mechanism. Abstract Exaggerated vasoconstriction plays a critical role in the development of hypertension in metabolic syndrome (MetS). A crude methanolic extract of Euryops arabicus (EA) was found to alleviate MetS-associated exaggerated vasoconstriction. The methanolic extract of EA had a direct vasodilatory effect which might account for the alleviation of vasoconstriction. Bio-guided fractionation revealed that the chloroform fraction is responsible for this effect. The observed vasodilation was not affected by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide (NO) synthase inhibitor or methylene blue (MB), a guanylate cyclase inhibitor, while it was increased by tetraethylammonium (TEA), a potassium channel blocker. In addition, the chloroform extract showed concentration-dependent inhibition of calcium-induced contraction. Chemical investigations of the chloroform fraction of EA revealed three new furanoeremophilanes, namely, 6-β-(2`-methyl-2`,3`-epoxy-propionyloxy)-10-α-H-9-oxofuranoeremophilane ( 4 ), 6- α -(2`-methyl, 2`,3`-epoxy-butyryloxy)-10-α-H-9-oxofuranoeremophilane ( 7 ), and 6-β-(2`-methyl, 2`,3`-epoxy-butyryloxy)-euryopsin ( 8 ), in addition to five other known metabolites, namely, 6-isovaleryloxy-euryopsin ( 1) , 6-isopropionyl-euryopsin (adenostylone) ( 2 ), 6-senecioyl-euryopsin-9-one ( 3 ) 6-β -(2`-methyl-2`,3`-epoxy-butyryloxy)-10-α-H-9-oxofuranoeremophilane ( 5 ), and euryopsonol-senecioate ( 6 ). All the isolated compounds showed significant vasodilatory effects that might involve calcium channel blocking, and compounds 7 and 8 were found to be the most bioactive ones.

The Vasodilating Effect and Angiotensin Converting Enzyme Inhibition Activity of Three Dietary Flavonols: Comparsion between Myricetin, Quercetin and Morin, &lt;i&gt;in vitro&lt;/i&gt;

The aim of this study is to compare the vasodiating effects and angiotensin converting enzyme inhibition activity of three dietary flavonols, myricetin, quercetin and morin, in vitro. The three flavonols ranging from 0 to 200 μM show no cytotoxicity to small vessel endothelial cells (SVEC). For vasodilative assay, of the three flavonols, myricetin showed the greatest induction in the levels of nitric oxide (NO) and prostacyclin (PGI2), and the expression of cyclooxygenase (COX-2). Myricetin, quercetin and morin enhanced the expression of eNOS, but no significant differences (p > 0.05) were found between three flavonols. Myricetin, quercetin and morin showed marked inhibitory effect on reactive oxygen species (ROS) production in H2O2-induced SVEC cells. In addition, myricetin and quercetin showed relatively higher inhibitory activity on ACE activity than morin. Taken together, of the three flavonols, myricetin with the substitution by more hydroxyl groups in the flavonol structure enhanced vasodilating activity. Enzyme kinetic analysis showed myricetin is a non-competitive inhibitor of ACE. These structure-function relationships facilitate the design of new antihypertensive drugs based on flavonols.

L-cysteine/cystathionine-β-synthase-induced relaxation in mouse aorta involves a L-serine/sphingosine-1-phosphate/NO pathway.

Among the three enzymes involved in the transsulfuration pathway, only cystathionine β-synthase (CBS) converts L-cysteine into L-serine and H2 S. L-serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl-CoA by the action of serine palmitoyltransferase (SPT). Here, we have investigated if L-serine contributes to the vasorelaxant effect. The presence of CBS in mouse vascular endothelium was assessed by immunohistochemistry and immunofluorescence. The relaxant activity of L-serine (0.1-300μM) and L-cysteine (0.1-300μM) was estimated on mouse aorta rings, with or without endothelium. A pharmacological modulation study evaluated NO and sphingosine-1-phosphate (S1P) involvement. Levels of NO and S1P were also measured following incubation of aorta tissue with either L-serine (1, 10, and 100μM) or L-cysteine (10, 100μM, and 1mM). L-serine relaxed aorta rings in an endothelium-dependent manner. The vascular effect was reduced by L-NG-nitro-arginine methyl ester and wortmaninn. A similar pattern was obtained with L-cysteine. The S1P1 receptor antagonist (W146) or the SPT inhibitor (myriocin) reduced either L-serine or L-cysteine relaxant effect. L-serine or L-cysteine incubation increased NO and S1P levels in mouse aorta. L-serine, a by-product formed within the transsulfuration pathway starting from L-cysteine via CBS, contributes to the vasodilator action of L-cysteine. The L-serine effect involves both NO and S1P. This mechanism could be involved in the marked dysregulation of vascular tone in hyperhomocysteinemic patients (CBS deficiency) and may represent a feasible therapeutic target. This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Vasoactivity of Mantonico and Pecorello grape pomaces on rat aorta rings: An insight into nutraceutical development

The valorisation of agrochemical wastes has become a low cost and sustainable tendency for the development of functional food. In particular, these enriched products seem to be enjoyable tools to treat metabolic disorders. In this field, Calabrian autochthonous white grape pomaces (Mantonico and Pecorello cultivar) were firstly investigated for their vasoactive properties. Skins and seeds were extracted and characterized by NMR spectroscopy, revealig the presence of numerous vasoactive compounds. The effects of extracts were analyzed in in vitro experiments on rat aorta rings (with and without endothelium), contracted by phenylephrine or KCl. Seeds extracts showed, differently from skins, an appreciable endothelium-dependent, eNOS-mediated vasodilation in the range 1–100 µg/mL. From a food market point of view, all the extracts were enclosed into a pectin polymer matrix. In the same experimental conditions, the polymers demonstrated the persistance of vasodilator activity only for Pecorello seed extract, which presented the most rich chemical profile.

Treatment of Hypertension with Stable Analogue of 14, 15‐Epoxyeicosatrienoic Acid (EET‐A) in Spontaneously Hypertensive Rats

IntroductionHypertension and concomitant complications, such as blood circulation disorders, stroke, heart attack or kidney failure, became one of the leading causes of death in the world. Recent reports indicate on epoxyeicosatrienoic acids (EETs) as significant factors in blood pressure regulation. These cytochrome P‐450 dependent metabolites of arachidonic acid, exhibit vasodilator and natriuretic activity. It has been shown that EETs facilitate the production of vasodilatory NO, protect the endothelium, exhibit antioxidant properties and might inhibit inflammation. All of the above‐mentioned features should contribute to the reduction of blood pressure and adverse effect of hypertension, hence we postulate the usefulness of EETs as novel drugs for the prevention and/or treatment of hypertension. In the present study the potential hypotensive efficiency of a stable analogue of 14,15‐EET: disodium (S)‐2‐(13‐(3‐entyl)ureido)‐tridec‐8(Z)‐enamido) succinate, called EET‐A, in genetic model of hypertension (spontaneously hypertensive rat, SHR) was evaluated.MethodsMale SHR (n = 6) in the established stage of hypertension (16 weeks) were treated for four weeks with EET‐A dissolved in drinking water (10 mg/kg/day); aged‐matched control group received water only (n = 6). Systolic blood pressure (SBP) was measured by telemetry technique every three days. Once a week observations in metabolic cages (food and water intake, feces, diuresis) were performed; urine and blood samples were collected for further analysis. Nitric oxide metabolites and vascular endothelial growth factor (VEGF) content in urine was measured with commercial ELISA kit.ResultsPreliminary results showed that EET‐A did not impact the blood pressure of adult SHR. We did not observe any changes in diuresis, water and food intake. Also sodium excretion did not change after EET‐A treatment, however, surprisingly, it significantly increased in the control group (EET‐A day 0: 0.5 ± 0.1 vs day 28: 0.5 ± 0.1, NS; control group day 0: 0.4 ± 0.2 vs day 28: 1.0 ± 0.1#* mmol/24h, *p&lt;0.05 within the control group; # values on day 28th between groups, p&lt;0.05). The excretion rates of NO metabolites (nitrates/nitrites; NOx) and VEGF‐A increased significantly in the EET‐A treated group (NOx day 0: 0.99 ± 0.18 vs day 28: 1.56 ± 0.13 μmol/24h, p&lt;0.05; VEGF‐A day 0: 3.2 ± 0.7 vs day 28: 9.5 ± 2.0 ng/24h, p&lt;0.05).SummaryAnalysis of the obtained data suggests that EET‐A in the applied dose does not lower blood pressure. Further studies are necessary to investigate if, despite the lack of blood pressure decrease, EET‐A improved kidney function.Support or Funding InformationNational Science Centre 2017/26/M/NZ5/00367This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vascular Action of Insulin in Pregnancy

Physiological insulin resistance associated with pregnancy is attributed to the increase of anti‐insulin hormones such as placental lactogen and p85 (potent negative regulator of PI3K), human growth hormone, TNFα, as well as adipokines. Besides, AT1 receptor for angiotensin II has a clear role in insulin resistance while the role of AT2 receptors is not well understood. On the other hand, it has been described an increased vascular expression of AT2 receptor during pregnancy. On the other hand, insulin has shown a PI3K‐AKT NO mediated vasodilator effect that may contribute to its metabolic actions. Therefore, the aim of this study was to evaluate if pregnancy decrease in the vasodilatory action of insulin and AT2 receptors participation in this change. Using a conventional isolated organ preparation, the vasodilator effect of cumulative concentrations of insulin was evaluated in rat aortic rings pre‐contracted with phenylephrine. Vasorelaxation of aorta rings was compared at day 14 and day 20 (term) of pregnancy in the presence and absence of the AT2 receptor antagonist PD123319. Pregnancy produced resistance to insulin induced vasodilatation in the thoracic aorta while the vasodilator effect increased in the abdominal aorta only in rings with intact endothelium. AT2 receptors participation on the insulin induced vasodilation was more evident on day 14 (half) gestation. These results suggest that the vascular action of insulin is enhanced by the participation of AT2 receptors for angiotensin II. Also, that both insulin action and AT2 receptor participation during pregnancy depend on the vascular territory studied.Support or Funding InformationSIP Instituto Politécnico Nacional, COFFAAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.