High-dose trimethoprim-sulfamethoxazole and clindamycin for Staphylococcus aureus endocarditis.

OBJECTIVE: The mortality rate for Staphylococcus aureus endocarditis remains as high as 20-30% despite improvements in medical and surgical treatment. This study evaluated the efficiency and tolerance of a combination of intravenous trimethoprim-sulfamethoxazole and clindamycin (T&C) +/- rifampicin and gentamicin, with a rapid switch to oral administration of T&C. METHODS: This before-after intervention study compared the outcomes of 170 control patients before introduction of the T&C protocol (2001-2011) with the outcomes of 171 patients in the T&C group (2012-2016). All patients diagnosed with S. aureus infective endocarditis and referred to the study centre between 2001 and 2016 were included. Between 2001 and 2011, the patients received a standardized antibiotic treatment: oxacillin or vancomycin for 6 weeks, plus gentamicin for 5 days. Since February 2012, the antibiotic protocol has included a high dose of T&C (intravenous, switched to oral administration on day 7). Rifampicin and gentamicin are also given in cases of cardiac abscess or persistent bacteraemia. RESULTS: The two groups were slightly different. On intention-to-treat analysis, global mortality (19% vs 30%, P=0.024), in-hospital mortality (10% vs 18%, P=0.03) and 30-day mortality (7% vs 14%, P=0.05) were lower in the T&C group. The mean duration of hospital stay was significantly shorter in the T&C group (30 vs 39 days; P=0.005). CONCLUSIONS: The management of S. aureus infective endocarditis using a rapid shift to oral administration of T&C reduced the length of hospital stay and the mortality rate.

Targeted panel sequencing in adult patients with left ventricular non-compaction reveals a large genetic heterogeneity.

Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin; however, few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy.

Intracranial haemorrhage in infective endocarditis.

BACKGROUND: Although intracranial cerebral haemorrhage (ICH) complicating infective endocarditis (IE) is a critical clinical issue, its characteristics, impact, and prognosis remain poorly known. AIMS: To assess the incidence, mechanisms, risk factors and prognosis of ICH complicating left-sided IE. METHODS: In this single-centre study, 963 patients with possible or definite left-sided IE were included from January 2000 to December 2015. RESULTS: Sixty-eight (7%) patients had an ICH (mean age 57±13 years; 75% male). ICH was classified into three groups according to mechanism: ruptured mycotic aneurysm (n=22; 32%); haemorrhage after ischaemic stroke (n=27; 40%); and undetermined aetiology (n=19; 28%). Five variables were independently associated with ICH: platelet count<150×109/L (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.01-5.4; P=0.049); severe valve regurgitation (OR 3.2, 95% CI 1.3-7.6; P=0.008); ischaemic stroke (OR 4.2, 95% CI 1.9-9.4; P<0.001); other symptomatic systemic embolism (OR 14.1, 95% CI 5.1-38.9; P<0.001); and presence of mycotic aneurysm (OR 100.2, 95% CI 29.2-343.7; P<0.001). Overall, 237 (24.6%) patients died within 2.3 (0.7-10.4) months of follow-up. ICH was not associated with increased mortality (P not significant). However, the 1-year mortality rate differed according to ICH mechanism: 14%, 15% and 45% in patients with ruptured mycotic aneurysm, haemorrhage after ischaemic stroke and undetermined aetiology, respectively (P=0.03). In patients with an ICH, mortality was higher in non-operated versus operated patients when cardiac surgery was indicated (P=0.005). No operated patient had neurological deterioration. CONCLUSIONS: ICH is a common complication of left-sided IE. The impact on prognosis is dependent on mechanism (haemorrhage of undetermined aetiology). We observed a higher mortality rate in patients who had conservative treatment when cardiac surgery was indicated compared with in those who underwent cardiac surgery.

Apical four-chamber longitudinal left ventricular strain in patients with aortic stenosis and preserved left ventricular ejection fraction: analysis related with flow/gradient pattern and association with outcome.

Aims: To evaluate the prognostic value of apical four-chamber (A4-C) longitudinal strain (LS) in patients with aortic stenosis (AS). Methods and results: In a multicentre cohort, 582 patients (74.3 ± 10.9 years) with moderate or severe AS and preserved left ventricular (LV) ejection fraction (≥50%) were included in this retrospective study. Patients with severe AS were classified in four subgroups according to flow and gradient: low flow (LF) was defined as a stroke volume index <35 mL/m2 compared with normal flow (NF); low-gradient (LG) as a mean gradient <40 mmHg compared with high gradient (HG). The end point was all-cause of mortality. A4-C LS was measured by two-dimensional speckle tracking and was feasible in all patients. The degree of A4-C LV longitudinal dysfunction increased according to the severity and subgroups of severe AS: from the least to the most impaired: moderate AS, NF/HG, NF/LG, LF/HG, and LF/LG AS (P < 0.001). During a mean follow-up of 2.6 ± 0.2 years, 58(10%) patients died. The 2-year survival was 76.8% in patients with LF/LG vs. 89.3% in patients with other groups. The best threshold of A4-C LS associated with overall mortality was an absolute cut-off value of |13.75%|. According to this cut-off, the 2-year survival was higher both in patients with moderate AS (96.3 vs. 70%, P = 0.02) and those with severe AS (92.9 vs. 80.9%, P = 0.005). However when dichotomized according to flow/gradient patterns, the association was only statistically significant in the subgroup of patients with NF/HG. By multivariable cox regression analysis, A4-C LS <|13.75| remained independently associated with overall mortality (hazard ratio: 1.8; P = 0.045). Conclusion: A4-C LS is independently associated with death in patients with AS and preserved LVEF, however the flow/gradient pattern should also be considered as an important parameter. The management of these patients may use A4-C LS as a new parameter of evaluation of LV function and prognosis.

Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study.

BACKGROUND: Left atrial (LA) enlargement is frequent in patients with aortic stenosis (AS), yet its determinants and prognostic implications are poorly understood. AIMS: To identify the echocardiographic variables associated with increased LA volume index (LAVI), and test the prognostic value of LAVI in AS. METHODS: We prospectively included 715 patients with AS in sinus rhythm at enrolment. Echocardiography was performed at baseline. Median follow-up was 22.0 (9-34) months. Patients were divided into two groups according to the best cut-off for event prediction during follow-up (45mL/m2). RESULTS: Compared with LAVI<45mL/m2, patients with LAVI≥45mL/m2 had a lower stroke volume, cardiac output and left ventricular (LV) ejection fraction, greater LV volumes and mass and higher filling pressures. By linear regression, LAVI was best correlated with E wave mitral velocity (r=0.34), E/A ratio (r=0.34), E/e' ratio (r=0.28), indexed LV mass (r=0.29), systolic pulmonary artery pressure (r=0.34) and LV longitudinal strain (r=-0.28). Multivariable analysis confirmed the independent association of LAVI with age (P<0.001), indexed aortic valve area (P=0.04), indexed LV mass (P<0.001), LV ejection fraction (P=0.007), LV end-diastolic volume (P=0.001), E/A ratio (P<0.001) and E/e' ratio (P<0.001). LAVI≥45mL/m2 was independently predictive of the combined endpoint of cardiovascular death or hospitalization for heart failure (adjusted hazard ratio 1.69, 95% confidence interval 1.04-2.73). CONCLUSION: LA enlargement is correlated with AS severity, but also with variables reflecting LV systolic and diastolic dysfunction. Further studies are needed to investigate the outcome implication of LA enlargement in patients with AS.

Coronary events complicating infective endocarditis.

OBJECTIVE: Acute coronary syndromes (ACS) are a rare complication of infective endocarditis (IE). Only case reports and small studies have been published to date. We report the largest series of ACS in IE. The aim of our study was to describe the incidence and mechanisms of ACS associated with IE, to assess their prognostic impact and to describe their management. METHODS: In a bicentre prospective observational cohort study, all patients with a definite diagnosis of IE were prospectively included. The incidence, mechanism and prognosis of patients with ACS were studied. RESULTS: Among 1210 consecutive patients with definite IE, 26 patients (2.2%) developed an ACS. Twenty-three patients (88%) had a coronary embolism. Two patients had coronary compression by an abscess or a pseudoaneurysm and one patient had an obstruction of his bioprosthesis and left coronary ostium by a large vegetation. Nineteen (73%) patients with ACS developed heart failure and this complication was 2.5 times more frequent than in patients without ACS (p<0.0001). In the ACS population, mortality rate was twice than the population without ACS. CONCLUSIONS: ACS is a rare complication of IE but is associated with an increased risk of heart failure and high mortality rate.

Risk score for cardiac surgery in active left-sided infective endocarditis.

OBJECTIVE: To develop and validate a calculator to predict the risk of in-hospital mortality in patients with active infective endocarditis (IE) undergoing cardiac surgery. METHODS: Thousand two hundred and ninety-nine consecutive patients with IE were prospectively recruited (1996-2014) and retrospectively analysed. Left-sided patients who underwent cardiac surgery (n=671) form our study population and were randomised into development (n=424) and validation (n=247) samples. Variables statistically significant to predict in-mortality were integrated in a multivariable prediction model, the Risk-Endocarditis Score (RISK-E). The predictive performance of the score and four existing surgical scores (European System for Cardiac Operative Risk Evaluation (EuroSCORE) I and II), Prosthesis, Age ≥70, Large Intracardiac Destruction, Staphylococcus, Urgent Surgery, Sex (Female) (PALSUSE), EuroSCORE ≥10) and Society of Thoracic Surgeons's Infective endocarditis score (STS-IE)) were assessed and compared in our cohort. Finally, an external validation of the RISK-E in a separate population was done. RESULTS: Variables included in the final model were age, prosthetic infection, periannular complications, Staphylococcus aureus or fungi infection, acute renal failure, septic shock, cardiogenic shock and thrombocytopaenia. Area under the receiver operating characteristic curve in the validation sample was 0.82 (95% CI 0.75 to 0.88). The accuracy of the other surgical scores when compared with the RISK-E was inferior (p=0.010). Our score also obtained a good predictive performance, area under the curve 0.76 (95% CI 0.64 to 0.88), in the external validation. CONCLUSIONS: IE-specific factors (microorganisms, periannular complications and sepsis) beside classical variables in heart surgery (age, haemodynamic condition and renal failure) independently predicted perioperative mortality in IE. The RISK-E had better ability to predict surgical mortality in patients with IE when compared with other surgical scores.

Infective endocarditis in octogenarians.

OBJECTIVE: To describe the characteristics of infective endocarditis (IE) in octogenarians and assess their prognosis. METHODS: Patients with definite IE hospitalised at a referral centre between July 2008 and July 2013 were prospectively included. A total of 454 patients were divided into three groups: 230 patients under 65 years old, 173 patients between 65 and 80 years old, and 51 patients over 80 years old. The main end point was 1-year mortality. RESULTS: One-year mortality was higher in the ≥80 years old group (37.3%) than in the <65 years old group (13%; p<0.001) and the 65-80 years old group (19.7%; p=0.009). Enterococci and Streptococcus gallolyticus were the more frequent micro-organisms. Embolism under antibiotic therapy (n=11 (21.6%), p=0.03) and renal failure (n=23 (51%), p=0.004) were more frequent in the ≥80 years old group. Among the ≥80 years old group, 38 patients had theoretical indication for surgery. Mortality was low (6.3%) in the 16 operated patients, but very high (72.7%) in the 22 patients not operated. Even if octogenarians were less often operated, their survival after surgery was excellent like younger patients (93.7%, 89.9% and 90.4%, respectively), whereas the absence of surgery was associated with very poor prognosis. CONCLUSIONS: IE in octogenarians is a different disease, with Enterococci as the most frequent micro-organisms and with higher mortality than younger patients. ESC recommendations for surgery are less implemented than in younger patients, yielding dramatic mortality in patients not operated despite a theoretical indication for surgery, while operated patients have an excellent prognosis. These results suggest that surgery is underused in octogenarians.

Evaluation of empirical treatment for blood culture-negative endocarditis.

OBJECTIVES: Much progress has been made in understanding the main causes of blood culture-negative endocarditis (BCNE). Few studies concerning BCNE treatment (due to previous antibiotics used or fastidious pathogens) are available. We performed this study to evaluate the effectiveness of our therapeutic protocol in BCNE, based on compliance with the protocol, outcome and 1 year mortality. PATIENTS AND METHODS: We collected prospectively and analysed retrospectively cases of BCNE between 2002 and 2014, using a simplified and standardized protocol developed by our multidisciplinary team. We apply two kinds of protocols to treat BCNE, which include only four intravenous antimicrobial agents: amoxicillin, vancomycin, gentamicin and amphotericin B. RESULTS: We had 177 patients with definite BCNE. There were 154 (87.0%) patients treated with both appropriate antimicrobial agents and appropriate duration of treatment. We analysed the causes of inappropriate treatment in 13 (7.3%) cases and inappropriate duration in 10 (5.6%) cases. The treatment changes were justified in all cases except one of discharge against medical advice. The fatality rate was 5.1% (nine cases) and all deaths occurred in the group of patients who were treated with appropriate treatment; however, four deaths were not attributable to empirical treatment failure. Concerning the other deaths, the lack of surgical management, in association with empirical treatment, could explain our protocol's failure, such as poorly tolerated surgery. CONCLUSIONS: Our protocol is efficient and our mortality rate was low, compared with the literature review. This may result from a strategy that uses a sampling procedure and a standardized protocol at the same time.

Dopamine, Neurochemical Processes, and Oxygen Toxicity at Pressure.

All mammals, including man, exposed to breathing gas mixtures at high pressures exhibit central nervous system disturbances, which differ according to the gas used. With the use of compressed air, the increased oxygen partial pressure induces hyperoxic disturbances that consist of epileptic seizures that occur, on average, after 30 min exposure to 2.8 ATA in man or to 5 ATA in rats. Increased oxygen partial pressure induces reactive oxygen species and reactive nitrogen species production that could be related to neurotransmitter changes reported for the preepileptic phase or at pressures that produce epileptic seizures. In rats, oxygen pressures lower than 5 ATA induce a decrease of dopamine release in the stratum that could be due to disturbances of neurotransmitter regulatory processes that are different from those implicated for hyperbaric oxygen-induced epileptic seizures. © 2016 American Physiological Society. Compr Physiol 6:1339-1344, 2016.

Neurochemistry of Pressure-Induced Nitrogen and Metabolically Inert Gas Narcosis in the Central Nervous System.

Gases that are not metabolized by the organism are thus chemically inactive under normal conditions. Such gases include the "noble gases" of the Periodic Table as well as hydrogen and nitrogen. At increasing pressure, nitrogen induces narcosis at 4 absolute atmospheres (ATAs) and more in humans and at 11 ATA and more in rats. Electrophysiological and neuropharmacological studies suggest that the striatum is a target of nitrogen narcosis. Glutamate and dopamine release from the striatum in rats are decreased by exposure to nitrogen at a pressure of 31 ATA (75% of the anesthetic threshold). Striatal dopamine levels decrease during exposure to compressed argon, an inert gas more narcotic than nitrogen, or to nitrous oxide, an anesthetic gas. Inversely, striatal dopamine levels increase during exposure to compressed helium, an inert gas with a very low narcotic potency. Exposure to nitrogen at high pressure does not change N-methyl-d-aspartate (NMDA) glutamate receptor activities in Substantia Nigra compacta and striatum but enhances gama amino butyric acidA (GABAA) receptor activities in Substantia Nigra compacta. The decrease in striatal dopamine levels in response to hyperbaric nitrogen exposure is suppressed by recurrent exposure to nitrogen narcosis, and dopamine levels increase after four or five exposures. This change, the lack of improvement of motor disturbances, the desensitization of GABAA receptors on dopamine cells during recurrent exposures and the long-lasting decrease of glutamate coupled with the higher sensitivity of NMDA receptors, suggest a nitrogen toxicity induced by repetitive exposures to narcosis. These differential changes in different neurotransmitter receptors would support the binding protein theory. © 2016 American Physiological Society. Compr Physiol 6:1579-1590, 2016.

Alteration of striatal dopamine levels under various partial pressure of oxygen in pre-convulsive and convulsive phases in freely-moving rats.

The purpose of this study was to investigate the change in the striatal dopamine (DA) level in freely-moving rat exposed to different partial pressure of oxygen (from 1 to 5 ATA). Some works have suggested that DA release by the substantia nigra pars compacta (SNc) neurons in the striatum could be disturbed by hyperbaric oxygen (HBO) exposure, altering therefore the basal ganglia activity. Such changes could result in a change in glutamatergic and GABAergic control of the dopaminergic neurons into the SNc. Such alterations could provide more information about the oxygen-induced seizures observed at 5 ATA in rat. DA-sensitive electrodes were implanted into the striatum under general anesthesia. After 1 week rest, awaked rats were exposed to oxygen-nitrogen mixture at a partial pressure of oxygen of 1, 2, 3, 4 and 5 ATA. DA level was monitored continuously (every 3 min) by in vivo voltammetry before and during HBO exposure. HBO induced a decrease in DA level in relationship to the increase in partial pressure of oxygen from 1 ATA to 4 ATA (-15 % at 1 ATA, -30 % at 2 ATA, -40 % at 3 ATA, -45 % at 4 ATA), without signs of oxygen toxicity. At 5 ATA, DA level strongly decreases (-75 %) before seizure which occurred after 27 min ± 7 HBO exposure. After the epileptic seizure the decrease in DA level disappeared. These changes and the biphasic effect of HBO were discussed in function of HBO action on neurochemical regulations of the nigro striatal pathway.

Low-flow, low-gradient severe aortic stenosis despite normal ejection fraction is associated with severe left ventricular dysfunction as assessed by speckle-tracking echocardiography: a multicenter study.

BACKGROUND: Low-flow low-gradient (LFLG) is sometimes observed in severe aortic stenosis (AS) despite normal ejection fraction, but its frequency and mechanisms are still debated. We aimed to describe the characteristics of patients with LFLG AS and assess the presence of longitudinal left ventricular dysfunction in these patients. METHODS AND RESULTS: In a multicenter prospective study, 340 consecutive patients with severe AS and normal ejection fraction were studied. Longitudinal left ventricular function was assessed by 2D-strain and global afterload by valvulo-arterial impedance. Patients were classified according to flow and gradient: low flow was defined as a stroke volume index ≤35 mL/m(2), low gradient as a mean gradient ≤40 mm Hg. Most patients (n=258, 75.9%) presented with high-gradient AS, and 82 patients (24.1%) with low-gradient AS. Among the latter, 52 (15.3%) presented with normal flow and low gradient and 30 (8.8%) with LFLG. As compared with normal flow and low gradient, patients with LFLG had more severe AS (aortic valve area=0.7±0.12 cm(2) versus 0.86±0.14 cm(2)), higher valvulo-arterial impedance (5.5±1.1 versus 4±0.8 mm Hg/mL/m(2)), and worse longitudinal left ventricular function (basal longitudinal strain=-11.6±3.4 versus -14.8±3%; P<0.001 for all). CONCLUSIONS: LFLG AS is observed in 9% of patients with severe AS and normal ejection fraction and is associated with high global afterload and reduced longitudinal systolic function. Patients with normal-flow low-gradient AS are more frequent and present with less severe AS, normal afterload, and less severe longitudinal dysfunction. Severe left ventricular longitudinal dysfunction is a new explanation to the concept of LFLG AS.

Mechanism of action of nitrogen pressure in controlling striatal dopamine level of freely moving rats is changed by recurrent exposures to nitrogen narcosis.

In rats, a single exposure to 3 MPa nitrogen induces change in motor processes, a sedative action and a decrease in dopamine release in the striatum. These changes due to a narcotic effect of nitrogen have been attributed to a decrease in glutamatergic control and the facilitation of GABAergic neurotransmission involving NMDA and GABA(A) receptors, respectively. After repeated exposure to nitrogen narcosis, a second exposure to 3 MPa increased dopamine levels suggesting a change in the control of the dopaminergic pathway. We investigated the role of the nigral NMDA and GABA(A) receptors in changes in the striatal dopamine levels. Dopamine-sensitive electrodes were implanted into the striatum under general anesthesia, together with a guide-cannula for drug injections into the SNc. Dopamine level was monitored by in vivo voltammetry. The effects of NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) on dopamine levels were investigated. Rats were exposed to 3 MPa nitrogen before and after five daily exposures to 1 MPa. After these exposures to nitrogen narcosis, gabazine, NMDA and AP7 had no effect on the nitrogen-induced increase in dopamine levels. By contrast, muscimol strongly enhanced the increase in dopamine level induced by nitrogen. Our findings suggest that repeated nitrogen exposure disrupted NMDA receptor function and decreased GABAergic input by modifying GABA(A) receptor sensitivity. These findings demonstrated a change in the mechanism of action of nitrogen at pressure.

Valvular heart disease associated with benfluorex therapy: high prevalence in patients with unexplained restrictive valvular heart disease.

AIMS: Restrictive valvular disease (RVD) has recently been reported in patients after benfluorex exposure. However, little is known about its prevalence and echocardiographic features. The aim of our study was to assess the frequency of benfluorex exposure in patients with RVD and to describe their echocardiographic characteristics. METHODS AND RESULTS: In a single centre study, patients with a final diagnosis of unexplained RVD were studied. Patients were interrogated for their previous use of benfluorex or other appetite-suppressant drugs (ASDs). Forty seven consecutive patients, aged 59 ± 9.6 years, with RVD were found [42 (91%) women]. Among them, 35 (74%) had previous treatment with ASD, including benfluorex in 34 patients. Among the latter, 14 (40%) have been exposed to benfluorex alone, 20 (60%) in combination with another ASD. Echocardiographic features included isolated mitral or aortic restricted valve motion in 19 patients (40%), and combined mitral and aortic involvement in 28 (60%).Twenty-seven (96%) of the latter had been exposed to benfluorex. As compared with the 'no ASD' group (n= 12), patients in the benfluorex group (n= 34) were more frequently female, had more frequent arterial hypertension and hypertriglyceridemia, and presented more frequently with combined mitral and aortic disease (79 vs. 8%, P < 0.001). Valve stenosis and tricuspid involvement were rare in the benfluorex group. CONCLUSION: The frequency of benfluorex exposure is high in patients with unexplained RVD. Combined aortic and mitral restrictive valve regurgitation is highly suggestive of valvular disease associated with benfluorex or other ASD therapy and may alert clinician about the possibility of this diagnosis.

Alterations in nigral NMDA and GABAA receptor control of the striatal dopamine level after repetitive exposures to nitrogen narcosis.

Nitrogen pressure exposure in rats results in decreased dopamine (DA) release at the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, demonstrating the narcotic potency of nitrogen. This effect is attributed to decreased excitatory and increased inhibitory inputs to dopaminergic neurons, involving a change in NMDA and GABA(A) receptor function. We investigated whether repetitive exposures to nitrogen modify the excitatory and inhibitory control of the dopaminergic nigro-striatal pathway. We used voltammetry to measure dopamine levels in freely-moving rats, implanted with dopamine-sensitive electrodes in the striatum. NMDA/GABA(A) receptor agonists (NMDA/muscimol) and antagonists (AP7/gabazine) were administered through a guide-cannula into the SNc, and their effects on striatal dopamine levels were measured under normobaric conditions, before and after five repetitive exposures to 1 MPa nitrogen. NMDA-mediated dopamine release was greater following repetitive exposures, AP7-mediated inhibition of glutamatergic input was blocked, suggesting that NMDA receptor sensitivity was increased and glutamate release reduced. Muscimol did not modify dopamine levels following repetitive exposures, whereas the effect of gabazine was greater after exposures than before. This suggested that interneuronal GABA(A) receptors were desensitized, leading to an increased GABAergic input at dopaminergic cells. Thus, repetitive nitrogen exposure induced persistent changes in glutamatergic and GABAergic control of dopaminergic neurons, resulting in decreased activity of the nigrostriatal pathway.

The role of NMDA and GABAA receptors in the inhibiting effect of 3 MPa nitrogen on striatal dopamine level.

Nitrogen pressure exposure, in rats, resulted in a decreased dopamine (DA) level by the striatal terminals of the substantia nigra pars compacta (SNc) dopaminergic neurons, due to the narcotic potency of nitrogen. In the SNc, the nigrostriatal pathway is under glutamatergic and GABAergic control mediated by ion-channel NMDA and GABA(A) receptors, main targets of volatile anesthetics. The aim of this study was to investigate the role of these receptors in the regulation of striatal dopamine level under nitrogen narcosis. Under general anesthesia, male Sprague-Dawley rats were bilaterally implanted in the striatum with dopamine-sensitive electrodes and, in the SNc, with guide cannulae for drug injections. After recovery from surgery, the striatal dopamine level was quantified using differential pulse voltammetric measurements in freely moving rats. Focal injections of agonists (NMDA/muscimol) and antagonists (AP7/gabazine) of NMDA/GABA(A) receptors were made within SNc. Both normobaric condition and 3 MPa nitrogen pressure were studied. Control experiments confirmed a direct glutamatergic control on the striatal DA level through NMDA receptors. Both direct and indirect GABAergic control through two different types of GABA(A) receptors located on GABAergic interneurons and on DA cells were indicated. Under nitrogen pressure, the decrease in dopamine level (20%) was suppressed by both NMDA and GABA(A) agonist infusion. There was an unexpected increasing DA level, induced by AP7 (about 10%) and gabazine (about 30%). These results indicate that NMDA receptors remain functional and suggest a decreased glutamate release. The findings also describe an increase of GABA(A) receptor-mediated inhibition on DA cells under nitrogen pressure exposure.

Effects of repeated hyperbaric nitrogen-oxygen exposures on the striatal dopamine release and on motor disturbances in rats.

Previous studies have demonstrated disruptions of motor activities and a decrease of extracellular dopamine level in the striatum of rats exposed to high pressure of nitrogen. Men exposed to nitrogen pressure develop also motor and cognitive disturbances related to inert gas narcosis. After repetitive exposures, adaptation to narcosis was subjectively reported. To study the effects of repetitive exposures to hyperbaric nitrogen-oxygen, male Sprague-Dawley rats were implanted in the striatum with multifiber carbon dopamine-sensitive electrodes. After recovery from surgery, free-moving rats were exposed for 2 h up to 3 MPa of nitrogen-oxygen mixture before and after one daily exposure to 1 MPa of nitrogen-oxygen, for 5 consecutive days. Dopamine release was measured by differential pulse voltammetry and motor activities were quantified using piezo-electric captor. At the first exposure to 3 MPa, the striatal dopamine level decreased during the compression (-15%) to reach -20% during the stay at 3 MPa. Motor activities were increased during compression (+15%) and the first 60 min at constant pressure (+10%). In contrast, at the second exposure to 3 MPa, an increase of dopamine of +15% was obtained during the whole exposure. However, total motor activities remained unchanged as compared to the first exposure. Our results confirm that nitrogen exposure at 3 MPa led to a decreased striatal dopamine release and increased motor disturbances in naïve rats. Repetitive exposures to 1 MPa of nitrogen induced a reversal effect on the dopamine release which suggests a neurochemical change at the level of the neurotransmitter regulation processes of the basal ganglia. In contrast, motor activity remained quantitatively unchanged, thus suggesting that dopamine is not involved alone in modulating these motor disturbances.