Serotonergic Modulation of Neurovascular Transmission:A Focus on Prejunctional 5-HT Receptors/Mechanisms

5-Hydroxytryptamine (5-HT), or serotonin, plays a crucial role as a neuromodulator and/or neurotransmitter of several nervous system functions. Its actions are complex, and depend on multiple factors, including the type of effector or receptor activated. Briefly, 5-HT can activate: (i) metabotropic (G-protein-coupled) receptors to promote inhibition (5-HT1, 5-HT5) or activation (5-HT4, 5-HT6, 5-HT7) of adenylate cyclase, as well as activation (5-HT2) of phospholipase C; and (ii) ionotropic receptor (5-HT3), a ligand-gated Na+/K+ channel. Regarding blood pressure regulation (and beyond the intricacy of central 5-HT effects), this monoamine also exerts direct postjunctional (on vascular smooth muscle and endothelium) or indirect prejunctional (on autonomic and sensory perivascular nerves) effects. At the prejunctional level, 5-HT can facilitate or preclude the release of autonomic (e.g., noradrenaline and acetylcholine) or sensory (e.g., calcitonin gene-related peptide) neurotransmitters facilitating hypertensive or hypotensive effects. Hence, we cannot formulate a specific impact of 5-HT on blood pressure level, since an increase or decrease in neurotransmitter release would be favoured, depending on the type of prejunctional receptor involved. This review summarizes and discusses the current knowledge on the prejunctional mechanisms involved in blood pressure regulation by 5-HT and its impact on some vascular-related diseases.</p

Pharmacological Nature of the Purinergic P2Y Receptor Subtypes That Participate in the Blood Pressure Changes Produced by ADPβS in Rats

Purine nucleosides (adenosine) and nucleotides such as adenosine mono/di/triphosphate (AMP/ADP/ATP) may produce complex cardiovascular responses. For example, adenosine-5′-(β-thio)-diphosphate (ADPβS; a stable synthetic analogue of ADP) can induce vasodilatation/vasodepressor responses by endothelium-dependent and independent mechanisms involving purinergic P2Y receptors; however, the specific subtypes participating in these responses remain unknown. Therefore, this study investigated the receptor subtypes mediating the blood pressure changes induced by intravenous bolus of ADPβS in male Wistar rats in the absence and presence of central mechanisms with the antagonists MRS2500 (P2Y1), PSB0739 (P2Y12), and MRS2211 (P2Y13). For this purpose, 120 rats were divided into 60 anaesthetised rats and 60 pithed rats, and further subdivided into four groups (n = 30 each), namely: (a) anaesthetised rats, (b) anaesthetised rats with bilateral vagotomy, (c) pithed rats, and (d) pithed rats continuously infused (intravenously) with methoxamine (an α1-adrenergic agonist that restores systemic vascular tone). We observed, in all four groups, that the immediate decreases in diastolic blood pressure produced by ADPβS were exclusively mediated by peripheral activation of P2Y1 receptors. Nevertheless, the subsequent increases in systolic blood pressure elicited by ADPβS in pithed rats infused with methoxamine probably involved peripheral activation of P2Y1, P2Y12, and P2Y13 receptors.</p

Pharmacological Profile of the Purinergic P2Y Receptors That Modulate, in Response to ADPβS, the Vasodepressor Sensory CGRPergic Outflow in Pithed Rats

Calcitonin gene-related peptide (CGRP), an endogenous neuropeptide released from perivascular sensory nerves, exerts a powerful vasodilatation. Interestingly, adenosine triphosphate (ATP) stimulates the release of CGRP by activation of prejunctional P2X2/3 receptors, and adenosine 5′-O-2-thiodiphosphate (ADPβS), a stable adenosine diphosphate (ADP) analogue, produces vasodilator/vasodepressor responses by endothelial P2Y1 receptors. Since the role of ADP in the prejunctional modulation of the vasodepressor sensory CGRPergic drive and the receptors involved remain unknown, this study investigated whether ADPβS inhibits this CGRPergic drive. Accordingly, 132 male Wistar rats were pithed and subsequently divided into two sets. In set 1, ADPβS (5.6 and 10 µg/kg·min) inhibited the vasodepressor CGRPergic responses by electrical stimulation of the spinal T9–T12 segment. This inhibition by ADPβS (5.6 µg/kg·min) was reverted after i.v. administration of the purinergic antagonists MRS2500 (300 µg/kg; P2Y1) or MRS2211 (3000 µg/kg; P2Y13), but not by PSB0739 (300 µg/kg; P2Y12), MRS2211 (1000 µg/kg; P2Y13) or the KATP blocker glibenclamide (20 mg/kg). In set 2, ADPβS (5.6 µg/kg·min) failed to modify the vasodepressor responses to exogenous α-CGRP. These results suggest that ADPβS inhibits CGRP release in perivascular sensory nerves. This inhibition, apparently unrelated to activation of ATP-sensitive K+ channels, involves P2Y1 and probably P2Y13, but not P2Y12 receptors.</p

Metabolic Aspects of Migraine: Association With Obesity and Diabetes Mellitus

Migraine is a disabling neurovascular disorder, characterized by moderate to severe unilateral headaches, nausea, photophobia, and/or phonophobia, with a higher prevalence in women than in men, which can drastically affect the quality of life of migraine patients. In addition, this chronic disorder is related with metabolic comorbidities associated with the patient's lifestyle, including obesity and diabetes mellitus (DM). Beyond the personal and socioeconomic impact caused by migraine, obesity and DM, it has been suggested that these metabolic disorders seem to be related to migraine since: (i) they are a risk factor for developing cardiovascular disorders or chronic diseases; (ii) they can be influenced by genetic and environmental risk factors; and (iii) while clinical and epidemiological studies suggest that obesity is a risk factor for migraine, DM (i.e., type 1 and type 2 DM) have been reported to be either a protective or a risk factor in migraine. On this basis, and given the high worldwide prevalence of migraine, obesity, and DM, this article provides a narrative review of the current literature related to the association between the etiology and pathophysiology of migraine and these metabolic disorders, considering lifestyle aspects, as well as the possible involvement of neurotransmitters, neuropeptides, and/or sex hormones. While a link between migraine and metabolic disorders has been suggested, many studies are contradictory and the mechanisms involved in this association are not yet sufficiently established. Therefore, further research should be focused on understanding the possible mechanisms involved

Pharmacological evidence that α1- and α2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs

1. Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting antimigraine agents, including the triptans and ergot alkaloids. While 5-HT(1B/1D) receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with α-adrenoceptors. In the present study, we investigated the potential role of α1- and α2-adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. 2. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 μg kg-1 min-1) or BHT 933 (3, 10 and 30 μg kg-1 min-1) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. 3. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 μg kg-1, i.v.) and rauwolscine (300 μg kg-1, i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5-HT(1B/1D) receptor antagonist GR127935 (500 μg kg-1, i.v.). 4. These results show that both α1- and α2-adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the α2-adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current antimigraine agents and may eventually be helpful in the development of future treatment in migraine

The VVV Near-IR Galaxy Catalogue beyond the Galactic disk

Knowledge about the large-scale distribution of galaxies is far from complete in the Zone of Avoidance, which is mostly due to high interstellar extinction and to source confusion at lower Galactic latitudes. Past near-infrared (NIR) surveys, such as the Two Micron All Sky Survey (2MASS), have shown the power of probing large-scale structure at these latitudes. Our aim is to map the galaxy distribution across the Southern Galactic plane using the VISTA Variables in the V\'ia L\'actea Survey (VVV), which reach 2 to 4 magnitudes deeper than 2MASS. We used SExtractor + PSFEx to identify extended objects and to measure their sizes, the light concentration index, magnitudes, and colours. Morphological and colour constraints and visual inspection were used to confirm galaxies. We present the resulting VVV NIR Galaxy Catalogue of 5563 visually confirmed galaxies, of which only 45 were previously known. This is the largest catalogue of galaxies towards the Galactic plane, with 99% of these galaxies being new discoveries. We found that the galaxy density distribution closely resembled the distribution of low interstellar extinction of the existing NIR maps. We also present a description of the 185 2MASS extended sources observed in the region, of which 16% of these objects had no previous description, which we have now classified. We conclude that interstellar extinction and stellar density are the main limitations for the detection of background galaxies in the Zone of Avoidance. The VVV NIR Galaxy Catalogue is a new data set providing information for extragalactic studies in the Galactic plane.Comment: Accepted for publication in Monthly Notices of the Royal Astronomical Society Main Journal 21 page

Galaxy clustering in the VVV Near-IR Galaxy Catalogue

Mapping galaxies at low Galactic latitudes and determining their clustering status are fundamental steps in defining the large-scale structure in the nearby Universe. The VVV Near-IR Galaxy Catalogue (VVV NIRGC) allows us to explore this region in great detail. Our goal is to identify galaxy overdensities and characterize galaxy clustering in the Zone of Avoidance. We use different clustering algorithms to identify galaxy overdensities: the Voronoi tessellations, the Minimum Spanning Tree and the Ordering Points To Identify the Clustering Structure. We studied the membership, isolation, compactness, and flux limits to identify compact groups of galaxies. Each method identified a variety of galaxy systems across the Galactic Plane that are publicly available.We also explore the probability that these systems are formed by concordant galaxies using mock catalogues. Nineteen galaxy systems were identified in all of the four methods. They have the highest probability to be real overdensities. We stress the need for spectroscopic follow-up observations to confirm and characterize these new structures.Comment: 16 pages, 10 figures, 9 tables. Accepted for publication in Monthly Notices of the Royal Astronomical Society (MNRAS

Integral

Abstract In order to analyze the current process of operation of slaughterhouses and propose actions for an appropriate control, as well as implement the reduction of water used per slaughtered animal, this study of green production applied to the processes in a selected municipal slaughterhouse in Querétaro, Mexico was undertaken. Also, from treatability tests of wastewater, a mobile prototype of water treatment (1.5 m 3 /day) was conceptualized, designed and built. This prototype is operating at the slaughterhouse and demonstrates the efficiency of treatment of those waters. Along with the prototype, this project developed a technological folder with technical specifications, comparative analysis of production units and a business plan that brings together all the necessary information to evaluate the project and the general guidelines to implement it in other municipalities of Querétaro. The business plan is essential to seek funding, partners or investors, and serves as a guide for those leading the implementation of the results obtained in this project at other municipalities. Additionally, an environmental impact study was performed to identify and interpret the environmental impacts of a full scale project, with emphasis on environmental benefits

Trigeminovascular effects of propranolol in men and women, role for sex steroids

OBJECTIVE: Assess whether propranolol modulates the trigeminovascular system in both men and women. METHODS: We investigated the effect of propranolol (80 mg, 90 min after oral administration, corresponding to T (max)) on the increase in dermal blood flow of the forehead skin (innervated by the trigeminal nerve) by capsaicin application (0.6 mg/mL) and electrical stimulation (0.2–1.0 mA) before and after placebo (grapefruit juice) or propranolol (oral solution diluted in grapefruit juice) in a randomized, double‐blind, placebo‐controlled cross‐over study, including healthy males (n = 10) and females on contraceptives (n = 11). Additionally, we compared our results with data from the Dutch IADB.nl prescription database by analyzing the change in triptan use after propranolol prescription in a population similar to our dermal blood flow study subjects (males and females, 20–39 years old). RESULTS: Dermal blood flow responses to capsaicin were significantly attenuated after propranolol, but not after placebo. When stratifying by sex, no significant changes in the capsaicin‐induced dermal blood flow were observed in females after propranolol, whereas they remained significant in males. Dermal blood flow responses to electrical stimulation were not modified in any case. In our prescription database study, after propranolol, a more pronounced decrease in triptan use was observed in male patients than in female patients. INTERPRETATION: Propranolol (80 mg) inhibits capsaicin‐induced increases in dermal blood flow in a sex‐dependent manner. In patients, a more pronounced decrease in triptan use is observed in males when compared with females, suggesting an interaction between propranolol and sex steroids in the modulation of the trigeminovascular system

The efficacy and safety of oral mucopolysaccharide, type I collagen and vitamin C treatment in tendinopathy patients

Introduction and objectives Tendinopathy, which is accompanied by structural changes to the tendon, is a common sporting injury. The aim of this study was to evaluate the efficacy and safety of a nutritional supplement containing mucopolysaccharides, type I collagen and vitamin C (TendoactiveTM) on the clinical and structural evolution of tendinopathies of the Achilles tendon, patellar tendon and lateral epicondyle tendon in the elbow. Materials and methods A multicenter, open-label, non-comparative, prospective, exploratory phase iv study was performed. A total of 98 tendinopathy patients (32 Achilles, 32 patellar and 34 lateral epicondylar), who received a daily dose of 435 mg mucopolysaccharides, 75 mg type i collagen and 60 mg vitamin C (equivalent to three capsules of TendoactiveTM per day) for 90 consecutive days, were included. Every month, pain at rest and when active was assessed using a visual analogue scale (VAS), joint function was assessed using the VISA-A, VISA-P and PRTEE questionnaires, and the tendon affected was characterized by ultrasound. Results A significant reduction in pain both at rest and when active was observed between the first control visit (day 30) and the end of the study (day 90) for all three types of tendinopathy. Thus, a 38% improvement in VISA-A, 46% in VISA-P and 77% in PRTEE was observed on day 90 (P < .001). Similarly, a 12% decrease in the thickness of the Achilles tendon, a 10% decrease in the patellar tendon and a 20% decrease in the lateral epicondyle tendon was observed (P < .05). Conclusions The results of this study show that the administration of TendoactiveTM is safe and effective for improving the clinical symptoms and structural evolution of tendinopathies of the Achilles, patella and lateral epicondyle tendons