In this review, subtypes of functional α1-adrenoceptor are discussed. These are cell membrane receptors, belonging to the seven-transmembrane-spanning G-protein-linked family of receptors, which ...respond to the physiological agonist noradrenaline. α1-Adrenoceptors can be divided into α1A-, α1B- and α1D-adrenoceptors, all of which mediate contractile responses involving Gq/11 and inositol phosphate turnover. A fourth α1-adrenoceptor, the α1L-, represents a functional phenotype of the α1A-adrenoceptor. α1-Adrenoceptor subtype knock-out mice have refined our knowledge of the functions of α-adrenoceptor subtypes, particuarly as subtype-selective agonists and antagonists are not available for all subtypes. α1-Adrenoceptors function as stimulatory receptors involved particularly in smooth muscle contraction, especially contraction of vascular smooth muscle, both in local vasoconstriction and in the control of blood pressure and temperature, and contraction of the prostate and bladder neck. Central actions are now being elucidated.
Pharmacology of Drugs Used as Stimulants Docherty, James R.; Alsufyani, Hadeel A.
Journal of clinical pharmacology,
August 2021, 2021-08-00, 20210801, Letnik:
61, Številka:
S2
Journal Article
Recenzirano
Odprti dostop
Psychostimulant, cardiovascular, and temperature actions of stimulants involve adrenergic (norepinephrine), dopaminergic (dopamine), and serotonergic (serotonin) pathways. Stimulants such as ...amphetamine, 3,4‐methylenedioxymethamphetamine (MDMA), or mephedrone can act on the neuronal membrane monoamine transporters NET, DAT, and SERT and/or the vesicular monoamine transporter 2 to inhibit reuptake of neurotransmitter or cause release by reverse transport. Stimulants may have additional effects involving pre‐ and postsynaptic/junctional receptors for norepinephrine, dopamine, and serotonin and other receptors. As a result, stimulants may have a wide range of possible actions. Agents with cocaine or MDMA‐like actions can induce serious and potentially fatal adverse events via thermodysregulatory, cardiovascular, or other mechanisms. MDMA‐like stimulants may cause hyperthermia that can be life threathening. Recreational users of stimulants should be aware of the dangers of hyperthermia in a rave/club environment.
This review examines the functions of α1-adrenoceptor subtypes, particularly in terms of contraction of smooth muscle. There are 3 subtypes of α1-adrenoceptor, α1A- α1B- and α1D-adrenoceptors. ...Evidence is presented that the postulated α1L-adrenoceptor is simply the native α1A-adrenoceptor at which prazosin has low potency.
In most isolated tissue studies, smooth muscle contractions to exogenous agonists are mediated particularly by α1A-, with a lesser role for α1D-adrenoceptors, but α1B-adrenoceptors are clearly involved in contractions of some tissues, for example, the spleen. However, nerve-evoked responses are the most crucial physiologically, so that these studies of exogenous agonists may overestimate the importance of α1A-adrenoceptors. The major α1-adrenoceptors involved in blood pressure control by sympathetic nerves are the α1D- and the α1A-adrenoceptors, mediating peripheral vasoconstrictor actions.
As noradrenaline has high potency at α1D-adrenceptors, these receptors mediate the fastest response and seem to be targets for neurally released noradrenaline especially to low frequency stimulation, with α1A-adrenoceptors being more important at high frequencies of stimulation. This is true in rodent vas deferens and may be true in vasopressor nerves controlling peripheral resistance and tissue blood flow. The αlA-adrenoceptor may act mainly through Ca2+ entry through L-type channels, whereas the α1D-adrenoceptor may act mainly through T-type channels and exhaustable Ca2+ stores. α1-Adrenoceptors may also act through non-G-protein linked second messenger systems. In many tissues, multiple subtypes of α-adrenoceptor are present, and this may be regarded as the norm rather than exception, although one receptor subtype is usually predominant.
This article updates the guidance published in 2015 for authors submitting papers to British Journal of Pharmacology (Curtis et al., 2015) and is intended to provide the rubric for peer review. Thus, ...it is directed towards authors, reviewers and editors. Explanations for many of the requirements were outlined previously and are not restated here. The new guidelines are intended to replace those published previously. The guidelines have been simplified for ease of understanding by authors, to make it more straightforward for peer reviewers to check compliance and to facilitate the curation of the journal's efforts to improve standards.
These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health ...England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address:Which patients should commence surveillance post-polypectomy and post-cancer resection?What is the appropriate surveillance interval?When can surveillance be stopped? two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia);
five or more premalignant polyps The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG's guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant.two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia);
five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise
:two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia);
five or more premalignant polyps This cohort should undergo a one-off surveillance colonoscopy at 3 years. Post-CRC resection patients should undergo a 1 year clearance colonoscopy, then a surveillance colonoscopy after 3 more years.
G‐protein coupled receptors such as α1‐adrenergic receptors (AR) are linked via the G‐protein Gq/G11 to both Ca2+ entry and release of Ca2+ from stores, but can also activate the small GTP binding ...protein RhoA and Rho kinase to produce contractions involving Ca2+ sensitization. In rat portal vein, tonic but not phasic components of contractions to the α1‐AR agonist phenylephrine involve predominantly the α1B‐AR subtype, and are at least partly mediated by mechanisms involving Rho kinase sensitive to fasudil (Alsufyani & Docherty, 2021). In this study we examined the involvement of Rho Kinase in contractions involving α1‐AR in two further tissues to investigate the predominant α1‐AR subtype involved. We have examined the Rho kinase inhibitor fasudil in rat aorta and mouse spleen, tissues containing multiple α1‐AR subtypes. Male Wistar rats (250‐300g) and C57 mice were killed by CO2 overdose and cervical dislocation, and rat aortic rings and mouse spleens were mounted in organ baths under 0.5 g tension, and bathed with Krebs‐Henseleit solution at 37oC. Tissues were contracted with cumulative additions of norepinephrine (NE) in 0.5 log unit increments, over the concentration range 10‐8‐10‐3M. Both α2‐ and α1‐ARs mediate contractions of mouse spleen and the major α1‐AR involved is the α1B‐adrenoceptor, and this receptor interacts with an α1D‐AR at low, and an α1A‐AR at high, NE concentrations (Alsufyani et al., 2021). In mouse spleen, fasudil (3 μM) reduced contractions to both low and high concentrations of NE. In rat aorta, contractions to NE are reported to be mediated by two subtypes of α1‐AR: α1B‐ and α1D‐ARs, with responses to low but not high concentrations of NE being sensitive to the antagonist BMY7378. Responses to high concentrations of NE in rat aorta are sensitive to the non‐selective α1‐AR antagonist prazosin and the putative α1B‐AR antagonist cyclazosin. Fasudil (3 and 10 μM) significantly reduced contractions to both low and high concentrations of NE in rat aorta in a dose dependent manner in terms of maximum response. It is concluded that α1‐AR mediated contractions to NE in both rat aorta and mouse spleen are sensitive to non‐competitive block by the Rho kinase inhibitor fasudil in concentrations of 3‐10 μM. Although multiple subtypes of α1‐adrenoceptor are involved in contractions of both rat aorta and mouse spleen, the evidence suggests that, as previously reported in rat portal vein, α1B‐adrenoceptors are most likely linked to the Rho kinase pathway
Alsufyani HA & Docherty, J.R. Can J Physiol Pharmacol. 2021 Jun;99(6):654‐659. Alsufyani HA, et al. Basic Clin Pharmacol Toxicol. 2021 Dec;129(6):416‐426.
The vast majority of illicit stimulants act at monoaminergic systems, causing both psychostimulant and adverse effects. Stimulants can interact as substrates or antagonists at the nerve terminal ...monoamine transporter that mediates the reuptake of monoamines across the nerve synaptic membrane and at the vesicular monoamine transporter (VMAT‐2) that mediates storage of monoamines in vesicles. Stimulants can act directly at presynaptic or postsynaptic receptors for monoamines or have indirect monoamine‐mimetic actions due to the release of monoamines. Cocaine and other stimulants can acutely increase the risk of sudden cardiac death. Stimulants, particularly MDMA, in hot conditions, such as that occurring at a “rave,” have caused fatalities from the consequences of hyperthermia, often compounding cardiac adverse actions. This review examines the pharmacology of the cardiovascular and temperature adverse actions of stimulants.
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