Australian rural medical students' perceived readiness for work as a junior doctor: A cross-sectional national survey.

OBJECTIVE: To report self-perceived readiness for work as a junior doctor in a national cohort of rural clinical school students. DESIGN: Cross-sectional study using a self-report questionnaire. Independent variables included 14 individual readiness items related to clinical and professional tasks, sociodemographic data and reported experience of rural clinical school (RCS) training. Participants were 668 medical students (55.3% females) completing a full academic year in rural Australia. Multivariable analysis explored factors associated with overall readiness for work as a junior doctor. FINDINGS: 86% agreed that RCS experience prepared them to undertake the roles and responsibilities of a junior doctor. Self-ratings for specific clinical and professional tasks varied from a mean score of 5.9-8.0 out of 10, and 13 of the 14 items were associated with the outcome (p-value <0.001, except for performing spirometry). Lowest readiness scores were seen for some aspects including raising concerns about a colleague (mean score 6.1) or responding to workplace bullying (mean score 6.0). Aspects of the RCS experience that were strongly associated with overall readiness included: feeling a valued team-member (OR 9.28, 95%CI 2.43-35.39), feeling well-supported academically (OR 6.64, 95%CI 3.39-13.00), having opportunity for unsupervised but supported clinical practice (OR 4.67, 95%CI 1.45-15.00), having a rural mentor (OR 3.38, 95%CI 1.89-6.06) and having a previous health professional qualification (OR 2.7, 95%CI 1.32-5.54). DISCUSSION: Most RCS students felt ready for work as a junior doctor. Important aspects of RCS experience are likely to include students feeling integrated within the clinical team and having opportunities for authentic clinical roles. There remains a significant challenge for medical school curricula to address professional areas where graduates felt less prepared.

Insights into rural generalist therapeutic reasoning using a simulated multi-patient emergency scenario.

INTRODUCTION: Therapeutic reasoning focuses on the decisions related to patient disposition and management. This is in contrast to diagnostic reasoning, which is the focus of much of the current discourse in the medical literature. Few studies relate to therapeutic reasoning, and even fewer relate to the rural and remote context. This project sought to explore the therapeutic reasoning used by rural generalists working in a small rural hospital setting in Australia, caring for patients for whom it was unclear if escalation of care, including admission or interhospital transfer, was needed. METHODS: This study was conducted using an interpretivist approach. A simulation scenario was developed with rural generalists and experts in medical simulation to use as a test bed to explore the reasoning of the rural generalist participants. The simulation context was a small rural Australian hospital with resources and treatment options typical of those found in a similar real-life setting. A simulated patient and a registered nurse were embedded in the scenario. Participants needed to make decisions throughout the scenario regarding the simulated patient and two anticipated patients who were said to be coming to the department. The scenario was immediately followed by a semi-structured interview exploring participants' therapeutic reasoning when planning care for these three patients. An inductive content analysis approach was used to analyse the data, and a mental model was developed. The researchers then tested this mental model against the recordings of the participants' simulation scenarios. RESULTS: Eight rural generalists, with varying levels of experience, participated in this study. Through the semi-structured interviews, participants described five themes: assessing clinician capacity to manage patient needs; availability of local physical resources and team members; considering options for help when local management was not enough; patients' wishes and shared decision making; and anticipating future requirements. The mental model developed from these themes consisted of seven questions: 'What can I do for this patient locally and what are my limits?'; 'Who is in my team and who can I rely on?'; 'What are the advantages and disadvantages of local management vs transfer?'; 'Who else needs to be involved and what are their limits?;' 'How can we align the patient's wants with their needs?'; 'How do we adapt to the current and future situation?'; and 'How do I preserve the capacity of the health service to provide care?' CONCLUSION: This study explored the therapeutic reasoning of rural generalists using a simulated multi-patient emergency scenario. The mental model developed serves as a starting point when discussing therapeutic reasoning and is likely to be useful when providing education to medical students and junior doctors who are working in rural and remote contexts where resources and personnel may be limited.

Contemporary Australian socio-cultural factors and their influence on medical student rural career intent.

OBJECTIVE: To understand how contemporary socio-cultural factors may impact medical students' rural career intent. DESIGN: Cross-sectional study using data from the national Federation of Rural Australian Medical Educators survey. PARTICIPANTS/SETTING: Medical students across 18 Australian universities who completed a full academic year of clinical training in rural areas in 2019. MAIN OUTCOME MEASURE(S): Preferred location of practice post-training reported to be either: (i) a major city; (ii) a regional area or large town; or (iii) a small rural location. RESULTS: In total, 626 students completed the survey (70.1% response rate). A small rural location was the most preferred location of practice after graduation for 28.3% of the students (95% CI 21.6-36.0). Four socio-cultural factors were positively associated with a preference for a rural career location: poor health status of rural people, motor vehicle traffic congestion in cities, rural generalist training opportunities in the state and the Royal Flying Doctor Service. Other socio-cultural factors, including specialists' under-employment, Medicare freeze effect on doctors' income, bullying/sexual harassment in hospitals, climate change/natural disasters or recognised rural health personalities did not influence the investigated outcome. CONCLUSIONS: Our findings indicate a novel association between contemporary socio-cultural factors and rural career intention in a cohort of Australian rural clinical school students. These findings advocate for further consideration of research exploring socio-cultural factors shaping rural career intent and workforce outcomes.

The role of withdrawal in mesocorticolimbic drug cue reactivity in opioid use disorder.

Opioid use disorder (OUD) is characterized by heightened cognitive, physiological, and neural responses to opioid-related cues that are mediated by mesocorticolimbic brain pathways. Craving and withdrawal are key symptoms of addiction that persist during physiological abstinence. The present study evaluated the relationship between the brain response to drug cues in OUD and baseline levels of craving and withdrawal. We used functional magnetic resonance imaging (fMRI) to examine brain responses to opioid-related pictures and control pictures in 29 OUD patients. Baseline measures of drug use severity, opioid craving, and withdrawal symptoms were assessed prior to cue exposure and correlated with subsequent brain responses to drug cues. Mediation analysis was conducted to test the indirect effect of drug use severity on brain cue reactivity through craving and withdrawal symptoms. We found that baseline drug use severity and opioid withdrawal symptoms, but not craving, were positively associated with the neural response to drug cues in the nucleus accumbens, orbitofrontal cortex, and amygdala. Withdrawal, but not craving, mediated the effect of drug use severity on the nucleus accumbens' response to drug cues. We did not find similar effects for the neural responses to stimuli unrelated to drugs. Our findings emphasize the central role of withdrawal symptoms as the mediator between the clinical severity of OUD and the brain correlates of sensitization to opioid-related cues. They suggest that in OUD, baseline withdrawal symptoms signal a high vulnerability to drug cues.

Low pre-operative heart rate variability and complexity are associated with hypotension after anesthesia induction in major abdominal surgery.

Significant hypotension after induction of general anesthesia is common and has the potential for serious complications. This study aimed to determine if pre-operative heart rate variability (HRV) was associated with post-induction hypotension in patients undergoing major abdominal surgery. Patients undergoing semi-elective major abdominal surgery were consecutively recruited during pre-admission clinic assessment. Exclusion criteria included cardiac conduction disease, arrhythmias or severe liver or renal disease. Ten minutes of electrocardiogram at 1024 Hz were recorded a median of 3 days pre-operatively. Pre-operative HRV parameters were compared in patients who experienced significant hypotension (fall in systolic and mean arterial pressure (MAP) >30% baseline and MAP ≤60 mmHg) versus those who remained haemodynamically stable after induction of general anesthesia with propofol and fentanyl. Patients who experienced hypotension after general anesthesia induction had significantly lower pre-operative HRV (SDNN 16 vs. 37 ms, p < 0.001), reduced spectral power (total power 262 vs. 1236 ms2, p = 0.002) and reduced correlation dimension, a measure of signal complexity (0.11 vs. 2.13, p < 0.001). Hypotension occurred relatively frequently in our cohort and was associated with a higher ASA grade (36 vs. 6% ASA 3, p = 0.036), hence post-induction hypotension and lower HRV may be associated with severity of illness or poor physiological reserve. Pre-operative HRV was a useful screening tool in identifying patients undergoing major abdominal surgery who were at risk of haemodynamic instability after anesthesia induction.

The effect of intravenous lidocaine infusion on bispectral index during major abdominal surgery.

Intraoperative lidocaine infusion has become widely accepted as an adjunct to general anesthesia where its use has been associated with opioid-sparing and enhanced recovery. The aims of this study were to determine whether or not intravenous (IV) lidocaine infusion (a) has an anesthetic sparing effect during major colorectal procedures and (b) if it also affects level of hypnosis as measured by bispectral index (BIS). Twenty-five patients undergoing laparotomy for resection of colorectal tumours were randomized to receive either IV lidocaine (1.5 mg kg-1 bolus then 1 mg kg-1 per hour) or an equivalent volume of normal saline commenced after intravenous induction of general anesthesia. Anesthesia was maintained with volatile anesthetic agent combined with intermittent IV fentanyl titrated to hemodynamic stability. Minimum alveolar concentration (MAC) of volatile was calculated using an age-adjusted algorithm (corrected MAC). BIS values were recorded throughout; however, treating anesthesiologists were blinded to BIS values and hence they were not used to guide depth of anesthesia. No other regional anesthesia techniques were used. During the maintenance phase of anesthesia, corrected MAC of volatile agent was lower (1.0 versus 1.1, p = 0.003); whereas BIS values were higher (45 versus 39, p < 0.001) in patients who received lidocaine versus placebo. No differences in mean arterial pressure (80 versus 80 mmHg, p = 0.796) or total fentanyl dose (538 versus 444 mcg, p = 0.24) were observed between the two groups. Heart rate was slightly higher in patients who received lidocaine versus placebo (67 versus 64 bpm, p = 0.001). Lidocaine infusion resulted in mean plasma levels of 1.7 mcg ml-1 (1.3-2.0 mcg ml-1, 95% CI). Our results support an anesthetic sparing effect of lidocaine infusion indicated by lower MAC requirements. Higher BIS values in the lidocaine versus placebo group may indicate that levels of hypnosis were not equivalent. Alternatively, BIS may not be a sensitive indicator of synergistic interactions between local anesthetic and volatile agent. Our results advocate a cautious approach to titration of general anesthesia when combined with lidocaine infusion.

Mapping simulation-based activities for health professionals in rural and remote contexts in high-income countries: a scoping review protocol.

OBJECTIVE: This scoping review will aim to map the existing academic literature on simulation-based activities that are designed with and delivered for health professionals in geographically rural and remote contexts in high-income countries. INTRODUCTION: Simulation-based health care activities are implemented in health services to increase patient safety because they allow health professionals to prepare, learn, practice, rehearse, and improve clinical performance and teamwork. Simulation-based activities are increasingly being used in rural and remote areas, where resources are limited compared with metropolitan areas. INCLUSION CRITERIA: This review will include all primary and peer-reviewed research articles and abstracts that report health simulation methodologies and activities that have been used in rural and remote health care contexts in high-income countries. METHODS: The proposed review will follow the JBI guidelines for scoping reviews and the PRISMA-ScR reporting guidelines. Databases to be searched will include Embase, Emcare, and MEDLINE (all searched via Ovid), Scopus, PubMed, and the Cochrane Database. The title and abstracts will be screened independently by 2 reviewers, followed by full-text screening. Data will be extracted and analyzed to address the review questions. DETAILS OF THIS REVIEW CAN BE FOUND IN OPEN SCIENCE FRAMEWORK: https://doi.org/10.17605/OSF.IO/PU6GV.

An analysis of risk factors for venous thromboembolism in primary versus revision total joint arthroplasty.

Background: One of the most serious complications after primary or revision lower extremity total joint arthroplasty (TJA) is venous thromboembolism disease (VTE). Identifying patients at high risk for VTE allows tailoring of prophylactic anticoagulation regimens to those most vulnerable. This study aimed to identify risk factors for VTE in primary and revision lower extremity TJA. Methods: The Electronic Medical Record was queried from a single academic institution for all patients who underwent a lower extremity TJA between 2007 and 2020. Demographics, comorbid conditions, perioperative characteristics, and postoperative complications were identified. An Elastic Net Multiple Logistic Regression Model was used to assess 49 covariates and predict those associated with a significant risk of VTE. Results: We identified 4900 primary and revision total knee arthroplasty (TKA) and total hip arthroplasty (THA) patients. There was no significant difference between primary and revision THA. Primary TKA had a higher rate of VTE than revision TKA. Significant risk factors identified for VTE in THA patients include histories of deep vein thrombosis (DVT), pulmonary embolism (PE), metastatic tumors, hemiplegia, and Hispanic ethnicity. Risk factors for VTE in TKA patients include histories of DVT, PE, metastatic tumors, and postoperative warfarin and heparin use. In all patients, age was a significant predictor of VTE risk. Conclusion: Our work identifies many risk factors for VTE following TJA. While the increased rate of VTE in some populations may represent selection bias, it also highlights the incomplete understanding of the etiology and prevention of this complication in the joint arthroplasty population and requires further study.

Effects of emotional arousal on the neural impact and behavioral efficacy of cigarette graphic warning labels.

BACKGROUND AND AIMS: Graphic warning labels (GWLs) on cigarette packs have been adopted by many jurisdictions world-wide. In the United States, the introduction of GWLs has been delayed by claims that their high level of negative emotional arousal unnecessarily infringed upon the tobacco manufacturers' free speech. This study aimed to provide experimental data on the contribution of emotional arousal to GWL efficacy. DESIGN: Observational study using long-term naturalistic exposure and functional magnetic resonance imaging. SETTING: Research university in Philadelphia, PA, USA. PARTICIPANTS: A total of 168 adult smokers. MEASUREMENTS: For 4 weeks, participants received cigarettes in packs that carried either high-arousal or low-arousal GWLs (n = 84 versus 84). Smoking behavior, quitting-related cognitions and GWL-induced brain response were measured before and after the 4-week exposure. The amygdala and medial prefrontal cortex served as regions of interest. FINDINGS: Compared with the high-arousal group, the low-arousal group smoked fewer cigarettes [log10 -transformed, 1.076 versus 1.019; difference = 0.056, 95% confidence interval (CI) = 0.027, 0.085, χ2 (1)  = 14.21, P < 0.001] and showed stronger intention to quit (2.527 versus 2.810; difference = -0.283, 95% CI = -0.468, -0.098, χ2 (1) = 8.921, P = 0.007) and endorsement of the GWLs' textual component (4.805 versus 5.503; difference = -0.698, 95% CI = -1.016, -0.380, χ2 (1) = 18.47, P < 0.001). High-arousal GWLs induced greater amygdala response than low-arousal GWLs (0.157 versus 0.052; difference = 0.105, 95% CI = 0.049, 0.161, χ2 (1) = 23.52, P < 0.001), although the response to high-arousal GWLs declined over time (slope = -0.087 versus 0.016; difference = -0.103, 95% CI = -0.198, -0.009, χ2 (1) = 6.370, P = 0.046). Greater baseline amygdala response was associated with more smoking at 4 weeks in the high-arousal group, but less smoking in the low-arousal group (slope = 0.179 versus -0.122; difference = 0.287, 95% CI = 0.076, 0.498, χ2 (1) = 7.086, P = 0.008). Medial prefrontal response did not differ significantly between groups. CONCLUSIONS: High-arousal cigarette graphic warning labels (GWLs) appear to be less efficacious than low-arousal GWLs. The high emotional reaction that high-arousal GWLs elicit wanes over time. Baseline amygdala response negatively predicts efficacy of high-arousal GWLs and positively predicts efficacy of low-arousal GWLs. High emotional arousal may not be required for sustained GWL efficacy.

Neurocardiogenic pulmonary oedema: initial presentation of multiple sclerosis.

A previously healthy 20 year-old male presented with headache, acute pulmonary oedema and left ventricular dysfunction requiring intensive care admission. Cardiorespiratory symptoms resolved within three days; however, the patient complained of persistent headache and had gait unsteadiness. Magnetic resonance imaging showed a large demyelinating lesion in the caudal medulla with scattered cerebral plaques. The patient was subsequently diagnosed with multiple sclerosis. This case describes a rare initial presentation of multiple sclerosis with acute pulmonary oedema and cardiac dysfunction secondary to a lower brainstem lesion.

Five-year analysis of operative mortality and neonatal outcomes in congenital heart disease.

BACKGROUND: We sought to compare overall mortality with neonatal outcomes over a five year period to define risk factors for mortality and service development priorities. METHODS: A retrospective cohort study of surgical outcomes following repair or palliation of structural congenital heart defects January 2005-2010. We defined mortality according to contemporary international guidelines and classified surgical procedures using the Risk Adjustment in Congenital Heart Surgery (RACHS-1) score. The effect of age and weight at operation on mortality and annual variation in case-complexity and surgeon case-mix were assessed. Subgroup analysis was performed in patients who were ≤30 days at operation (neonates). RESULTS: Overall mortality within 30 days of operation or prior to hospital discharge was 1.3 and 1.9%, respectively. Mortality was higher in neonates (6.8%) and low birth weight infants (≤2.5kg) (12.1%). Mortality was similar in bypass versus non-bypass procedures (odds ratio 0.74, p=0.425). Annual mortality rates were consistent despite a marked increase in case-complexity. Neonates overall required longer periods of intensive care support and were more likely to suffer serious complications compared to older children. Age, weight and RACHS-1 score were independent risk factors for mortality on multivariate analysis. In neonates undergoing bypass procedures, only RACHS-1 score was a significant risk factor. CONCLUSIONS: This study provides an accurate and contemporary audit of mortality risk associated with congenital heart surgery. Outcomes compare favourably to international benchmarks but highlight the risks of morbidity and mortality associated with neonatal cardiac surgery.

Transitioning from university to postgraduate medical training: A narrative review of work readiness of medical graduates.

CONTEXT: Work readiness is often described in terms of the clinical competence medical graduates bring to day 1 of internship. Despite being increasingly viewed as a key graduate outcome, work readiness has remained poorly defined. OBJECTIVE: This narrative review draws on the international literature to explore how different research methods provide differing insight into what constitutes work readiness of medical graduates. From this, we explored contributory factors and developed a conceptual framework to better understand work readiness. METHODS: Databases were searched using the terms including "ready," "readiness," "preparedness," "medical graduates," "intern," and "junior doctor." Information was summarized using a textual description template that included information on study setting, participants, methodologies, limitations, and key result areas (including measures/themes and study conclusions). Consensus discussions between authors led to the naming and understanding of the key themes. RESULTS: Seventy studies were included in the review. Study participants included final-year medical students (n = 20), junior doctors early in internship (n = 24), and junior doctors late in internship or postgraduate year 2 and above (n = 23). Most studies explored work readiness through the retrospective self-report of the students and/or junior doctor participants. Quantitative research methods elaborated on key skills-based competencies, whereas qualitative research methods provided insight into key contextual and individual characteristics that contributed to preparedness. CONCLUSIONS: Different research methods provided insight into competencies, as well as individual and contextual aspects, associated with preparedness for practice. The transition from university to clinical practice is significant and requires personal capability and confidence, as well as a supportive training context. Enabling students to engage authentically in clinical environments enhanced preparedness by promoting understanding of role and responsibility. Individual resilience is important, but contextual factors, including provision of adequate support and feedback, can enhance or subtract from feeling prepared. We propose a novel conceptual framework for better understanding work readiness.

Multiorgan failure following gastroenteritis: a case report.

BACKGROUND: This report highlights the first published case of fatal septic shock associated with Clostridium perfringens and Enterococcus avium bacteremia due to infective gastroenteritis. CASE PRESENTATION: We report a case of hepatic infarction, abscess, and death following gastroenteritis in a 63-year-old Aboriginal man who initially presented to a rural hospital with suspected food poisoning. The patient had persistent fever and was commenced on empirical antibiotics. His blood culture results were positive for Clostridium perfringens and Enterococcus avium. He was transferred to a tertiary center but developed organ failure and refractory shock. Initial computed tomography of the abdomen was unremarkable, but repeat imaging showed small bowel enteritis, hepatic abscess, and infarction as a result of portal vein septic thromboembolism. Despite maximal intensive care treatment, including percutaneous drainage of hepatic abscess and broad antibiotic cover, the patient died 6 days after initial presentation. CONCLUSIONS: This case highlights the rare but commonly fatal course of sepsis associated with Clostridium perfringens bacteremia and demonstrates detrimental effects of coinfection with Enterococcus avium, including potential for rapidly seeding abscess formation. Lessons for rural practice are highlighted, including the need for urgent and early referral for intensive care support, particularly for patients with complex comorbidities.

Central command regulation of circulatory function mediated by descending pontine cholinergic inputs to sympathoexcitatory rostral ventrolateral medulla neurons.

Central command is a feedforward neural mechanism that evokes parallel modifications of motor and cardiovascular function during arousal and exercise. The neural circuitry involved has not been elucidated. We have identified a cholinergic neural circuit that, when activated, mimics effects on tonic and reflex control of circulation similar to those evoked at the onset of and during exercise. Central muscarinic cholinergic receptor (mAChR) activation increased splanchnic sympathetic nerve activity (SNA) as well as the range and gain of the sympathetic baroreflex via activation of mAChR in the rostral ventrolateral medulla (RVLM) in anesthetized artificially ventilated Sprague-Dawley rats. RVLM mAChR activation also attenuated and inhibited the peripheral chemoreflex and somatosympathetic reflex, respectively. Cholinergic terminals made close appositions with a subpopulation of sympathoexcitatory RVLM neurons containing either preproenkephalin mRNA or tyrosine hydroxylase immunoreactivity. M2 and M3 receptor mRNA was present postsynaptically in only non-tyrosine hydroxylase neurons. Cholinergic inputs to the RVLM arise only from the pedunculopontine tegmental nucleus. Chemical activation of this region produced increases in muscle activity, SNA, and blood pressure and enhanced the SNA baroreflex; the latter effect was attenuated by mAChR blockade. These findings indicate a novel role for cholinergic input from the pedunculopontine tegmental nucleus to the RVLM in central cardiovascular command. This pathway is likely to be important during exercise where a centrally evoked facilitation of baroreflex control of the circulation is required to maintain blood flow to active muscle.

A novel pressor area at the medullo-cervical junction that is not dependent on the RVLM: efferent pathways and chemical mediators.

Chemical stimulation of a region extending from the most caudal ventrolateral medulla into the upper cervical spinal cord evoked large sympathetically mediated pressor responses. These responses were not dependent on the integrity of the rostral ventrolateral medulla (RVLM) and may be mediated by glutamatergic neurons embedded in the white matter that project to the thoracic spinal cord. We term this new region the medullo-cervical pressor area (MCPA). This region is distinct from the caudal pressor area, because blockade of the RVLM with muscimol inhibited this pressor response but not that evoked from the MCPA. This is the first study to provide functional evidence for a cardiovascular role for neurons in the cervical spinal cord white matter that innervate sympathetic preganglionic neurons (Jansen and Loewy, 1997). Using retrograde tracing, in combination with immunohistochemistry and in situ hybridization, we identified two groups of spinally projecting neurons in the region. Approximately 50% of neurons in one group were excitatory because they contained vesicular glutamate transporter 1 (VGluT1)/VGluT2 mRNA, whereas the other contained a mixed population of neurons, some of which contained either VGluT1/VGluT2 or GAD67 (glutamic acid decarboxylase 67) mRNA. Despite the fact that activation of the MCPA causes potent sympathoexcitation, it does not act to restore arterial pressure after chemical lesion of the RVLM so that a role for this novel descending sympathoexcitatory region remains to be elucidated.

Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats.

1. The nature of the cardiorespiratory effects mediated by cannabinoids in the hindbrain is poorly understood. In the present study we investigated whether cannabinoid receptor activation in the rostral ventrolateral medulla oblongata (RVLM) affects cardiovascular and/or respiratory function. 2. Initially, we looked for evidence of CB1 receptor gene expression in rostral and caudal sections of the rat ventrolateral medulla (VLM) using reverse transcription-polymerase chain reaction. Second, the potent cannabinoid receptor agonists WIN55,212-2 (0.05, 0.5 or 5 pmol per 50 nl) and HU-210 (0.5 pmol per 50 nl) or the CB1 receptor antagonist/inverse agonist AM281 (1 pmol per 100 nl) were microinjected into the RVLM of urethane-anaesthetised, immobilised and mechanically ventilated male Sprague-Dawley rats (n=22). Changes in splanchnic nerve activity (sSNA), phrenic nerve activity (PNA), mean arterial pressure (MAP) and heart rate (HR) in response to cannabinoid administration were recorded. 3. The CB1 receptor gene was expressed throughout the VLM. Unilateral microinjection of WIN55,212-2 into the RVLM evoked short-latency, dose-dependent increases in sSNA (0.5 pmol; 175+/-8%, n=5) and MAP (0.5 pmol; 26+/-3%, n=8) and abolished PNA (0.5 pmol; duration of apnoea: 5.4+/-0.4 s, n=8), with little change in HR (P<0.005). HU-210, structurally related to Delta9-tetrahydrocannabinol (THC), evoked similar effects when microinjected into the RVLM (n=4). Surprisingly, prior microinjection of AM281 produced agonist-like effects, as well as significantly attenuated the response to subsequent injection of WIN55,212-2 (0.5 pmol, n=4). 4. The present study reveals CB1 receptor gene expression in the rat VLM and demonstrates sympathoexcitation, hypertension and respiratory inhibition in response to RVLM-administered cannabinoids. These findings suggest a novel link between CB1 receptors in this region of the hindbrain and the central cardiorespiratory effects of cannabinoids. The extent to which these central effects contribute to the cardiovascular and respiratory outcomes of cannabis use remains to be investigated.

Differential muscarinic receptor gene expression levels in the ventral medulla of spontaneously hypertensive and Wistar-Kyoto rats: role in sympathetic baroreflex function.

OBJECTIVE: We demonstrated previously that central muscarinic cholinergic receptor (mAChR) activation increased splanchnic sympathetic nerve activity and sympathetic baroreflex function via activation of mAChR in the rostral ventrolateral medulla (RVLM), and we found that some RVLM bulbospinal neurons contain muscarinic M2R mRNA. Here, we examined the gene expression, cellular distribution and functional role of muscarinic receptors in the RVLM in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto (WKY) rats. METHOD AND RESULTS: Using the sensitive technique of quantitative real time reverse transcriptase-PCR, M2R mRNA level was elevated two-fold (P<0.05) and M4R mRNA was downregulated two-fold (P<0.001), with all other receptors expressed at similar levels, in the rostral ventral medulla of SHR compared with WKY. Bulbospinal, but not catecholaminergic neurons, in the RVLM expressed M2R mRNA (M2RR), and similar numbers were found in the RVLM of SHR and WKY. Could elevated M2R within individual neurons or enhanced presynaptic activity reflects enhanced cholinergic effects in the RVLM? Activation of central mAChR using oxotremorine evoked a larger increase in mean arterial pressure in SHR compared with WKY (P<0.01); however, oxotremorine-induced increases in splanchnic sympathetic nerve activity, and sympathetic baroreflex function were similar in SHR and WKY. CONCLUSION: These data indicate that enhanced pressor responses in SHR, following centrally mediated mAChR activation, are not associated with RVLM-mediated constriction of the splanchnic circulation or effects on the sympathetic baroreflex, but could reflect modified mAChR gene expression elsewhere. RVLM-dependent splanchnic sympathetic nerve activity effects, evoked by mAChR activation, are not mediated by the differential M2/M4 receptor mRNA levels identified in SHR compared with WKY.

Impaired serotonergic regulation of heart rate may underlie reduced baroreflex sensitivity in an animal model of depression.

Serotonin (5-HT) is crucial to normal reflex vagal modulation of heart rate (HR). Reduced baroreflex sensitivity [spontaneous baroreflex sensitivity (sBRS)] and HR variability (HRV) reflect impaired neural, particularly vagal, control of HR and are independently associated with depression. In conscious, telemetered Flinders-Sensitive Line (FSL) rats, a well-validated animal model of depression, we tested the hypothesis that cardiovascular regulatory abnormalities are present and associated with deficient serotonergic control of reflex cardiovagal function. In FSL rats and control Flinders-Resistant (FRL) and Sprague-Dawley (SD) rat strains, diurnal measurements of HR, arterial pressure (AP), activity, sBRS, and HRV were made. All strains had normal and similar diurnal variations in HR, AP, and activity. In FRL rats, HR was elevated, contributing to the reduced HRV and sBRS in this strain. In FSL rats, sBRS and high-frequency power HRV were reduced during the night, indicating reduced reflex cardiovagal activity. The ratio of low- to high-frequency bands of HRV was increased in FSL rats, suggesting a relative predominance of cardiac sympathetic and/or reflex activity compared with FRL and SD rats. These data show that conscious FSL rats have cardiovascular regulatory abnormalities similar to depressed humans. Acute changes in HR, AP, temperature, and sBRS in response to 8-hydroxy-2-(di-n-propylamino)tetralin, a 5-HT(1A), 5-HT(1B), and 5-HT(7) receptor agonist, were also determined. In FSL rats, despite inducing an exaggerated hypothermic effect, 8-hydroxy-2-(di-n-propylamino)tetralin did not decrease HR and AP or improve sBRS, suggesting impaired serotonergic neural control of cardiovagal activity. These data suggest that impaired serotonergic control of cardiac reflex function could be one mechanism linking reduced sBRS to increased cardiac risk in depression.

Impaired cardiac and sympathetic autonomic control in rats differing in acetylcholine receptor sensitivity.

Acetylcholine receptors (AChR) are important in premotor and efferent control of autonomic function; however, the extent to which cardiovascular function is affected by genetic variations in AChR sensitivity is unknown. We assessed heart rate variability (HRV) and baroreflex sensitivity (BRS) in rats bred for resistance (FRL) or sensitivity (FSL) to cholinergic agents compared with Sprague-Dawley rats (SD), confirmed by using hypothermic responses evoked by the muscarinic agonist oxotremorine (0.2 mg/kg i.p.) (n > or = 9 rats/group). Arterial pressure, ECG, and splanchnic sympathetic (SNA) and phrenic (PNA) nerve activities were acquired under anesthesia (urethane 1.3 g/kg i.p.). HRV was assessed in time and frequency domains from short-term R-R interval data, and spontaneous heart rate BRS was obtained by using a sequence method at rest and after administration of atropine methylnitrate (mATR, 2 mg/kg i.v.). Heart rate and SNA baroreflex gains were assessed by using conventional pharmacological methods. FRL and FSL were normotensive but displayed elevated heart rates, reduced HRV and HF power, and spontaneous BRS compared with SD. mATR had no effect on these parameters in FRL or FSL, indicating reduced cardiovagal tone. FSL exhibited reduced PNA frequency, longer baroreflex latency, and reduced baroreflex gain of heart rate and SNA compared with FRL and SD, indicating in FSL dual impairment of cardiac and circulatory baroreflexes. These findings show that AChR resistance results in reduced cardiac muscarinic receptor function leading to cardiovagal insufficiency. In contrast, AChR sensitivity results in autonomic and respiratory abnormalities arising from alterations in central muscarinic and or other neurotransmitter receptors.