Vasodilator Activity Research Articles

Phytochemical, Pharmacological, and Toxicological Studies on Peganum harmala L.: An Overview of the Last Decade

Objective: Plants have been used to treat ailments since the dawn of humanity. The use of medicinal plants for various purposes such as preventing diseases, treating diseases and supporting medical treatment is increasing day by day. On the other hand, medicinal plants are important sources of raw materials for the pharmaceutical industry. It has been demonstrated that Peganum harmala L. and the phytochemicals it contains have a wide variety of pharmacological activities. P. harmala and its active ingredients can be an important resource for the pharmaceutical industry. In this review, the phytochemistry, pharmacological effects, clinical studies, and toxicity of P. harmala are discussed under the current information. 
 Methods: Studies on P. harmala were searched using Pubmed, Scopus, Science Direct databases, and Google Scholar search engine. As a result of the searches, 96 articles were included in the study. 
 Results: The main group of secondary metabolites responsible for the biological activities of P. harmala is alkaloids. The plant and its isolated secondary plant compounds have been shown to have many pharmacological actions, counting antiamnestic, anticancer, antidepressant, antiinflammatory, cardiovascular, gastroprotective, hepatoprotective, nephroprotective, and vasodilator activities. Studies evaluating the plant's clinical effects have been carried out in recent years. However, it has been recorded in the literature that the use of P. harmala causes poisoning with symptoms such as neurosensory symptoms, visual hallucination, bradycardia, hypotension, agitation, tremor, ataxia, and vomiting. Conclusion: Considering the pharmacological effects, the number of studies on the efficacy and safety of P. harmala and its secondary metabolites should be increased.

Aloperine protects pulmonary hypertension via triggering PPARγ signaling and inhibiting calcium regulatory pathway in pulmonary arterial smooth muscle cells.

Previous studies have reported the beneficial role of Aloperine (ALO), an active vasodilator purified from the seeds and leaves of the herbal plant Sophora alopecuroides L., on experimental pulmonary hypertension (PH); however, detailed mechanisms remain unclear. In this study, monocrotaline-induced PH (MCT-PH) rat model and primarily cultured rat distal pulmonary arterial smooth muscle cells (PASMCs) were used to investigate the mechanisms of ALO on experimental PH, pulmonary vascular remodeling, and excessive proliferation of PASMCs. Results showed that first, ALO significantly prevented the disease development of MCT-PH by inhibiting right ventricular systolic pressure (RVSP) and right ventricular hypertrophy indexed by the Fulton Index, normalizing the pulmonary arterials (PAs) remodeling and improving the right ventricular function indexed by transthoracic echocardiography. ALO inhibited the excessive proliferation of both PAs and PASMCs. Then, isometric tension measurements showed vasodilation of ALO on precontracted PAs isolated from both control and MCT-PH rats via activating the KCNQ channel, which was blocked by specific KCNQ potassium channel inhibitor linopirdine. Moreover, by using immunofluorescence staining and nuclear/cytosol fractionation, we further observed that ALO significantly enhanced the PPARγ nuclear translocation and activation in PASMCs. Transcriptome analyses also revealed activated PPARγ signaling and suppressed calcium regulatory pathway in lungs from MCT-PH rats treated with ALO. In summary, ALO could attenuate MCT-PH through both transient vasodilation of PAs and chronic activation of PPARγ signaling pathway, which exerted antiproliferative roles on PASMCs and remodeled PAs.NEW & NOTEWORTHY Aloperine attenuates monocrotaline-induced pulmonary hypertension (MCT-PH) in rats by inhibiting the pulmonary vascular remodeling and proliferation of pulmonary arterial smooth muscle cells (PASMCs). In mechanism, Aloperine not only exerts a transient KCNQ-dependent vasodilation in precontracted pulmonary arteries (PAs) from both control and MCT-PH rats but also activates PPARγ nuclear translocation and signaling transduction in PASMCs, which chronically inhibits the calcium regulatory pathway and proliferation of PASMCs.

Abstract P120: Effect Of Alamandine On Isoproterenol-induced Left Ventricular Dysfunction, Cardiac Remodeling And Immune Responses In Rat

Alamandine, a newly identified derivative of angiotensin II has been shown to exert antihypertensive and vasodilative actions, and may represent a novel component of cardioprotective axis of renin angiotensin system. We sought to determine the protective effects of alamandine on isoproterenol (ISO) induced cardiac remodeling and dysfunction in rats. Male SD rats (n=6 in each group) received a two-week subcutaneous infusion of vehicle, ISO (10 mg/kg/day) or a combination of ISO and alamandine (50 ng/kg/min). Compared with vehicle group, the ratio of heart/body weight (mg/g) in ISO treated rats was significantly (*P<0.05) elevated (3.93 ± 0.18 vs. 3.07 ± 0.08*), which was markedly attenuated by alamandine (3.50 ± 0.08*). Echocardiographic assessment showed that alamandine improved ISO-induced left ventricular (LV) dysfunction evidenced by reducing LV thickness (1.68 ± 0.07* vs 1.90 ± 0.02 mm), end diastolic and systolic volume. Rats treated with alamandine had reduced E/E' ratio (15.16 ± 1.04* vs 26.81 ± 3.79) and increased E'/A' ratio (1.09 ± 0.05 vs 0.57 ± 0.07 ** P<0.01), indicating the improved diastolic cardiac function. The reduced myocardial performance index (0.74 ± 0.06* vs. 1.24 ± 0.15) in alamandine treated rats demonstrated an improvement of global cardiac dysfunction. Histological analysis also revealed that alamandine attenuated ISO induced increase in cardiomyocyte size (372.46 ± 11.13** vs 551.99 ± 11.79 μm 2 ) and myocardial fibrosis (1.39 ± 0.16 ** vs 4.57 ± 0.35), along with reduced mRNA expression of hypertrophy biomarkers atrial natriuretic peptide (2.45 ± 0.71** vs 8.08 ± 0.74), brain natriuretic peptide (2.86 ± 0.35 ** vs 12.53 ± 1.12), beta myosin heavy chain (1.71 ± 0.25* vs 5.38 ± 0.95) and fibrosis genes – collagen-1 (1.97 ± 0.45* vs 4.25 ± 0.6), fibronectin (2.04 ± 0.32** vs 5.05 ± 0.74), α-smooth muscle actin (1.53 ± 0.1** vs 2.71 ± 0.17). Flow cytometry analysis unveiled that alamandine reduced neutrophil, CD8 T cells and M1 monocytes, but increased M2 monocytes of left ventricle, implying the reduction of inflammation of the heart. These data suggest that alamandine plays a cardioprotective role in improving cardiac hypertrophy and fibrosis, probably via an immune mechanism to alleviate inflammatory responses during cardiac remodeling.

Synthesis, Structure, and Properties of the Iron Nitrosyl Complex with 2-Ethyl-4-pyridinecarbothioamide

The synthesis and data on the physicochemical characteristics and biological activity of the newiron nitrosyl complex (Q+)2[Fe2(S2O3)2(NO)4]2– (I), where Q+ is protonated 2-ethyl-4-pyridinecarbothioamide(C8H11N2S), are presented. The structure and properties of the complex were studied by X-ray diffraction,elemental analysis, IR and Mössbauer spectroscopy, and amperometry. The complex showed antibacterialactivity and efficiently inhibited cyclic guanosine monophosphate phosphodiesterase (cGMP PDE),which may suggest its antihypertensive, anti-aggregation, and vasodilator activities.

Vasodilator activity of Poecilotheria ornata venom involves activation of the NO/cGMP pathway and inhibition of calcium influx to vascular smooth muscle cells.

Tarantula venoms may be a natural source of new vasodilator components useful in pharmacological research. Moreover, biological function data of the venoms are important to enhance the knowledge about the biodiversity and evolution of these species. The present study aims to describe the vasodilatory activity induced by the venom of Poecilotheria ornata on isolated rat aortic rings. This venom induced a vasodilator activity that was significantly reduced after incubation with L-NAME or ODQ. Measurements of nitrite concentrations on rat aorta homogenates showed that the venom significantly increased the basal levels. Moreover, the venom attenuates the contraction induced by calcium. These results suggest that P. ornata venom contains a mixture of vasodilator components that act through the activation of the nitric oxide/cGMP pathway, as well as, through an endothelium-independent mechanism that involves the calcium influx into vascular smooth muscle cells.

Elucidating the Effect of hesperidin on Behavioral and biochemical markers of liver and kidney function in Sprague Dawley Rats

Background: Hesperidin is a naturally occurring Bioflavonoid found in citrus fruits. It has anti-inflammatory, antioxidant, antihypertensive, antimicrobial, anti-carcinogenic and vasodilator activities. Hesperidin’s effect on normal behavioral is not clear. Hence the present study is aimed to elucidate the effects of hesperidin on behavioral and biochemical markers of liver and kidney function in Sprague Dawley (SD) rats. Method: Healthy, adult, male SD rats were used for the study. Animals were divided into 5 groups (n = 6) viz., Group I: Control, Group II: Vitamin C(200mg/kg), Group III: Hesperidin (25mg/kg), Group IV: Hesperidin (50mg/kg) and GroupV: Hesperidin (100mg/kg). The standard and test drugs were suspended in 0.5% w/v carboxymethyl cellulose and administered once daily through oral gavage for 28 consecutive days. Throughout the study changes in behavioral functions (locomotor activity, muscular strength, learning and memory) and body weight were monitored at regular intervals. Blood samples were collected from all the experimental rats and used for biochemical parameters analysis. Results: Vitamin C and hesperidin did not show any significant alterations in locomotion, grip strength, muscular strength and spatial memory when compared with normal control. Both vitamin C and hesperidin improved the normal anxiety behavior without affecting regular body weight gain and biochemical markers of liver and kidney function. Conclusion: The experimental rats administered with hesperidin at the dose levels of 25, 50and100 mg/kg did not show any changes in psychomotor behavior and significantly improved their alertness without affecting the biochemical markers of liver and kidney function.

Abstract P2142: Evaluation Of Novel A3 Adenosine Receptor Agonist In Hypertension

The search for alternative strategies for treatment of cardiovascular diseases, lead to the design and synthesis of N -acylhydrazone derivative, named LASSBio-2062, which is a new ligand of adenosine receptor and that is a possible therapeutic target to reduce blood pressure because of its vasodilatory action and antioxidant properties. This work investigated the effects of a new A 3 adenosine receptor agonist (LASSBio-2062) in spontaneously hypertensive rats (SHR). Animal Care and Use Committee at Universidade Federal do Rio de Janeiro approved the protocols (017/19). Vascular reactivity was evaluated using isometric tension recording of pre-contracted thoracic aorta from male Wistar rats after exposure to increasing concentrations of LASSBio-2062 (0.1 - 100 μM) in the absence or presence of antagonist of adenosine A 2A receptor, ZM-241385 (0.1 μM), an antagonist of adenosine A 3 receptor, MRE 3008F20 (0.1 μM), a blocker of K ATP channel, glibenclamide (10 μM), an inhibitor of Kv channels, 4-AP, inhibitor of BK Ca , TEA (3 mM). Mechanical removal of endothelium increased the EC 50 for vasodilation from 15.5 ± 6.5 to 49.4 ± 10.0 μM, indicating partial dependence on the functional integrity of vascular endothelium. Vascular relaxation was not altered by ZM-241385 but the concentration-response curve shifted to the right with MRE 3008F20 and reduced maximum relaxation from 72.1 ± 4.0 to 23.6 ± 7.7%, indicating that vasodilation occurred by activation of the adenosine receptor type A 3 , but not A 2A . Reduced maximum vascular response by glibenclamide, TEA and 4-AP suggests that activation of A 3 adenosine receptor promotes hyperpolarization as a result reduces intracellular calcium. Antihypertensive effect was investigated in spontaneously hypertensive rats (SHR, 12-15 wks old), through the measurement of mean blood pressure (MBP) after intravenous injection of 10 and 30 μmol/kg of LASSBio-2062. After intravenous administration of LASSBio-2062 (10 umol/kg) in SHR, systolic and diastolic pressures reduced from 155.1 ± 10.1 to 110.6 ± 8.0 and from 111.0 ± 9.1 to 63.9 ± 14.7 mmHg, respectively. HR was also changed from 248.1 ± 12.1 to 146.5 ± 21.0 bpm. In conclusion, the N -acylhydrazone, LASSBio-2062 is a potential therapeutic agent to treat arterial hypertension.

Duality in response of intracranial vessels to nitroglycerin revealed in rats by imaging photoplethysmography.

Among numerous approaches to the study of migraine, the nitroglycerin (NTG) model occupies a prominent place, but there is relatively insufficient information about how NTG affects intracranial vessels. In this study we aim to assess the effects of NTG on blood-flow parameters in meningeal vessels measured by imaging photoplethysmography (iPPG) in animal experiments. An amplitude of the pulsatile component (APC) of iPPG waveform was assessed before and within 2.5h after the NTG administration in saline (n = 13) or sumatriptan (n = 12) pretreatment anesthetized rats in conditions of a closed cranial window. In animals of both groups, NTG caused a steady decrease in blood pressure. In 7 rats of the saline group, NTG resulted in progressive increase in APC, whereas decrease in APC was observed in other 6 rats. In all animals in the sumatriptan group, NTG administration was accompanied exclusively by an increase in APC. Diametrically opposite changes in APC due to NTG indicate a dual effect of this drug on meningeal vasomotor activity. Sumatriptan acts as a synergist of the NTG vasodilating action. The results we obtained contribute to understanding the interaction of vasoactive drugs in the study of the headache pathophysiology and methods of its therapy.

Degradation Profiling of Nardosinone at High Temperature and in Simulated Gastric and Intestinal Fluids.

Nardosinone, a predominant bioactive product from Nardostachys jatamansi DC, is well-known for its promising therapeutic applications, such as being used as a drug on anti-inflammatory, antidepressant, cardioprotective, anti-neuroinflammatory, anti-arrhythmic, anti-periodontitis, etc. However, its stability under varying environmental conditions and its degradation products remain unclear. In this study, four main degradation products, including two previously undescribed compounds [2-deoxokanshone M (64.23%) and 2-deoxokanshone L (1.10%)] and two known compounds [desoxo-narchinol A (2.17%) and isonardosinone (3.44%)], were firstly afforded from the refluxed products of nardosinone in boiling water; their structures were identified using an analysis of the extensive NMR and X-ray diffraction data and the simulation and comparison of electronic circular dichroism spectra. Compared with nardosinone, 2-deoxokanshone M exhibited potent vasodilatory activity without any of the significant anti-neuroinflammatory activity that nardosinone contains. Secondly, UPLC-PDA and UHPLC-DAD/Q-TOF MS analyses on the degradation patterns of nardosinone revealed that nardosinone degraded more easily under high temperatures and in simulated gastric fluid compared with the simulated intestinal fluid. A plausible degradation pathway of nardosinone was finally proposed using nardosinonediol as the initial intermediate and involved multiple chemical reactions, including peroxy ring-opening, keto-enol tautomerization, oxidation, isopropyl cleavage, and pinacol rearrangement. Our findings may supply certain guidance and scientific evidence for the quality control and reasonable application of nardosinone-related products.

The Interaction of Kidneys and Gut in Development of Salt-Sensitive Hypertension.

The incidence of salt-sensitive hypertension is quite common and varies between 30-60% in hypertensive patients. Regarding the causal role of high salt intake in the development of salt-sensitive hypertension, recent evidence has demonstrated that the gut through its microbiota plays a significant role in its genesis. Besides the gut, the kidneys also play important role in salt-sensitive hypertension and there is clinical and experimental evidence of an interrelationship between the gut and the kidneys in the development of salt-sensitive hypertension through the so-called "gastro-renal axis." The gut besides being an absorptive organ, it is also a hormonal secretory organ involving the secretion of gastrin, dopamine, norepinephrine, angiotensin, and aldosterone which through their action with the kidneys are involved in the development of salt-sensitive hypertension. In addition, the kidneys exert a protective role against the development of hypertension through the secretion of prostaglandins and their vasodilatory action. To assess the current evidence on the role of high salt intake and the interplay of the gut and kidneys in its development, a Medline search of the English literature was contacted between 2012 and 2022, and 46 pertinent papers were selected. These papers together with collateral literature will be discussed in this review.

Nitric oxide delivery and heme-assisted S-nitrosation by the bedbug nitrophorin

Nitrophorins are heme proteins used by blood feeding insects to deliver nitric oxide (NO) to a victim, leading to vasodilation and antiplatelet activity. Cimex lectularius (bedbug) nitrophorin (cNP) accomplishes this with a cysteine ligated ferric (Fe(III)) heme. In the acidic environment of the insect's salivary glands, NO binds tightly to cNP. During a blood meal, cNP-NO is delivered to the feeding site where dilution and increased pH lead to NO release. In a previous study, cNP was shown to not only bind heme, but to also nitrosate the proximal cysteine, leading to Cys-NO (SNO) formation. SNO formation requires oxidation of the proximal cysteine, which was proposed to be metal-assisted through accompanying reduction of ferric heme and formation of Fe(II)-NO. Here, we report the 1.6 Å crystal structure of cNP first chemically reduced and then exposed to NO, and show that Fe(II)-NO is formed but SNO is not, supporting a metal-assisted SNO formation mechanism. Crystallographic and spectroscopic studies of mutated cNP show that steric crowding of the proximal site inhibits SNO formation while a sterically relaxed proximal site enhances SNO formation, providing insight into specificity for this poorly understood modification. Experiments examining the pH dependence for NO implicate direct protonation of the proximal cysteine as the underlying mechanism. At lower pH, thiol heme ligation predominates, leading to a smaller trans effect and 60-fold enhanced NO affinity (Kd = 70 nM). Unexpectedly, we find that thiol formation interferes with SNO formation, suggesting cNP-SNO is unlikely to form in the insect salivary glands.

Mechanisms of Cardiovascular Changes of Phototherapy in Newborns with Hyperbilirubinemia.

During phototherapy of jaundiced newborns, vasodilation occurs in the skin circulation compensated by vasoconstriction in the renal and mesenteric circulation. Furthermore, there is a slight decrease in cardiac systolic volume, and blood pressure, as well as an increase in heart rate and discrete changes in the heart rate variability (HRV). The primary change during phototherapy is the skin vasodilation mediated by multiple mechanisms: 1) Passive vasodilation induced by direct skin heating effect of the body surface and subcutaneous blood vessels, modified by myogenic autoregulation. 2) Active vasodilation mediated via the mechanism provided by axon reflexes through nerve C-fibers and humoral mechanism via nitric oxide (NO) and endothelin 1 (ET-1). During and after phototherapy is a rise in the NO:ET-1 ratio. 3) Regulation of the skin circulation through the sympathetic nerves is unique, but their role in skin vasodilation during phototherapy was not studied. 4) Special mechanism is a photorelaxation independent of the skin heating. Melanopsin (opsin 4) - is thought to play a major role in systemic vascular photorelaxation. Signalling cascade of the photorelaxation is specific, independent of endothelium and NO. The increased skin blood flow during phototherapy is enabled by the restriction of blood flow in the renal and mesenteric circulation. An increase in heart rate indicates activation of the sympathetic system as is seen in the measures of the HRV. High-pressure, as well as low-pressure baroreflexes, may play important role in these adaptation responses. The integrated complex and specific mechanism responsible for the hemodynamic changes during phototherapy confirm adequate and functioning regulation of the neonatal cardiovascular system, including baroreflexes.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

Abstracts from The Aerosol Society Drug Delivery to the Lungs 33.

C25 TEMPORAL TREND MORTALITY AND IN–HOSPITAL MORTALITY PREDICTORS IN AN ISCHEMIC CARDIOGENIC SHOCK POPULATION: A 10 YEARS SINGLE–CENTRE RETROSPECTIVE STUDY

Abstract Background Cardiogenic shock (CS) after acute myocardial infarction (AMI) represents the most severe form of acute heart failure (AHF) syndromes with an high rate of in–hospital mortality. Purpose describe predictors of in–hospital mortality; evaluate ten years mortality temporal trend in our CICU; assess the feasibility of CARDSHOCK risk score; elaborate a simpler version of CARDSHOCK risk score. Methods All consecutive patients with CS after AMI admitted at our CICU from March 2012 to July 2021 were included in this single–centre retrospective study. Results We included 167 patients [males 67%; age 71 years] with ischemic CS. Patients had severe LV dysfunction in 66%. Baseline serum lactate was 5,2 mmol/L. All patients required inotropes: 71% required dopamine, 65% noradrenaline, 32% dobutamine; 32% adrenalina,17,4% received levosimendan alone. Mechanical cardiac support (MCS) was pursued in 91,1% [65% IABP, 23% Impella CP, 4% VA–ECMO]. From March 2012 to July 2021 we observed a significative temporal trend mortality reduction (p=0.0015) from 57% of first time–quartile to 29% of the fourth quartile (fig1). In addition we noted a significant increase in Impella catheter use (p=0,0005) with a consequent reduction of IABP (p=0,01), a reduction in dopamine administration (p=0,007) and a greater use of inotropic drugs with vasodilatory action (p=0,015 and p=0,001). In our population of AMI–CS patients CARDSHOCK risk score was a reliable in–hospital mortality predictor tool (p=0.00011). After the multivariate analysis only EF at baseline (p=0,009), lactate level at presentation (p=0,015) and presence of three–vessels CAD (p=0,0038) resulted to be in–hospital mortality predictors. A new prediction model composed by those three variables was created and it exhibited better predictive performance for in–hospital mortality than Cardshock risk score (AUC 0,94 vs 0,72 respectively, p=0,015) (fig2). Conclusions In our retrospective single–centre study a significant reduction of mortality through the years is observed, probably due to more extensive use of micro axial pumps and a greater use of inodilators drug therapies. Cardshock risk score represents a feasible tool to predict in–hospital mortality also in our sample composed only of ischemic CS patients. A new prediction model composed by three clinical variables demonstrates at least the same predictive performance but future validation in a larger population could be advisable to validate the simplified score.

Elucidating mechanisms of attenuated skin vasodilation during passive heat stress in persons with spinal cord injury

Objective Persons with spinal cord injury (SCI) are unable to efficiently dissipate heat via thermoregulatory vasodilation as efficiently as able-bodied persons during whole body passive heat stress (PHS). Skin blood flow (SkBF) is controlled by dual sympathetic vasomotor systems: noradrenergic vasoconstrictor (VC) nerves and cholinergic vasodilator (VD) nerves. Thus, impaired vasodilation could result from inappropriate increases in noradrenergic VC tone that compete with cholinergic vasodilation or diminished cholinergic tone. To address this issue, we used bretylium (BR) which selectively blocks neural release of norepinephrine, thereby reducing noradrenergic VC tone. If impaired vasodilation during PHS is due to inappropriate increase in VC tone, BR treatment will improve SkBF responses during PHS. Design Prospective interventional trial. Setting laboratory. Participants 22 veterans with SCI. Interventions Skin surface areas with previously defined intact vs. impaired thermoregulatory vasodilation were treated with BR iontophoresis with a nearby untreated site serving as control/CON. Participants underwent PHS until core temperature rose 1°C. Outcome Measures Laser doppler flowmeters measured SkBF over BR and CON sites in areas with impaired and intact thermoregulatory vasodilation. Cutaneous vascular conductance (CVC) was calculated for all sites. Peak-PHS CVC was normalized to baseline (BL): (CVC peak-PHS/CVC BL) to quantify SkBF change. Results CVC rise in BR sites was significantly less than CON sites in areas with intact (P = 0.03) and impaired (P = 0.04) thermoregulatory vasodilation. Conclusion Cutaneous blockade of neural release of noradrenergic neurotransmitters affecting vasoconstriction did not enhance thermoregulatory vasodilation during PHS in persons with SCI; rather BR attenuated the response. Cutaneous blockade of neural release of noradrenergic neurotransmitters affecting vasoconstriction did not restore cutaneous active vasodilation during PHS in persons with SCI.

Genetics of spontaneous cervical and coronary artery dissections.

Spontaneous cervical artery dissections (SCeAD) and coronary artery dissections (SCoAD) are major causes of neurovascular and cardiovascular morbidity in young adults. Although multiple aspects of their etiology are still unknown, most consensuses are focused on the presence of constitutional genetic aspects and environmental triggers. Since recent evidence of genetic contribution points to a possible overlap between these conditions, we aimed to describe current information on SCeAD and SCoAD genetics and their potential shared pathological aspects. A narrative review is presented. Publications in English and Spanish were queried using database search. The articles were evaluated by one team member in terms of inclusion criteria. After collecting, the articles were categorized based on scientific content. Given that patients with SCeAD and SCoAD rarely present connective tissue disorders, other genetic loci are probably responsible for the increased susceptibility in some individuals. The common variant rs9349379 at PHACTR1 gene is associated with predisposition to pathologies of the arterial wall, likely mediated by variations in Endothelin-1 (ET-1) levels. The risk of arterial dissection may be increased for those who carry the rs9349379(A) allele, associated with lower expression levels of ET-1; however, the local effect of this vasomotor imbalance remains unclear. Sex differences seen in SCeAD and SCoAD support a role for sex hormones that could modulate risk, tilting the delicate balance and forcing vasodilator actions to prevail over vasoconstriction due to a reduction in ET-1 expression. New evidence points to a common gene variation that could explain dissection in both the cervical and coronary vasculatures. To further confirm the risk conferred by the rs9349379 variant, genome wide association studies are warranted, hopefully in larger and ethnically diverse populations.

Development of Novel High-Affinity Antagonists for the Relaxin Family Peptide Receptor 1.

H2 relaxin is a peptide hormone that exerts its biological actions through the G protein-coupled receptor, RXFP1. The numerous important biological functions of H2 relaxin, including potent renal, vasodilatory, cardioprotective, and anti-fibrotic actions, have resulted in considerable interest in its use as a therapeutic for various cardiovascular diseases and other fibrotic indications. Interestingly though, H2 relaxin and RXFP1 have been shown to be overexpressed in prostate cancer, allowing for the downregulation or blocking of relaxin/RXFP1 to decrease prostate tumor growth. These findings suggest the application of an RXFP1 antagonist for the treatment of prostate cancer. However, these therapeutically relevant actions are still poorly understood and have been hindered by the lack of a high-affinity antagonist. In this study, we chemically synthesized three novel H2 relaxin analogues that have complex insulin-like structures with two chains (A and B) and three disulfide bridges. We report here the structure-activity relationship studies on H2 relaxin that resulted in the development of a novel high-affinity RXFP1 antagonist, H2 B-R13HR (∼40 nM), that has only one extra methylene group in the side chain of arginine 13 in the B-chain (ArgB13) of H2 relaxin. Most notably, the synthetic peptide was shown to be active in a mouse model of prostate tumor growth in vivo where it inhibited relaxin-mediated tumor growth. Our compound H2 B-R13HR will be an important research tool to understand relaxin actions through RXFP1 and may be a potential lead compound for the treatment of prostate cancer.

Synthesis of pyrazolo[1,5-a][1,3,5]triazine and oxazolo[4,5-d]pyrimidine derivatives and study of their vasodilator activity

A number of pyrazolo[1,5-a][1,3,5]triazine and oxazolo[4,5-d]pyrimidine derivatives were synthesized and characterized. Pyrazolo[1,5-a][1,3,5]triazines with various substituents in the fourth position and a dichloromethyl group in the second position were obtained by the heterocyclization reaction of available N-(2,2-dichloro-1-cyanoethenyl)carboxamides and 5-aminopyrazoles. Oxazolo[4,5-d]pyrimidines were obtained by treating 2-phenyl-4-dichloromethylene-1,3-oxazol-5(4H)-one with the corresponding arylamidine hydrochloride in the presence of triethylamine. The resulting 4,5-dihydro-1H-imidazol-5(4)-ones undergo recyclization with subsequent cyclocondensation to the corresponding oxazolo[4,5-d]pyrimidin-7-ones when heated in pyridine. Oxazolo[4,5-d]pyrimidines with a labile chlorine atom in position 7, whose substitution with various amines leads to 7-aminoderivatives of oxazolo[4,5-d]pyrimidine, were obtained by heating the latter in phosphorus (V) oxychloride in the presence of N,N-dimethylaniline. The study of the effect of the synthesized compounds on vascular tone showed that some of the studied samples exhibited vasodilator activity of varying strength. It was established that 2-dichloromethyl-7-methyl-4-(furan-2-yl)pyrazolo[1,5-a][1,3,5]triazine and 2-dichloromethyl-7-methyl-4-(pyridin-3-yl)pyrazolo[1,5-a][1,3,5]triazine showed a pronounced dose-dependent vasodilator effect and therefore, subject to their further research, may be promising for the development of new vasodilator drugs. The study of the biological activity of oxazolo[4,5-d]pyrimidine derivatives did not reveal potential vasodilator agents among the presented compounds, as they demonstrated a low vasodilator effect or did not show vasoactivity.

Costunolide covalently targets and inhibits CaMKII phosphorylation to reduce ischemia-associated brain damage

BackgroundChronic cerebral hypoperfusion (CCH) is a leading cause of disability and mortality worldwide. Restoring cerebral blood flow (CBF) through vasodilatation is particularly important in the treatment of CCH. Costunolide (Cos) is a natural sesquiterpenoid compound with vasodilatory effect, but its mechanism is unclear. PurposeThis study aimed to investigate the vasodilatory mechanism of Cos and provide a new therapeutic regimen for treating CCH. MethodsThe therapeutic effect of Cos on CCH was assessed in a rat model of permanent common carotid artery occlusion. The direct target protein for improving CBF was identified by drug affinity responsive target stability combined with quantitative differential proteomics analysis. The molecular mechanism of Cos acting on its target protein was analyzed by multidisciplinary approaches. The signalling involved was assessed using site-directed pharmacological intervention. ResultsCos has a significant therapeutic effect on ischemic brain injury by restoring CBF. Multifunctional calcium/calmodulin-dependent protein kinase II (CaMKII) was identified as a direct target of the natural small molecule Cos with a therapeutic effect on CCH. Mechanistic studies revealed that the α,β-unsaturated-γ-lactone ring of Cos covalently binds to the Cys116 residue of CaMKII. It then inhibits the phosphorylation of CaMKII and reduces the calcium concentration in vascular smooth muscle cells, thus playing a role in vasodilation and increasing CBF. Notably, this covalent binding between Cos and CaMKII can exert a long-term vasodilator activity. ConclusionWe reported for the first time that Cos reduced ischemia-associated brain damage by covalently binding to the Cys116 residue of CaMKII, inhibiting CaMKII phosphorylation, and exerting long-term vasodilatory activity. This study not only found a new covalent inhibitor against the phosphorylation of CaMKII but also suggested that pharmacologically targeting CaMKII is a promising therapeutic strategy for CCH.

FRUITS OF VEGETABLE EUTERPE AS A VALUABLE SOURCE OF FOOD AND BIOLOGICALLY ACTIVE COMPOUNDS (REVIEW)

Vegetable euterpe (Euterpe oleracea) belongs to the Arecaceae family, grows in tropical and subtropical areas. The people call the fruits of acai. Of the wild species of Brazil, the most important are Euterpe oleracea, Euterpe edulis and Euterpe precatoria. A botanical description, a review of the chemical composition of secondary metabolites, a description of the biological and pharmacological activity of Euterpe oleracea are presented. The main biologically active compounds are anthocyanins (cyanidin–3-O-glucoside, cyanidin-3-O-rutinosideo), flavonoids (quercetin, rutin), tannins (catechin, gallic acid), phenylpropanoids (chlorogenic acid), carotenoids (α-carotene, β-carotene). There is evidence of antioxidant, vasodilating, anti-atherosclerotic, anti-inflammatory, neuroprotective and antitumor activity. A wide variety of biologically active compounds that cause a multidirectional pharmacological effect in this plant makes vegetable euterpe a promising object for the development of pharmaceutical substances.