Vasodilator Activity Research Articles

Hawthorn berry (crataegus songarica) causes endothelium-dependent relaxation of the porcine coronary artery: Role of Estrogen receptors

BACKGROUND: Fruits of Crataegus songarica are commonly used for the treatment of vascular insufficiency and heart problems. OBJECTIVE: Our aim was to determine the effect of C. songarica on vascular tone and to determine the mechanisms underlying the vasorelaxant properties. METHODS: Extracts of C. songarica were tested for vasodilator activity of porcine coronary artery after pre-contraction with the thromboxane mimetic U46619 in the presence or absence of inhibitors of intracellular signaling cascades. Reactive oxygen species were assessed by dihydroethidine staining and the level of eNOS and AKT phosphorylation was measured by immunohistochemical staining. RESULTS: Extracts of C. songarica berries produced endothelium dependent vasorelaxation, with most significant effect induced by aqueous fraction (AS-CS). This vasorelaxant effect of AS-CS was reduced by inhibition of nitric oxide pathways and inhibition of potassium channels. Inhibition of phosphatidylinositol 3- kinase and Src tyrosine kinase, as well as scavenging of reactive oxygen species, produced an attenuation of the relaxation response. Estrogen receptor antagonists (tamoxifen and ICI 182,782) reduced the AS-CS mediated vasorelaxation. AS-CS also stimulated the endothelial formation of ROS and phosphorylation of Akt and eNOS. CONCLUSION: The data indicated that C. songarica produces an endothelium-dependent vasorelaxation, which is partly dependent upon estrogen receptors, and sensitive to inhibition of ROS/Src/PI3K/NO pathways.

Vasorelaxation effect of oxysophoridine on isolated thoracicc aorta rings of rats.

Oxysophoridine (OSR) is a main active alkaloid extracted from Sophora alopecuroides, which is a traditional Chinese herbal medicine that has been used widely. In this study, we used thoracic aorta rings isolated from Sprague-Dawley rats to explore the vasodilative activity of OSR and its potential mechanisms. The isolated rat thoracic aorta rings were used to observe the effects of different concentrations of OSR (0.4-2.0 g·L-1) on the resting normal rings and the phenylephrine precontracted endothelium-intact or endothelium-denudedisolated thoracic aorta rings, respectively. The interactions among OSR and barium chloride (BaCl2), tetraethylamine, 4-aminopyridine, glibenclamide (Gli), L-nitroarginine methyl ester (L-NAME), and cyclooxygenase (COX) inhibitor indomethacin (INDO) were evaluated. The experimental results show that OSR had no effect on the tension of resting vascular rings, but the vasodilating effect could be confirmed in a concentration-dependent manner on both endothelium-intact and endothelium-denuded vascular rings. This vasodilation effect of OSR on thoracic aorta vascular rings could be inhibited significantly by potassium channel blockers glibenclamide (Gli, 10 μmol·L-1) and 4-aminopyridine (4-AP, 5 mmol·L-1). In addition, vasodilatory effects of OSR were not inhibited in the presence of potassium channel blockers barium chloride (BaCl2, 1 mmol·L-1) and tetraethylamine (TEA, 10 mmol·L-1), nitric oxide synthase inhibitor (L-NAME, 0.1 mmol·L-1) and COX inhibitor (INDO, 10 μmol·L-1). In conclusion, the vasodilatory effects of OSR on thoracic aorta rings is associated with KV and KATP.

Ethnopharmacological investigations of the leaves of Cecropia pachystachya Trécul (Urticaceae): A native Brazilian tree species

Ethnopharmacological relevanceCecropia pachystachya Trécul (Urticaceae) is a medicinal plant popularly known as ‘embaúba’. In Brazil, the leaves of this species are used for the treatment of various kidney and cardiovascular diseases. However, there are no detailed studies on the renal and cardiovascular activities of this species. No studies on the anatomy or the quality control of this herbal drug is available thus far. AimThis study was aimed to investigate the ethnopharmacological properties of the leaves of C. pachystachya. Material and methodsThe leaves of C. pachystachya were analyzed by light and scanning electron microscopy for pharmacobotanical and anatomical characterization. The ethanol-soluble fraction of C. pachystachya leaf extract (ESCP) was characterized by high-performance liquid chromatograph equipped with diode array detector and mass spectrometry (HPLC-DAD-MS). The acute oral toxicity of ESCP on female Wistar rats was assessed. The acute and prolonged diuresis and antioxidant effects of ESCP (30, 100, and 300 mg/kg) were evaluated in male Wistar rats. In addition, the hypotensive effects of the ESCP as well as the vasodilatory activity in isolated and perfused mesenteric vascular beds were investigated. ResultsThe anatomical markers obtained in this study can help in the identification of C. pachystachya, as well as to distinguish it from the other ‘embaúbas’. The metabolites found in the ESCP were phenolic compounds, mainly C- and O-glycosylated flavonoids. The ESCP did not exhibit any toxic effects at a dose of 2000 mg/kg. Significant diuretic activities were observed at the doses of 30, 100, and 300 mg/kg. In addition, a significant modulating activity of the tissue redox state was observed after prolonged treatment. On the other hand, no hypotensive or vasodilator activity was observed. ConclusionThe key findings of the present study can contribute to the taxonomy, species identification and quality control of C. pachystachya. Chemical studies have shown the presence of glycosylated flavonoids, phenylpropanoid derivative and proanthocyanidins. The pharmacological studies showed significant diuretic and antioxidant effects of C. pachystachya leaf extract, indicating a possible validation of its popular medicinal use.

A case report on the management of severe vasospasm in subarachnoid hemorrhagic patients using intra-arterial nimodipine, intrathecal sodium nitroprusside and intra-arterial papaverine

Management and prevention of vasospasm in subarachnoid haemorrhage are one of the complex dictums so far. Aneurysmal subarachnoid haemorrhage (aSAH) is the condition in which bleeding occurs in subarachnoid space. Vasospasm is a complex immunologically active phenomenon which requires a multimodality approach in the treatment of established vasospasm. Various treatment strategies for vasospasm and related disabilities include vasodilators such as nimodipine, sodium nitroprusside and papaverine. Intra-arterial nimodipine shows drastic improvement in several patients by resolving and preventing vasospasm. Intra-arterial administration of nimodipine can cause hypotension which can be easily managed. Papaverine is also an efficient drug-producing vasodilatory action on cerebral arteries. Papaverine is considered as the first intraarterial agent to reduce angiographic cerebral vasospasm which has the side effect of elevated intracranial pressure. Besides, the intrathecal administration of sodium nitroprusside has also demonstrated the effect in ischemic vasospasm after subarachnoid haemorrhage. Intraarterial administration of this drug can induce arterial hypotension which is not a recommended method. Vomiting is the main side effect of sodium nitroprusside, which can be managed with antiemetics such as ondansetron. Here we present a case of management of cerebral vasospasm in subarachnoid patients using the combination of these three effective drugs which showed a remarkable improvement in the resolution of aneurysmal vasospasm.

Phytochemical screening and HPLC- UV method quantiϐication of Flavonoids in Coffee Arabica green seeds

The green coffee bean is the most commonly used beverages in India and it is one of the most commercialised food products. They have a rich source of biologically active compounds that are important for human health. The coffee tree or a shrub belongs to the family Rubiaceae. Commercially available, two species of green coffee bean are Coffea Arabica and Coffea canephora. Cancer is the most important cause of death. Apart from cancer, quercetin can also prevent Osteoporosis. The phytochemicals present in the green coffee bean can be used as an alternate therapy for cancer due to its antimitotic activity and free radical scavenging activity. Total antioxidant shows IC50 value 45.81. Kaempferol is a potent antioxidant that can defence against free radicals and cure chronic diseases. Flavonoids are phenolic substances that act as an antioxidant, anti-inflammatory, anti-allergenic, antiviral and also have vasodilating actions. Green coffee bean shows a high concentration of Flavonoids in hydroethanolic extraction. The aim of this study is used to analyse the presence of Flavonoids in green coffee bean by using High-performance Liquid Chromatography (HPLC). Flavonoids are potent antioxidant that can bind to a protein. Flavonoids show a wide range of biological and pharmacological activities like anti-allergic, anti-inflammatory, anti-cancer and anti-microbial activity.

Early nebivolol treatment is beneficial in myocardial infarction in rats partly through β3-adrenoceptor remodelling.

It remains unknown whether β-blockers are useful and safe in acute myocardial infarction (MI). Owing to its pharmacological profile and vasodilating action, nebivolol (N) is useful in MI. The aim of the present study was to assess in rat whether early nebivolol treatment could be beneficial in MI. It remains unknown whether β-blockers are useful and safe in acute MI. On day (D) 0, male Sprague-Dawley rats underwent left coronary artery ligation (MI) or simple thoracotomy (SHAM). On D1 and D2, the rats were treated with either nebivolol (5mg.kg-1 .day-1 , MI-N and Sham-N) or vehicle (V, MI-V and Sham-V). On D3, heart rate, left ventricle (LV) intrinsic contractility (PESmid) and arterial elastance were measured. Cardiac and aortic β-Adrenoceptor (AR) subtype mRNA were quantified using real time quantitative RT-qPCR. Catecholamine response was assessed on isolated heart and aortic rings with isoproterenol. PESmid was decreased in MI without worsening the decrease nebivolol. In LV, β1 - and β3 -AR mRNA were respectively decreased and increased in all MI. β3 -AR mRNA increase was partly limited by nebivolol. Ex vivo, basal contractility was less decreased in MI-N than in MI-V. Isoproterenol response was only altered in MI-V. In MI aorta, Nebi prevented β2 - and β3 -AR mRNA increases. In addition, Acetylcholine-induced relaxation was lowered in MI-V but preserved with nebivolol. We demonstrated an early modulation of cardiovascular β3 -AR transcription early MI. Despite its putative negative inotropic properties, nebivolol did not worsen cardiac function in basal conditions and preserved LV catecholamine response.

Endothelium-independent vasorelaxant effect of Asphodelus tenuifolius Cav. via inhibition of myosin light chain kinase activity in the porcine coronary artery

Ethnopharmacological relevanceAsphodelus tenuifolius Cav. (Asphodelaceae), a wild, terrestrial, annual stemless herb, is widely used in traditional medicine for the treatment of hypertension, diabetes, atherosclerosis and circulatory problems. A previous research study from our laboratory revealed that A. tenuifolius has beneficial effects in reducing blood pressure and improves aortic endothelial dysfunction in chronically glucose fed rats. Despite the fact that A. tenuifolius reduces blood pressure and improves endothelial function in vivo, there are no detailed studies about its possible mechanism of action. Aim of the studyThis study was designed to provide pharmacological basis and mechanism of action for the traditional use of A. tenuifolius in hypertension and circulatory problems. We explored the vasorelaxant effect of A. tenuifolius and its underlying vasorelaxation mechanism in porcine coronary artery rings. Materials and methodsAqueous methanolic crude extract of A. tenuifolius was prepared by maceration process and then activity guided fractionation was carried out by using different polarity based solvents. Phytochemical studies were carried out using LC-DAD-MS. Segments of porcine distal coronary artery were set up in a wire myograph for isometric force measurements. Extract/fractions of A. tenuifolius seeds were tested for vasodilator activity by measurement of changes in tone after pre-contraction with the thromboxane mimetic U46619 in the presence or absence of inhibitors of intracellular signaling cascades. ResultsCrude extract/fractions of A. tenuifolius produced dose dependent endothelium independent vasorelaxant response in coronary rings, whereas, the butanol fraction of A. tenuifolius (BS-AT) produced the largest relaxation response with 100% relaxation at 1 mg/ml, therefore the mechanism of relaxation of this fraction was determined. The relaxation to BS-AT was unaffected by removal of the endothelium, pre-contraction with KCl, or the presence of the non-selective potassium channel blocker tetraethylammonium, indicating that the relaxation was endothelium-independent, and does not involve activation of potassium channels. BS-AT (1 mg/ml) inhibited the contractile response to calcium,the L-type calcium channel activator BAY K8664,and ionomycin, indicating that it inhibits calcium-induced contractions. The relaxation response to BS-AT was attenuated in the absence of extracellular calcium. However, relaxations to BS-AT were also reduced after deletion of calcium from intracellular stores with cyclopiazonic acid. Incubation with 1 mg/ml BS-AT also inhibited phosphorylation of myosin light chains in homogenates of coronary artery. ConclusionThe butanol extract of Asphodelus tenuifolius produces a large endothelium-independent relaxation of the porcine coronary artery through inhibition of calcium-induced contractions. The effect appears to be downstream of calcium influx, possibly through inhibition of myosin light chain kinase. This study supports previous studies demonstrating that A. tenuifolius reduces blood pressure. Future studies will aim to determine the active compounds underlying this response.

Chuanxiongdiolides R4 and R5, phthalide dimers with a complex polycyclic skeleton from the aerial parts of Ligusticum chuanxiong and their vasodilator activity

Chuanxiongdiolides R4-R6 (1–3), three novel phthalide dimers featuring two classes of unreported monomeric units (ligustilide/senkyunolide A and ligustilide/neocnidilide) with an unprecedented linkage style (3a,7′/7a,7′a), were isolated from the aerial parts of Ligusticum chuanxiong, together with three pairs of enantiomeric phthalide dimers [(−)/(+)-4a/4b, 5a/5b, and 6a/6b]. The bioassays revealed that compounds 1, 3, 4, 5, and 6 showed significant vasodilation effects, and the mechanism may be attributed to Cav1.2 activation blockade. Based on the established compounds library, the structure activity relationship of the phthalides was proposed. Our findings afford possible leads for developing new vasodilator against cardiovascular and cerebrovascular diseases such as hypertension and ischemic stroke.

High-density lipoprotein's vascular protective functions in metabolic and cardiovascular disease - could extracellular vesicles be at play?

High-density lipoprotein (HDL) is a circulating complex of lipids and proteins known primarily for its role in reverse cholesterol transport and consequent protection from atheroma. In spite of this, therapies aimed at increasing HDL concentration do not reduce the risk of cardiovascular disease (CVD), and as such focus has shifted towards other HDL functions protective of vascular health - including vasodilatory, anti-inflammatory, antioxidant and anti-thrombotic actions. It has been demonstrated that in disease states such as CVD and conditions of insulin resistance such as Type 2 diabetes mellitus (T2DM), HDL function is impaired owing to changes in the abundance and function of HDL-associated lipids and proteins, resulting in reduced vascular protection. However, the gold standard density ultracentrifugation technique used in the isolation of HDL also co-isolates extracellular vesicles (EVs). EVs are ubiquitous cell-derived particles with lipid bilayers that carry a number of lipids, proteins and DNA/RNA/miRNAs involved in cell-to-cell communication. EVs transfer their bioactive load through interaction with cell surface receptors, membrane fusion and endocytic pathways, and have been implicated in both cardiovascular and metabolic diseases - both as protective and pathogenic mediators. Given that studies using density ultracentrifugation to isolate HDL also co-isolate EVs, biological effects attributed to HDL may be confounded by EVs. We hypothesise that some of HDL's vascular protective functions in cardiovascular and metabolic disease may be mediated by EVs. Elucidating the contribution of EVs to HDL functions will provide better understanding of vascular protection and function in conditions of insulin resistance and potentially provide novel therapeutic targets for such diseases.

Abstract 13027: Differential Direct Effects of Equal Hypotensive Natriuretic Peptides (NPs) of ANP, BNP and CNP on Left Ventricular Contractile Performance in Heart Failure: Assessment by Left Ventricular Pressure-Volume Analysis

Background: Natriuretic peptides (NPs) play a crucial role in maintaining cardiovascular homeostasis. NPs stimulate the production and release of cGMP, leading to the vasodilating and natriuretic actions. In heart failure (HF), circulating and cardiac ANP, BNP, and CNP are increased and exhibit a range of actions. However, although they serve as therapeutic agents, their direct cardiac effects in HF are uncertain due to the confounding influence of NPs-produced changes in loading condition on conventional measures of LV function. We test the hypothesis that equal hypotensive 3 NPs may have different inotropic effects on LV contractility and relaxation in HF. Methods: We assessed the cardiac effects of intravenous infusion (20 min) of ANP (2 μg/kg plus 0.5 μg/kg/min), BNP (2 μg/kg plus 0.04 μg/kg/min) and CNP (2 μg/kg plus 0.4 μg/kg/min) on different days in 6 instrumented conscious dogs with pacing-induced HF by using pressure (P)-volume (V) analysis, a load-independent measure of LV contractility. Results: Versus baselines, 3 NPs produced arterial vasodilation with similar and significant decreases in LV end-systolic pressure (10 to 12 mmHg) with relatively unchanged heart rate. ANP caused significant reductions (13%) of E ES (4.2 vs 4.8 mmHg/ml) and M SW (54.6 vs 62.8 mmHg). The time constant of LV relaxation (τ, 45.1 vs 37.6 ms) was lengthened. The LV-arterial coupling, E ES / E A (arterial elastance) (0.57 vs 0.58) was unaltered. The peak mitral flow, dV/dt max was only increased by 7% (178 vs 166 ml/s). With BNP, there were no significant changes in E ES (5.1 vs 4.9 mmHg/ml) and M SW, but E ES /E A was improved 30% (0.74 vs 0.57) due to decreased E A . τ (33.4 vs 37.9 ms) was significantly shortened and dV/dt max increased 15% (189 vs 165 ml/s). In contrast, CNP produced significant increases (~30%) in E ES (6.3 vs 4.8 mmHg/ml) and M SW (80.5 vs 62.4 mmHg) with enhanced increase in E ES /E A (50%, 0.87vs 0.58), but decrease in τ (25%, 28.4 vs 38.1 ms) and significantly greater augmented dV/dt max (25%, 205 vs 164 ml/s). Similar observations of NPs were made at constant heart rate, or after autonomic blockade. Conclusion: In conscious dogs with HF, equal hypotensive ANP, BNP and CNP have negative, no effect, and positive inotropic effects on LV contractility and relaxation, respectively.

William Harvey reinterpreted in the light of species evolution (I) - How and why circulation phylogenesis integrates itself within species evolution

In this first part we describe the different steps of the evolution of species and the circulatory modifications, which accompany it. From the open circulation in invertebrates, via the in-series closed circulation in fish, to the in-parallel closed circulation in mammals, the local ability to vasodilate in relation to the specific metabolic demand of territorial activity was the driving force for circulatory evolution. This capacity was achieved by the progressive muscularization of small arteries, generating frictional forces, which systemically determine high arterial pressure, and locally determine active vasodilation via the inhibition of vasomotor tone. This determinism differentially impacts the small resistance arteries, which generate blood pressure, and the large conductance arteries, which support the tensional stress generated by the blood pressure.

Puerarin improves intestinal barrier function through enhancing goblet cells and mucus barrier

• Puerarin enhanced mucus barrier through increasing goblet cell numbers and mucins production. • Puerarin stimulate mucin production by increasing beneficial metabolites. • Puerarin produced significantly structure changes on the commensal microflora. Puerarin is a kind of isoflavones in Puerariae Lobatae Radix with physiological activities, such as anti-inflammatory and vasodilatory activities. The aim of this study was to investigate the effects of puerarin on intestinal barrier dysfunction induced by 2,4,6 trinitrobenzene sulfonic acid (TNBS) and its underlying mechanism. Puerarin treatment attenuated the mucus barrier dysfunction, and increased the level of mucins (Muc2 and Muc4) and the number of goblet cells compared to TNBS group. Puerarin treatment significantly increased the content of indole-3-propionic acid, compared to TNBS group, and not indoleacrylic acid and butyrate. Puerarin treatment changed the structure of the commensal microbiota as evidenced by the obvious decrease in the relative abundances of Bacteroidetes. Additionally, puerarin increased the proportion of the mucin-utilizing bacterium Akkermansia . Puerarin improves intestinal barrier function through enhancing goblet cells and mucus barrier. Food enriched with puerarin could protect and repair intestinal barrier for improving gut health.

Understanding the Potential Role and Delivery Approaches of Nitric Oxide in Chronic Wound Healing Management.

Nitric oxide (NO) is a promising pharmaceutical component that has vasodilator, anti-bacterial, and wound healing activities. Chronic ulcers are non-healing disorders that are generally associated with distortion of lower limbs. Among the severe consequence derivatives of these diseases are the problems of chronic wound progression. NO, which is categorized as the smallest gaseous neurotransmitter, has beneficial effects in different phases of chronic inflammation. The defensive mechanism of NO is found useful in several severe conditions, such as gestational healing, gastrointestinal healing, and diabetic healing. The current review presents an updated collection of literature about the role of NO in chronic ulcers due to the prevalence of diabetes, DPN, and diabetic foot ulcers, and because of the lack of available effective treatments to directly address the pathology contributing to these conditions, novel treatments are being sought. This review also collects information about deficiency of NO synthase in diabetic patients, leading to a lack of vascularization of the peripheral nerves, which causes diabetic neuropathy, and this could be treated with vasodilators such as nitric oxide. Apart from the pharmacological mechanism of NO, the article also reviewed and analyzed to elucidate the potential of transdermal delivery of NO for the treatment of chronic ulcers.

An animal model of gestational obesity and prediabetes: HISS-dependent insulin resistance induced by a high-sucrose diet in Sprague Dawley rats.

This study developed an animal model of gestational obesity and prediabetes in Sprague Dawley rats using 35% sucrose supplementation (SS). Postprandially, insulin stimulates glucose uptake and nutrient partitioning via insulin-dependent action as well as hepatic insulin sensitizing substance (HISS) - dependent action. HISS is glycogenic in heart, kidney, and skeletal muscle (contrasting insulin's lipogenic actions in liver and adipose tissue) and is responsible for the vasodilatory action of insulin. Postprandial insulin sensitivity was quantified using the rapid insulin sensitivity test (RIST). Animals at 15-day gestation and virgin animals received SS for 8 weeks (with a 2-week recovery), 10 weeks, or 22 weeks. SS in pregnant and virgin rats eliminated HISS-dependent glucose uptake, resulting in compensatory hyperinsulinemia and resultant hypertriglyceridemia and obesity. In groups with SS for 8 weeks followed by a 2-week recovery, there was spontaneous partial recovery of HISS-dependent glucose uptake in virgins and complete recovery in pregnancy. The 10-week SS resulted in complete absence of HISS-dependent glucose uptake and produced a model of gestational obesity and prediabetes. The 22-week SS did not produce hyperglycemia or worsen hyperinsulinemia but did increase hypertriglyceridemia above 10-week SS. This substantiates the use of 10-week SS as a model of gestational obesity and (or) prediabetes, allowing further studies into treatments of gestational obesity and insulin resistance.

Anti-hypertensive vasodilatory action of Gynura procumbens mediated by kaempferol 3-O-rutinoside

Introduction: Gynura procumbens (GP), otherwise known as longevity spinach or “Sambung Nyawa” in Malay, is an evergreen herb found in Africa and Southeast Asian countries (including Brunei) used traditionally to treat various diseases such as fever, diabetes and hypertension. We examined GP’s vasodilatory action to determine its possible role via the cholinergic-mediated pathway. Methods: GP leaves were prepared by filtration and evaporation to obtain the aqueous (AEGP) and methanol (MEGP) extracts followed by screening for phytochemical constituents. The total phenol, total flavonoid and flavonol contents were determined using the corresponding Folin–Ciocalteau, and aluminium colorimetric methods and the presence of kaempferol 3-O-rutinoside in the extracts was detected using HPLC analysis. Organ bath studies were conducted to determine the vasodilatory activity using intact and denuded isolated rat aortic rings by exposure to either increasing concentration of extracts (0.25, 0.5, 1.0, and 2.0 mg/mL) or 10 µg/mL kaempferol 3-O-rutinoside in the presence or absence of acetylcholine (ACh) after pre-contraction by noradrenaline (NA). Results: MEGP contained more phytochemical constituents and higher content of total flavonoid and total flavonol but less phenolic content than AEGP. Furthermore, MEGP yielded a 20% elevated amount of kaempferol 3-O-rutinoside than AEGP. Both extracts significantly amplified ACh-endothelium dependent vasodilation and mediated relaxation at 1 mg/mL in endothelium-intact and endothelium-denuded aortic rings with MEGP as a more effective vasodilator than AEGP. Overall, these results imply the involvement of extracts in potentiating cholinergic pathway, which might be mediated by kaempferol, as shown by its vasorelaxation effects in endothelium-intact and –denuded aorta. Conclusions: The present findings demonstrate that the vasodilatory activities of the two Gynura procumbens extracts, AEGP and MEGP, in thoracic aorta rings isolated from rats are potentially mediated via a cholinergic pathway through the action of a flavonoid particularly kaempferol 3-O-rutinoside.

DECRIPTION OF A HEREDITARY ANGIONEUROTIC EDEMA FORM IN A CHILD

Congenital deficiency of the C1-component inhibitor of the complement cascade, or hereditary angioneurotic edema, is a rare autosomal dominant disease due to a mutation in the human C1-esterase inhibitor. Caused by C1 deficiency unregulated cleavage of high molecular weight plasma kininogen results in excess production of a mediator with vasodilating action – bradykinin. Hereditary type 1 angioedema develops as a result of C1 inhibitor deficiency, while type 2 is caused by decreased C1 inhibitor activity. The disease manifests itself in childhood or adolescence as recurrent episodes of edema in the skin, subcutaneous fiber and mucous membranes. Localization of edemas in the submucous layer of the larynx represents a threat to life, which can lead to the development of laryngostenosis and acute respiratory failure. The article describes a case of hereditary angioneurotic edema in a girl, which manifested in early childhood. There were no great difficulties in diagnosing the disease, as patients with this pathology were already identified earlier in the family. A significant reduction in C1-inhibitor content was found in the patient, which made it possible to clarify the type of hereditary angioneurotic edema and to categorize it to type 1. A synthetic antifibrinolytic agent with the ability to block kinins and angioneurotic edemas was successfully used in the treatment and prevention of swelling attacks in the patient. The analysis of the case shows that hereditary angioneurotic edema remains a problem difficult enough for a practical doctor requiring careful history taking, assessment of disease development dynamics and performing a laboratory – genetic examination. In most cases, only differential diagnostics can give the opportunity to suspect the dangerous pathology in the patient in a timely manner which requires immediate hospitalization and providing aid adequate to the disease.

Duration of Vasodilatory Action After Intra-arterial Infusions of Calcium Channel Blockers in Animal Model of Cerebral Vasospasm.

In medically refractory vasospasm, invasive intervention may be required. A commonly used approach is intra-arterial (IA) drug infusion. Although calcium channel blockers (CCBs) have been widely applied in this setting, studies comparing their efficacies and durations of action have been few. This study was performed to compare attributes of three CCBs (nicardipine, nimodipine, and verapamil), focusing on duration of the vasodilatory action based on angiography. Vasospasm was produced in New Zealand white rabbits (N = 22) through experimentally induced subarachnoid hemorrhage and confirmed in each via conventional angiography, grouping them by IA-infused drug. After chemoangioplasty, angiography was performed hourly for 5h to compare dilated and vasospastic arterial diameters. Drug efficacy, duration of action, and changes in mean arterial pressure (relative to baseline) were analyzed by group. Effective vasodilation was evident in all three groups immediately after IA drug infusion. The vasodilative effects of nimodipine and nicardipine peaked at 1h and were sustained at 2h, returning to initial vasospastic states at 3h. In verapamil recipients, effects were more transient by comparison, entirely dissipating at 1h. Only the nicardipine group showed a significant 3-h period of lowered blood pressure. Although nimodipine and nicardipine proved longer acting than verapamil in terms of vasodilation, their effects were not sustained beyond 2h after IA infusion. Further study is required to confirm the vasodilatory duration of IA CCB based on perfusion status, and an effort should be made to find new alternative to extend the duration.

Discovery of Novel Pyrazolo[3,4-b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension.

Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.

Proteomic Mapping of Multifunctional Complexes Within Triatomine Saliva.

Triatomines are hematophagous insects that transmit Trypanosoma cruzi, the etiological agent of Chagas disease. This neglected tropical disease represents a global health issue as it is spreading worldwide. The saliva of Triatominae contains miscellaneous proteins crucial for blood feeding acquisition, counteracting host's hemostasis while performing vasodilatory, anti-platelet and anti-coagulant activities, besides modulating inflammation and immune responses. Since a set of biological processes are mediated by protein complexes, here, the sialocomplexomes (salivary protein complexes) of five species of Triatominae were studied to explore the protein-protein interaction networks. Salivary multiprotein complexes from Triatoma infestans, Triatoma dimidiata, Dipetalogaster maxima, Rhodnius prolixus, and Rhodnius neglectus were investigated by Blue-Native- polyacrylamide gel electrophoresis coupled with liquid chromatography tandem mass spectrometry. More than 70 protein groups, uncovering the landscape of the Triatominae salivary interactome, were revealed. Triabin, actin, thioredoxin peroxidase and an uncharacterized protein were identified in sialocomplexes of the five species, while hexamerin, heat shock protein and histone were identified in sialocomplexes of four species. Salivary proteins related to triatomine immunity as well as those required during blood feeding process such as apyrases, antigen 5, procalins, and nitrophorins compose different complexes. Furthermore, unique proteins for each triatomine species were revealed. This study represents the first Triatominae sialocomplexome reference to date and shows that the approach used is a reliable tool for the analysis of Triatominae salivary proteins assembled into complexes.

HYPOXIA AND REPRODUCTIVE HEALTH: Reproductive challenges at high altitude: fertility, pregnancy and neonatal well-being.

High altitude offers a natural laboratory for studying the effects of chronic hypoxia on reproductive health. Counter to early accounts, fertility (the number of livebirths) appears little affected although stillbirths are more common. Birth weights are lower due to fetal growth restriction, not shortened gestation. Multigenerational (Andean or Tibetan) compared with newcomer residents appear relatively protected from pregnancy loss as well as altitude-associated fetal growth restriction, perhaps due in part to preservation of the normal rise in uterine artery blood flow. Myometrial artery vasodilator response, a key determinant of uterine blood flow, is blunted in healthy Colorado high-altitude residents, similar to what occurs in intrauterine growth restriction or preeclampsia at low altitude. The high-altitude vessels are also more sensitive to the vasodilatory actions of AMP kinase (AMPK) activation. The gene region containing PRKAA1 (coding for AMPK's alpha-1 catalytic subunit) has been acted upon by natural selection in Andeans and is related to preservation of normal blood flow and fetal growth at high altitude, suggesting one mechanism by which high-altitude adaptation may have been achieved. Preeclampsia is more common at high altitudes but unknown is whether multigenerational residents are protected relative to newcomers. Postnatal loss is diminished in Tibetans vs Han with equal access to health care, perhaps due in part to better maintained arterial O2 saturation during infancy. Finally, pregnancy and intrauterine development not only affect immediate survival but also susceptibility to the later-in-life cardiovascular disease, chronic mountain sickness.