Diagnostic yield from symptomatic gastroscopy in the UK: British Society of Gastroenterology analysis using data from the National Endoscopy Database.

OBJECTIVE: This national analysis aimed to calculate the diagnostic yield from gastroscopy for common symptoms, guiding improved resource utilisation. DESIGN: A cross-sectional study was conducted of diagnostic gastroscopies between 1 March 2019 and 29 February 2020 using the UK National Endoscopy Database. Mixed-effect logistic regression models were used, incorporating random (endoscopist) and fixed (symptoms, age and sex) effects on two dependent variables (endoscopic cancer; Barrett's oesophagus (BO) diagnosis). Adjusted positive predictive values (aPPVs) were calculated. RESULTS: 382 370 diagnostic gastroscopies were analysed; 30.4% were performed in patients aged <50 and 57.7% on female patients. The overall unadjusted PPV for cancer was 1.0% (males 1.7%; females 0.6%, p<0.01). Other major pathology was found in 9.1% of procedures, whereas 89.9% reported only normal findings or minor pathology (92.5% in females; 94.6% in patients <50).Highest cancer aPPVs were reached in the over 50s (1.3%), in those with dysphagia (3.0%) or weight loss plus another symptom (1.4%). Cancer aPPVs for all other symptoms were below 1%, and for those under 50, remained below 1% regardless of symptom. Overall, 73.7% of gastroscopies were carried out in patient groups where aPPV cancer was <1%.The overall unadjusted PPV for BO was 4.1% (males 6.1%; females 2.7%, p<0.01). The aPPV for BO for reflux was 5.8% and ranged from 3.2% to 4.0% for other symptoms. CONCLUSIONS: Cancer yield was highest in elderly male patients, and those over 50 with dysphagia. Three-quarters of all gastroscopies were performed on patients whose cancer risk was <1%, suggesting inefficient resource utilisation.

Involvement of α1B-adrenoceptors and Rho kinase in contractions of rat aorta and mouse spleen.

α1-adrenoceptors link via the G-protein Gq/G11 to both Ca2+ entry and release from stores, but may also activate Rho kinase, which causes calcium sensitization. This study aimed to identify the subtype(s) of α1-adrenoceptor involved in Rho kinase-mediated responses in both rat aorta and mouse spleen, tissues in which contractions involve multiple subtypes of α1-adrenoceptor. Tissues were contracted with cumulative concentrations of noradrenaline (NA) in 0.5 log unit increments, before and in the presence of an antagonist or vehicle. Contractions produced by NA in rat aorta are entirely α1-adrenoceptor mediated as they are competitively blocked by prazosin. The α1A-adrenoceptor antagonist RS100329 had low potency in rat aorta. The α1D-adrenoceptor antagonist BMY7378 antagonized contractions in rat aorta in a biphasic manner: low concentrations blocking α1D-adrenoceptors and high concentrations blocking α1B-adrenoceptors. The Rho kinase inhibitor fasudil (10 µM) significantly reduced aortic contractions in terms of maximum response, suggesting inhibition of α1B-adrenoceptor mediated responses. In the mouse spleen, a tissue in which all 3 subtypes of α1-adrenoceptor are involved in contractions to NA, fasudil (3 µM) significantly reduced both early and late components to the NA contraction, the early component involving α1B- and α1D-adrenoceptors, and the late component involving α1B- and α1A-adrenoceptors. This suggests that fasudil inhibits α1B-adrenoceptor mediated responses. It is concluded that α1D- and α1B-adrenoceptors interact in rat aorta and α1D-, α1A- and α1B-adrenoceptors interact in the mouse spleen to produce contractions and these interactions suggest that one of the receptors preferentially activates Rho kinase, most likely the α1B-adrenoceptor.

Joint ACPGBI and The Duke's Club statement on colonoscopy training.

Colorectal surgeons across the UK currently undertake a large proportion of routine diagnostic and therapeutic colonoscopy in most NHS Trusts [1]. Meanwhile, the new UK General Surgical curriculum now includes an indicative requirement of 200 diagnostic colonoscopies for surgical trainees who have declared a colorectal subspecialty interest (hereafter termed 'colorectal trainees'), indicating the JCST's (Joint Committee on Surgical Training) commitment to colonoscopy training. However, several studies have reported a marked deficiency in colonoscopy training opportunities and accreditation for surgical trainees compared with gastroenterology trainees [2-4].

Involvement of G proteins and Rho kinase in α1-adrenoceptor mediated contractions of the rat portal vein.

Contractions of the rat portal vein in response to the α1-adrenoceptor agonist phenylephrine consist of phasic contractions at low concentrations, with tonic contractions superimposed at higher concentrations. The α1D-adrenoceptor antagonist BMY7378 (7.0, -log M) did not affect phasic or tonic contractions to phenylephrine. The relatively nonselective α1-adrenoceptor antagonist prazosin (7.5) shifted equally the potencies of phenylephrine at producing phasic and tonic contractions, with pKB values of 8.85 and 8.83 (-log M), respectively. The α1A-adrenoceptor antagonist RS100329 (8.5) produced a significantly greater shift in phenylephrine potency for phasic (pKB of 10.51) than tonic contractions (pKB of 9.78). Prazosin was less effective than RS100329 at reducing the effects of phenylephrine on frequency of phasic contractions. The Rho kinase inhibitor fasudil (5.0) did not affect phasic contractions to phenylephrine, but significantly reduced tonic contractions. It is concluded that there is no evidence for involvement of α1D-adrenoceptors in responses of the rat portal vein to phenylephrine, but phasic responses involve predominantly α1A-adrenoceptors. Tonic responses may involve predominantly α1B-adrenoceptors and are at least partly mediated by mechanisms involving Rho kinase sensitive to fasudil.

Roles for α1-adrenoceptors during contractions by electrical field stimulation in mouse vas deferens.

We have investigated the relative roles of α1-adrenoceptors and purinoceptors in contractions to low and high frequency stimulation of the mouse vas deferens, in terms of the time course of responses. In separate experiments, isometric contractile responses were obtained to 10 pulses at 1 Hz and 40 pulses at 10 Hz. Responses to 1 Hz stimulation consisted of a series of discrete peaks. The α1A-adrenoceptor antagonist RS100329 (10-9M-10-7M) significantly reduced the response to the first pulse, the α1D-adrenoceptor antagonist BMY7378 (10-7M-10-6M) significantly reduced the response to the first two pulses, and the non-selective α1-adrenoceptor antagonist prazosin (10-8M) reduced the response to the first 4 pulses at 1 Hz. Responses to 10 Hz stimulation consisted of an early peak response and a maintained plateau response. RS100329 significantly reduced the peak response but did not significantly affect the plateau response. Prazosin, significantly reduced both the peak and plateau responses. The α1A-adrenoceptor antagonist RS17053 in high concentrations reduced mainly the plateau response leaving a clear early peak response. The plateau response of contraction was almost abolished by the purinoceptor antagonist suramin. These results suggest that there is a relatively minor early α1D-adrenoceptor and a larger early α1A-adrenoceptor component to stimulationevoked contractions of mouse vas deferens, but the major α1-adrenoceptor component is revealed by prazosin to be α1B-adrenoceptor mediated. α1B-Adrenoceptor activation probably facilitates contractions mediated by other α1-adrenoceptors and by purinoceptors. These results suggest that combined non-selective α1-adrenoceptor blockade, particularly α1B-adrenoceptor blockade, in addition to P2X1-purinoceptor blockade is useful in reducing male fertility.

British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland/Public Health England post-polypectomy and post-colorectal cancer resection surveillance guidelines.

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); or 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); or five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either: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); or 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.

The renin angiotensin aldosterone system and COVID-19.

The ongoing pandemic has stimulated study of the Renin Angiotensin Aldosterone System (RAAS), and how it can be manipulated to treat COVID-19. Studies are examining whether drugs that act on the RAAS system might be useful to treat COVID-19. COVID-19 and the RAAS are closely linked both in infection and in possible post-infection inflammatory cascades. We detail the Physiology and Pharmacology of the RAAS including the effects of aldosterone and atrial natriuretic peptide. It is appropriate that the theoretical benefits of modulation of the RAAS should be considered based on available knowledge of the complexity of the system. In this short review we have tried to explain the actions of the angiotensin family of peptides and produce a relatively simple model and diagrammatic summary of the RAAS and the possible sites of intervention.

A carboxymethylcellulose-heparin combination for the prevention of surgical adhesions.

BACKGROUND: Adhesions are a major clinical problem after abdominal surgery. Despite decades of research, therapies to prevent adhesion formation are suboptimal. MATERIALS AND METHODS: We have investigated combinations of carboxymethylcellulose (CMC) and heparin at preventing surgical adhesions in two rat models of adhesion formation. The first was the well-established cecal abrasion model, and the second was a model developed in our laboratory, the avascular mesenteric knot model. This model consistently produced adhesions at the knot in 90% of experiments and causes little or no tissue injury. RESULTS: Topical administration of CMC 4% gave optimal results in the avascular knot model, but was less effective in the cecal abrasion model. This concentration of CMC was combined with a range of heparin doses between 0.5 and 160 IU/mL in the cecal abrasion model. These heparin doses, apart from the lowest (0.5 IU/mL), were effective in preventing adhesion formation in combination with CMC, as was the commercially available topical product Lipactin. The optimal dose was 30 IU/mL, that abolished adhesions, but there was little difference at doses between 2 and 160 IU. Heparin was effective in doses as low as 2 IU/mL when in combination with CMC. Heparin 160 IU/mL, but not heparin 30 IU/mL or Lipactin, significantly increased the degree of bleeding post cecal abrasion surgery. CONCLUSIONS: Topical application of tiny doses of heparin, in combination with CMC 4% gel, significantly reduces adhesion formation in experimental models. We suggest that this cheap and, as far as we know, safe intervention should be evaluated in human clinical trials.

Diagnostic yield from symptomatic lower gastrointestinal endoscopy in the UK: A British Society of Gastroenterology analysis using data from the National Endoscopy Database.

BACKGROUND: The value of lower gastrointestinal endoscopy (LGIE; colonoscopy or sigmoidoscopy) relates to its ability to detect clinically relevant findings, predominantly cancers, preneoplastic polyps or inflammatory bowel disease. There are concerns that many LGIEs are performed on low-risk patients with limited benefit. AIMS: To determine the diagnostic outcomes of LGIE for common symptoms. METHODS: We performed a cross-sectional study of diagnostic LGIE between March 2019 and February 2020 using the UK National Endoscopy Database. We used mixed-effects logistic regression models, incorporating random (endoscopist) and fixed (symptoms, patient age, and sex) effects upon two dependent variables (large polyp [≥10 mm] and cancer diagnosis). Adjusted positive predictive values (aPPVs) were calculated. RESULTS: We analysed 384,510 LGIEs; 33.2% were performed on patients aged under 50 and 53.6% on women. Regarding colonoscopies, the unadjusted PPV for cancer was 1.5% (95% CI: 1.4-1.5); higher for men than women (1.9% vs. 1.1%, p < 0.01). The PPV for large polyps was 3.2% (95% CI: 3.1-3.2). The highest colonoscopy cancer aPPVs were in the over 50s (1.9%) and in those with rectal bleeding (2.5%) or anaemia (2.1%). Cancer aPPVs for other symptoms were <1% despite representing 54.3% of activity. In patients under 50, aPPVs were 0.4% for cancer and 1.6% for large polyps. Results were similar for sigmoidoscopy. CONCLUSIONS: Most colonoscopies were performed on patients with low-risk symptoms, where cancer risk was similar to the general population. Cancer and large polyp yield was highest in elderly patients with rectal bleeding or anaemia, although still fell short of FIT-based screening yields.

Effects of RS17053 on α1 -adrenoceptors in rat vas deferens and aorta.

BACKGROUND: RS17053 is classed as an α1A -adrenoceptor selective antagonist. OBJECTIVES: We have examined its profile of action at all subtypes of α1 -adrenoceptor. METHODS: Noradrenaline (NA) evoked contractions of rat vas deferens involve α1D -adrenoceptors in phasic contractions and α1A -adrenoceptors in tonic contractions. Contractions of rat aorta to NA involve α1D - and α1B -adrenoceptors. RESULTS: RS17053 (10-5  M) shifted NA potency and virtually abolished tonic contractions to NA, with little or limited effect on phasic contractions. The α1D -adrenoceptor antagonist BMY7378 (3 × 10-7 M) significantly inhibited the remaining phasic component of the contractions, and the α1A -adrenoceptor antagonist RS100329 (10-7  M) inhibited further the residual tonic contraction. Hence, RS17053 shows high selectivity for α1A -adrenoceptors over α1D -adrenoceptors in rat vas deferens. However, RS17053 (10-5  M) produced a large shift in the potency of NA in rat aorta, with a pKB of 6.82. Large shifts of NA potency in rat aorta involve α1B -adrenoceptor blockade. CONCLUSION: Results in rat vas deferens demonstrate low potency of RS17053 at α1D -adrenoceptors, but results from rat aorta can only be explained as demonstrating α1B -adrenoceptor antagonism by RS17053. RS17053 may be a useful pharmacological tool when reclassified as a mainly α1A - and to a lesser extent α1B -adrenoceptor antagonist with little effect at α1D -adrenoceptors.

UK endoscopy workload and workforce patterns: is there potential to increase capacity? A BSG analysis of the National Endoscopy Database.

Background: The lack of comprehensive national data on endoscopy activity and workforce hampers strategic planning. The National Endoscopy Database (NED) provides a unique opportunity to address this in the UK. We evaluated NED to inform service planning, exploring opportunities to expand capacity to meet service demands. Design: Data on all procedures between 1 March 2019 and 29 February 2020 were extracted from NED. Endoscopy activity and endoscopist workforce were analysed. Results: 1 639 640 procedures were analysed (oesophagogastroduodenoscopy (OGD) 693 663, colonoscopy 586 464, flexible sigmoidoscopy 335 439 and endoscopic retrograde cholangiopancreatography 23 074) from 407 sites by 4990 endoscopists. 89% of procedures were performed in NHS sites. 17% took place each weekday, 10% on Saturdays and 6% on Sundays. Training procedures accounted for 6% of total activity, over 99% of which took place in NHS sites. Median patient age was younger in the independent sector (IS) (51 vs 60 years, p<0.001). 74% of endoscopists were male. Gastroenterologists and surgeons each comprised one-third of the endoscopist workforce; non-medical endoscopists (NMEs) comprised 12% yet undertook 23% of procedures. Approximately half of endoscopists performing OGD (52%) or colonoscopies (48%) did not meet minimum annual procedure numbers. Conclusion: This comprehensive analysis reveals endoscopy workload and workforce patterns for the first time across both the NHS and the IS in all four UK nations. Half of all endoscopists perform fewer than the recommended minimum annual procedure numbers: a national strategy to address this, along with expansion of the NME workforce, would increase endoscopy capacity, which could be used to exploit latent weekend capacity.

Guidance for the use and reporting of anaesthetic agents in BJP manuscripts involving work with animals.

Scientists who plan to publish in the British Journal of Pharmacology (BJP) should read this article before undertaking studies utilising anaesthetics in mammalian animals. This editorial identifies certain gaps in the reporting of details on the use of anaesthetics in animal research studies published in the BJP. The editorial also provides guidance, based upon current best practices, for performing in vivo experiments that require anaesthesia. In addition, mechanisms of action and physiological impact of specific anaesthetic agents are discussed. Our goal is to identify best practices and to provide guidance on the information required for manuscripts submitted to the BJP that involve the use of anaesthetic agents in studies with experimental animals.

Preliminary Effects of Osteopathic Manipulative Medicine on Reactive Oxygen Species in Parkinson's Disease: A Randomized Controlled Pilot Study.

Context Parkinson's disease (PD) is the second most common neurodegenerative disorder and causes many clinical manifestations including bradykinesia, tremor, postural instability, and musculoskeletal stiffness. Neurodegeneration is commonly associated with oxidative stress. Oxidative stress has not been measured in PD in relation to the manual techniques used in Osteopathic Manipulative Treatment (OMT). Objective To investigate the effect of OMT on oxidative stress biomarkers in PD. Methods In this randomized non-blinded study, 32 PD subjects were separated by block randomization into counseling and OMT groups, receiving respective interventions twice a week for six weeks. The counseling arm received informative sessions while the OMT arm received a set treatment protocol. Biomarkers of oxidative stress, malondialdehyde (MDA), dityrosine (DT), 3-nitrotyrosine (3-NT), 8-hydroxy-2-deoxyguanosine (8-OHdG), and 8-isoprostane were measured before and after the first session and at weeks three, six, and 10 (four weeks after conclusion of intervention). Results No significant changes were found in blood plasma levels of MDA, DT, 3-NT, or 8-OHdG during or after intervention compared to controls (p > 0.05). No significant changes were found in urine 8-OHdG or 8-isoprostane during or after intervention compared to controls (p > 0.05). Conclusion OMT used in this study did not significantly affect the chosen oxidative stress biomarkers, however many limitations of the study may have impeded possible findings.

The Effect of Pedal Pump Lymphatic Technique Versus Passive Recovery Following Maximal Exercise: A Randomized Cross-Over Trial.

CONTEXT: Muscle damage and delayed onset muscle soreness (DOMS) can occur following intense exercise. Various modalities have been studied to improve blood lactate accumulation, which is a primary reason for DOMS. It has been well established that active recovery facilitates blood lactate removal more rapidly that passive recovery due to the pumping action of the muscle. The pedal pump is a manual lymphatic technique used in osteopathic manipulative medicine to increase lymphatic drainage throughout the body. Pedal pump has been shown to increase lymphatic flow and improve immunity. This may improve circulation and improve clearance of metabolites post-exercise. OBJECTIVE: This study compared the use of pedal pump lymphatic technique to passive supine recovery following maximal exercise. METHODS: 17 subjects (male n = 10, age 23 ± 3.01; female n = 7, age 24 ± 1.8), performed a maximal volume O2 test (VO2 max) using a Bruce protocol, followed by a recovery protocol using either pedal pump technique or supine passive rest for 10 min, followed by sitting for 10 min. Outcome measures included blood lactate concentration (BL), heart rate (HR), systolic blood pressure (SBP) and VO2. Subjects returned on another day to repeat the VO2 max test to perform the other recovery protocol. All outcomes were measured at rest, within 1- minute post-peak exercise, and at minutes 4, 7, 10 and 20 of the recovery protocols. A 2 × 6 repeated measures ANOVA was used to compare outcome measures (p ≤ 0.05). RESULTS: No significant differences were found in VO2, HR, or SBP between any of the recovery protocols. There was no significant difference in BL concentrations for recovery at minutes 4, 7, or 10 (p > 0.05). However, the pedal pump recovery displayed significantly lower BL concentrations at minute 20 of recovery (p = 0.04). CONCLUSION: The pedal pump significantly decreased blood lactate concentrations following intense exercise at recovery minute 20. The use of manual lymphatic techniques in exercise recovery should be investigated further.

Stapled versus handsewn methods for ileocolic anastomoses.

BACKGROUND: Ileocolic anastomoses are commonly performed for right-sided colon cancer and Crohn's disease. The anastomosis may be constructed using a linear cutter stapler or by suturing. Individual trials comparing stapled versus handsewn ileocolic anastomoses have found little difference in the complication rate but they have lacked adequate power to detect potential small difference. This is an update of a Cochrane review first published in 2007. OBJECTIVES: To compare outcomes of ileocolic anastomoses performed using stapling and handsewn techniques. The hypothesis tested was that the stapling technique is associated with fewer complications. SEARCH STRATEGY: MEDLINE, EMBASE, Cochrane Colorectal Cancer Group specialised register SR-COLOCA, Cochrane Library were searched for randomised controlled trials comparing use of a linear cuter stapler with any type of suturing technique for ileocolic anastomoses in adults from 1970 to 2005 and were updated in December 2010. Abstracts presented to the following society meetings between 1970 and 2010 were handsearched: American Society of Colon and Rectal Surgeons, the Association of Coloproctology of Great Britain and Ireland, European Association of Coloproctology. SELECTION CRITERIA: Randomised controlled trials comparing use of linear cutter stapler (isoperistaltic side to side or functional end to end) with any type of suturing technique in adults. DATA COLLECTION AND ANALYSIS: Eligible studies were selected and their methodological quality assessed. Relevant results were extracted and missing data sought from the authors. RevMan 5 was used to perform meta-analysis when there were sufficient data. Sub-group analyses for cancer inflammatory bowel disease as indication for ileocolic anastomoses were performed. MAIN RESULTS: After obtaining individual data from authors for studies that include other anastomoses, seven trials (including one unpublished) with 1125 ileocolic participants (441 stapled, 684 handsewn) were included. The five largest trials had adequate allocation concealment.Stapled anastomosis was associated with significantly fewer anastomotic leaks compared with handsewn (S=11/441, HS=42/684, OR 0.48 [0.24, 0.95] p=0.03). One study performed routine radiology to detect asymptomatic leaks. For the sub-group of 825 cancer patients in four studies, stapled anastomosis led to significantly fewer anastomotic leaks (S=4/300, HS=35/525, OR 0.28 [0.10, 0.75] p=0.01). In subgroup analysis of non-cancer patients (3 studies, 264 patients) there were no differences for any reported outcomes. All other outcomes: stricture, anastomotic haemorrhage, anastomotic time, re-operation, mortality, intra-abdominal abscess, wound infection, length of stay, showed no significant difference. AUTHORS' CONCLUSIONS: Stapled functional end to end ileocolic anastomosis is associated with fewer leaks than handsewn anastomosis.

Subtypes of functional alpha1-adrenoceptor.

In this review, subtypes of functional alpha1-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. alpha1-Adrenoceptors can be divided into alpha1A-, alpha1B- and alpha1D-adrenoceptors, all of which mediate contractile responses involving Gq/11 and inositol phosphate turnover. A fourth alpha1-adrenoceptor, the alpha1L-, represents a functional phenotype of the alpha1A-adrenoceptor. alpha1-Adrenoceptor subtype knock-out mice have refined our knowledge of the functions of alpha-adrenoceptor subtypes, particuarly as subtype-selective agonists and antagonists are not available for all subtypes. alpha1-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.

Interaction between α1B - and other α1 - and α2 -adrenoceptors in producing contractions of mouse spleen.

We have investigated the interaction of α1 - and α2 -adrenoceptor subtypes in producing isometric contractions to NA in mouse whole spleen. The α1 -adrenoceptor antagonist prazosin (10-8  M) or the α2 -adrenoceptor antagonist yohimbine (10-6  M) alone produced only small shifts in NA potency in wild type (WT) mice, but the combination produced a large shift in NA potency. In spleen from α1A/D -KO mice, the effects of prazosin and the combination of prazosin and yohimbine were similar to their effects in WT mice. Hence, in α1A/D -KO mice, in which the only α1 -adrenoceptor present is the α1B -adrenoceptor, prazosin still antagonized contractions to NA. The α1A -adrenoceptor antagonist RS100329 (3 × 10-9 M) produced significant shifts in the effects of higher concentrations of NA (EC50 and EC75 levels) and the α1D -adrenoceptor antagonist BMY7378 (3 × 10-8 M) produced significant shifts in the effects of lower concentrations of NA (EC25 and EC50 levels). The effects of BMY7378 and RS00329 demonstrate α1D -adrenoceptor and α1A -adrenoceptor components and suggest that the α1B -adrenoceptor interacts with an α1D -adrenoceptor, and to a lesser extent an α1A -adrenoceptor, at low, and an α1A -adrenoceptor at high, NA concentrations. This study demonstrates the complex interaction between α1 - and α2 -adrenoceptor subtypes in producing contractions of mouse spleen and may have general implications for α-adrenoceptor mediated control of smooth muscle.

Pharmacology of Drugs Used as Stimulants.

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.

Cardiovascular and temperature adverse actions of stimulants.

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.