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Background and Purpose: Opioids are effective painkillers. However, their risk-benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids., Experimental Approach: The TREK1 potassium channel is activated downstream of μ receptor and involved in the antinociceptive activity of morphine but not in its adverse effects. Bypassing the μ opioid receptor to directly activate TREK1 could therefore be a safer analgesic strategy., Key Results: We developed a selective TREK1 activator, RNE28, with antinociceptive activity in naive rodents and in models of inflammatory and neuropathic pain. This activity was lost in TREK1 knockout mice or wild-type mice treated with the TREK1 blocker spadin, showing that TREK1 is required for the antinociceptive activity of RNE28. RNE28 did not induce respiratory depression, constipation, rewarding effects, or sedation at the analgesic doses tested., Conclusion and Implications: This proof-of-concept study shows that TREK1 activators could constitute a novel class of painkillers, inspired by the mechanism of action of opioids but devoid of their adverse effects., (© 2020 The British Pharmacological Society.)

In order to contribute to a better knowledge on the relationship between amyloid and tau pathology, and electroencephalography (EEG) disturbances, the aim of this study was to evaluate the effects of injection of beta amyloid Abeta(1-42) peptide, tau (a recombinant AAV (Adeno-Associated Virus) containing the human transgene tau with the P301 L mutation on rats and the combination of both, on the power of brain's rhythm (delta, theta, alpha, beta and gamma waves) during the different sleep/wake states of animals by EEG recording. Currently, no preclinical studies explore the effect of the tau pathology on EEG. The experimentations were performed 3 weeks and 3 months post injections. Beta amyloid deposits and hyperphosphorylated Tau are observed by immunohistofluorescence, only in the hippocampus. Furthermore, using a radial arm water maze, the main effect was observed on working memory which was significantly impaired in Abeta-Tau group only 3 months post injections. However, on EEG, as early as the 3 rd week, an overall decrease of the EEG bands power was observed in the treated groups, particularly the theta waves during the rapid eye movement (REM) sleep. Beta amyloid was mainly involved in these perturbations. Obviously, EEG seems to be an interesting tool in the early diagnostic of amyloid and tau pathologies, with a good sensitivity and the possibility to perform a follow up during a large period., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Asthma is a chronic respiratory disease, commonly treated with inhaled therapy. Better understanding of the mechanisms of aerosol deposition is required to improve inhaled drug delivery. Three-dimensional ultrashort echo time (UTE) MRI acquisitions at 1.5 T were combined with spontaneous nose-only inhalation of aerosolized gadolinium (Gd) to map the aerosol deposition and to characterize signal enhancement in asthmatic rat lungs. The rats were sensitized to ovalbumin (OVA) to develop asthmatic models and challenged before imaging by nebulization of OVA to trigger asthmatic symptoms. The negative controls were not sensitized or challenged by nebulization of saline. The animal lungs were imaged before and after administration of Gd-based aerosol in freely breathing rats, by using a T 1 -weighted 3D UTE sequence. A contrast-enhanced quantitative analysis was performed to assess regional concentration. OVA-sensitized rats had lower signal enhancement and lower deposited aerosol concentration. Their enhancement dynamics showed large inter-subject variability. The signal intensity was homogeneously enhanced for controls while OVA-sensitized rats showed heterogeneous enhancement. Contrast-enhanced 3D UTE was applied with aerosolized Gd to efficiently measure spatially resolved deposition in asthmatic lungs. The small administered dose (around 1 μmol/kg body weight) and the use of standard clinical MRI suggest a potential application for the exploration of asthma., (© 2018 John Wiley & Sons, Ltd.)

Background and Purpose: Increase in high-frequency beat-to-beat heart rate oscillations by torsadogenic hERG blockers appears to be associated with signs of parasympathetic and sympathetic co-activation which cannot be assessed directly using classic methods of heart rate variability analysis. The present work aimed to find a translational model that would allow this particular state of the autonomic control of heart rate to be assessed., Experimental Approach: High-frequency heart rate and heart period oscillations were analysed within discrete 10 s intervals in a cohort of 200 healthy human subjects. Results were compared to data collected in non-human primates and beagle dogs during pharmacological challenges and torsadogenic hERG blockers exposure, in 127 genotyped LQT1 patients on/off β-blocker treatment and in subgroups of smoking and non-smoking subjects., Key Results: Three states of autonomic modulation, S1 (parasympathetic predominance) to S3 (reciprocal parasympathetic withdrawal/sympathetic activation), were differentiated to build a new model of heart rate variability referred to as high-frequency autonomic modulation. The S2 state corresponded to a specific state during which both parasympathetic and sympathetic systems were coexisting or co-activated. S2 oscillations were proportionally increased by torsadogenic hERG-blocking drugs, whereas smoking caused an increase in S3 oscillations., Conclusions and Implications: The combined analysis of the magnitude of high-frequency heart rate and high-frequency heart period oscillations allows a refined assessment of heart rate autonomic modulation applicable to long-term ECG recordings and offers new approaches to assessment of the risk of sudden death both in terms of underlying mechanisms and sensitivity., (© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: The Safety Pharmacology Society (SPS) and National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) conducted a survey and workshop in 2015 to define current industry practices relating to housing of non-rodents during telemetry recordings in safety pharmacology and toxicology studies. The aim was to share experiences, canvas opinion on the study procedures/designs that could be used and explore the barriers to social housing., Methods: Thirty-nine sites, either running studies (Sponsors or Contract Research Organisations, CROs) and/or outsourcing work responded to the survey (51% from Europe; 41% from USA)., Results: During safety pharmacology studies, 84, 67 and 100% of respondents socially house dogs, minipigs and non-human primates (NHPs) respectively on non-recording days. However, on recording days 20, 20 and 33% of respondents socially house the animals, respectively. The main barriers for social housing were limitations in the recording equipment used, study design and animal temperament/activity. During toxicology studies, 94, 100 and 100% of respondents socially house dogs, minipigs and NHPs respectively on non-recording days. However, on recording days 31, 25 and 50% of respondents socially house the animals, respectively. The main barriers for social housing were risk of damage to and limitations in the recording equipment used, food consumption recording and temperament/activity of the animals., Conclusions: Although the majority of the industry does not yet socially house animals during telemetry recordings in safety pharmacology and toxicology studies, there is support to implement this refinement. Continued discussions, sharing of best practice and data from companies already socially housing, combined with technology improvements and investments in infrastructure are required to maintain the forward momentum of this refinement across the industry., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Ventricular arrhythmias induced by human ether-a-go-go related gene (hERG; Kv 11.1 channel) blockers are a consequence of alterations in ventricular repolarisation in association with high-frequency (HF) oscillations, which act as a primary trigger; the autonomic nervous system plays a modulatory role. In the present study, we investigated the role of β1 -adrenoceptors in the HF relationship between magnitude of heart rate and QT interval changes within discrete 10 s intervals (sorted into 5 bpm heart rate increments) and its implications for torsadogenic hERG blockers., Experimental Approach: The HF relationship was studied under conditions of autonomic blockade with atenolol (β1 -adrenoceptor blocker) in the absence or presence of five hERG blockers in beagle dogs. In total, the effects of 14 hERG blockers on the HF relationship were investigated., Key Results: All the torsadogenic hERG blockers tested caused a vertical shift in the HF relationship, while hERG blockers associated with a low risk of Torsades de Pointes did not cause any vertical shift. Atenolol completely prevented the effects four torsadogenic agents (quinidine, thioridazine, risperidone and terfenadine) on the HF relationship, but only partially reduced those of dofetilide, leading to the characterization of two types of torsadogenic agent., Conclusions and Implications: Analysis of the vertical shift in the HF relationship demonstrated that signs of transient sympathetic activation during HF oscillations in the presence of torsadogenic hERG blockers are mediated by β1 -adrenoceptors. We suggest the HF relationship as a new biomarker for assessing Torsades de pointes liability, with potential implications in both preclinical studies and the clinic., (© 2015 The British Pharmacological Society.)

Background and Purpose: The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K(+) channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency., Experimental Approach: The short-term variability of beat-to-beat QT interval (STVQT ), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium., Key Results: Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans., Conclusions and Implications: These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals., (© 2015 The British Pharmacological Society.)

Introduction: In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic., Methods: Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax., Results: All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man., Discussion: The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: Power spectral analysis of heart rate variability is a tool known to provide information of interest on the autonomic control of heart rate in human. However, its use and its conditions of application and interpretation for safety purposes are not well defined for cardiovascular safety pharmacology studies. Likewise, data of power spectral analysis of heart rate variability in cynomolgus monkeys, a species often appropriate for use as second non rodent species in preclinical safety programmes, are not available. This study was designed to evaluate the relevance of this biomarker in this non human primate species, and to compare results with those from beagle dogs under the conditions of safety evaluation studies., Methods: Power spectral analysis of heart rate variability was performed on data collected in both species by telemetry following a standard design for cardiovascular safety pharmacology studies. Various pharmacological agents were tested in order to compare the profile of responses in both species after modifying the autonomic nervous balance., Results: Heart rate variability in cynomolgus monkeys is mainly driven by the parasympathetic nervous system as in beagle dogs although vagal tone is less than in dogs. Power spectral analysis of heart rate variability allows detection of interaction with the autonomic nervous system in both species in all investigated situations, i.e. sympatholytic/sympathomimetic and parasympatholytic/parasympathomimetic drug induced effects. However, due to species difference in the autonomic control of heart rate, cynomolgus monkeys are likely to be more sensitive than beagle dogs for assessment of sympatholytic properties., Discussion: This study confirms that power spectral analysis of heart rate variability from data derived from ECG recordings in telemetry studies is applicable in cardiovascular safety pharmacology studies and may provide relevant information about possible interaction with the autonomic nervous system when new drug entities are evaluated in either species. However, interspecies differences in autonomic control must be taken into account when interpreting possible drug effects., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: In a previous study, two electrophysiological patterns for torsadogenic drugs were characterised in the model of isolated canine Purkinje fibres from their respective effects on action potential. This study was designed to elucidate the possible mechanisms underlying these two electrophysiological profiles., Methods: Effects of representative torsadogenic agents and non torsadogenic drugs on I(Kr), I(Ks), I(K1), I(Na) and I(CaL) were studied in transfected HEK 293 cells using the path-clamp method as well as in conscious beagle dogs and cynomolgus monkeys by telemetry., Results: Patch-clamp studies confirmed that torsadogenic molecules could be discriminated into at least two subgroups. The first subgroup can be defined as apparently pure I(Kr) blockers. The second subgroup can be defined as I(Kr) blockers with ancillary properties on sodium and/or calcium channels which counterbalance the I(Kr) prolongation component. This discrimination is transposable to the telemetered cynomolgus monkey model in terms of QT prolongation but not to the telemetered beagle dog model. This latter inter-species difference could be related to the sympathetic/parasympathetic balance and could involve reserve repolarisation dependent mechanisms., Discussion: The confirmation that torsadogenic drugs might have at least two different electrophysiological profiles should be taken into consideration in preclinical safety pharmacology studies because it increases the value of the cynomolgus monkey model in two particular situations: firstly when an NCE causes sympathetic activation and secondly, when an NCE exhibits a pure I(Kr) blocker pattern independently of its potency to block HERG channels., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: QT interval assessment by telemetry has become one of the most useful models in testing strategies adopted for detection of drug induced QT prolongation in non-clinical safety pharmacology studies. This study reports experimental data showing that the autonomic nervous system might influence drug induced QT prolongation., Methods: Animals were instrumented with telemetric transmitters and epicardial ECG leads. Effects on QT interval of reference drugs such as thioridazine and terfenadine were analysed with different approaches, the Holzgrefe's probabilistic method, the QT shift method and an individual analysis of beat-to-beat QT/RR pair distribution visualised as points-cloud., Results: Two cases of unexpected absence of QT interval prolongation are reported with thioridazine and terfenadine in conscious beagle dogs under conditions of concomitant tachycardia. The pro-arrhythmic properties of these two molecules were unmasked by co-treatment with sympatholytic agents, atenolol and clonidine respectively suggesting that sympathetic activation and/or parasympathetic withdrawal might impair a drug induced QT prolongation., Discussion: The apparent absence of changes in the QT interval due to novel drug candidates should be interpreted cautiously under conditions of concomitant tachycardia or elevated heart rate levels in non-clinical safety studies., (2010 Elsevier Inc. All rights reserved.)

Introduction: Drug-induced QT interval prolongation is a major concern in new drug candidate development. This study presents a method of assessment of drug-induced QT interval prolongation without need for QT correction in conscious Beagle dogs and Cynomolgus monkeys monitored by telemetry. Accuracy and reliability are analysed by comparison with a reference QT correction method (Holzgrefe) from experiments performed with reference substances terfenadine, thioridazine and sotalol., Methods: The QT shift method principle is assessment of any drug-induced QT interval shift directly from the individual QT/RR relationship. The individual QT/RR relationship is built from a treatment-free 24-hour recording period. QT and RR intervals are determined from a beat-to-beat analysis. A probabilistic method is used to define the individual QT/RR relationships. Checks were performed to compare results obtained with the QT shift method and the QT correction methods. The robustness of the QT shift method was tested under various conditions of drug-induced heart rate change (i.e. normal, bradycardia and tachycardia)., Results: The extent of agreement with the used reference QT correction method, Holzgrefe formula, was excellent (3-4 ms) in both animal species under the various drug induced effects on heart rate. The statistical sensitivity threshold for detection of QT prolongation according to a standard safety pharmacology study design was 7-8 ms., Discussion: When combined with the probabilistic determination of individual QT/RR relationships, this simple method provides a direct assessment of a drug-induced effect on QT interval, without any curve fitting or application of correction formula. Despite noticeably different shapes in QT/RR relationships, the QT shift method is applicable to both Beagle dogs and Cynomolgus monkeys. It is likely that the QT shift method will be particularly helpful in problematic cases, enabling detection of drug-induced prolongation of less than 10 ms.

The effects of an n-3 PUFA-enriched diet on cardiac cell membrane phospholipid fraction compositions and associated protein kinase-C (PKC) translocation modification have never been studied in higher mammals. This is of importance since membrane fatty acid composition has been shown to influence PKC signalling pathways. In the present study, we have tested whether the incorporation of n-3 PUFA in cardiac membrane phospholipids correlated with changes in the fatty acid composition of diacylglycerols (DAG) and led to a differential translocation of PKC isoforms. Two groups of five dogs were fed the standard diet supplemented with palm oil or fish oil for 8 weeks. Dogs fed a fish oil-enriched diet showed a preferential incorporation of EPA and, to a lesser extent, of DHA, at the expense of arachidonic acid, in the circulating TAG, plasma phospholipids, erythrocyte phospholipids and cardiomyocyte phospholipid fractions. Analysis of 1,2-DAG fatty acid composition also indicated a preferential enrichment of EPA compared with DHA. Associated with these results, a reduction in the expression of PKC-delta and PKC-epsilon isoforms in the particulate fractions was observed whereas no effect was seen for PKC-alpha and PKC-zeta. We conclude that a fish oil-enriched diet induces a modification in fatty acid composition of cardiac membrane phospholipids, associated with a differential translocation of PKC isoforms. These results can be explained by the production of structurally different DAG that may participate in some of the protective effects of n-3 PUFA against various chronic diseases.

The relationship between high fish consumption and low mortality following coronary heart disease (CHD) and low incidence of breast cancer was first mentioned 3 decades ago. The fishes of interest are rich in omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which could be the active nutrients. The current consensus about cardioprotection is that omega-3 LC-PUFAs would mainly exert antiarrhythmic effects. One of the proposed mechanisms is that circulating non-esterified LC-PUFAs partition into cardiac cells membrane phospholipids and exert a direct effect on ionic channels and/or modify intracellular calcium homeostasis. In another hypothesis, changes in the metabolism of phosphoinositides would be involved and lead to the differential activation of PKC isoforms. As compared to the mechanisms proposed for the cardioprotective effects of omega-3 LC-PUFAs, less is known about the molecular mechanisms involved in breast cancers prevention. Some proposed mechanisms such as the modulation of phosphoinositides metabolism and/or modulation of intracellular calcium homeostasis, are common to both pathologies. Other hypotheses involve the alteration of the cellular redox status induced by highly peroxidizable polyunsaturated fatty acids (FA), or the modulation of gene expression, both phenomena being tightly linked to apoptosis. In this review, we report and compare some proposed mechanisms for the involvement of omega-3 LC-PUFAs in both cardiac and breast cancer protection. Deliberately, we chose to discuss only the mechanisms, which are less described in other reviews such as ionic channels in cancer, calcium homeostasis, PKC activation or matrix metalloproteinases in both cancer and cardiac models. The leitmotiv along this review is that cardio- and cancero-protective effects use common pathways. Comparison of the cellular effects might therefore help to highlight the "protective" pathways.

Torsade de Pointes (TdP) is a well-described major risk associated with various kinds of drugs. However, prediction of this risk is still uncertain both in preclinical and clinical trials. We tested 45 reference compounds on the model of isolated canine Purkinje fibres. Of them, 22 are clearly associated and/or labelled with a risk of TdP, and 13 others are drugs with published clinical evidence of QT prolongation, with only one or two exceptional cases of TdP. The 10 remaining drugs are without reports of TdP and QT prolongation. The relevance of different indicators such as APD(90) increase, reverse use dependency, action potential triangulation or effect on V(max) was evaluated by comparison with available clinical data. Finally, a complex algorithm called TDPscreen and based on two subalgorithms corresponding to particular electrophysiological patterns was defined. This latter algorithm enabled a clear separation of drugs into three groups: (A) drugs with numerous or several reports (>2 cases) of TdP, (B) drugs causing QT prolongation and/or TdP only, the latter at a very low frequency (< or =2 cases), (C) drugs without reports of TdP or QT prolongation. The use of such an algorithm combined with a database accrued from reference compounds with available clinical data is suggested as a basis for testing new candidate drugs in the early stages of development for proarrhythmic risk prediction.

In a normal and healthy skin, the regular elimination of the superficial corneocytes, called desquamation, is a fundamental physiologic process intended to protect the barrier function of the skin. This invisible loss of corneocytes, individually or in small groups, is incessantly compensated by the divisions of the proliferative layer and the upward cellular maturation in order to maintain the harmonious renewal of the epidermis and the integrity of the stratum corneum. The harmony of this desquamation process is intimately conditioned by a sufficient hydration of the stratum corneum: (i) an abnormal desquamation leads to a disruption of the water barrier function and consequently to a dehydration tendency of the stratum corneum, and (ii) a cutaneous dryness (whatever the cause) is able to disturb the desquamation process. Protecting the water content of the stratum corneum has always been a major preoccupation of the cosmetic industry scientists. Consequently, the moisturizing properties of a cosmetic product are objectively measured by various explorations directly targeted on the hydration (corneometry) and on the level of the water barrier function (transepidermal water loss (TEWL) measurements), which depends directly on the skin hydration state. This intimate linkage of the desquamation process and the water content of the stratum corneum enable us to suggest an indirect assessment of the hydration from a direct study of the desquamation by examining a skin-stripping sample (D-Squames) by an optical microscope (linked to a computer). We will describe this already known technique and mainly its new and unpublished semiologic exploitation, named Diagnoskin, whose advantages are its simplicity and its reproducibility particularly interesting in the case of sequential appraisal of dermatologic or cosmetic treatments.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used by topical application in management of joint pain and inflammation. Little is known, however, about their pharmacokinetics, especially in the synovial compartment versus the plasma compartment, following topical administration. Ketoprofen, a NSAID, was delivered by a single topical application (KETUM 2.5% gel) on the rabbit knee-joint region of one hind limb. Concentrations of ketoprofen were measured in plasma, synovial fluid, joint capsule and synovial fat tissue at 2, 4, 6 and 12 hours after application. Whatever the time period after application, ketoprofen concentrations in synovial fluid were much higher than in plasma. The time-course of the decrease in ketoprofen plasma concentrations was more rapid than that in synovial fluid. Similarly, concentrations in joint capsule were higher than those found in synovial fat tissue. Finally, while ketoprofen concentrations decreased rapidly in plasma and in synovial fat tissue, concentrations in joint capsule and particularly in synovial fluid were more sustained. The increase in residence time of ketoprofen in synovial fluid could be in favour of its efficiency in the management of joint pain and inflammation.

The effects of the dihydropyridine (DHP) calcium channel antagonist, nicardipine, on central cardiovascular regulation were investigated by injecting it into the cisterna magna or directly into the nucleus tractus solitarii (NTS), in anesthetized normotensive or spontaneously hypertensive (SHR) rats. Intracisternal injections of nicardipine (1-10 micrograms/kg) dose-dependently decreased blood pressure in SHR; there was no significant change in cardiovascular parameters in normotensive rats. In SHR, nicardipine (100 ng) microinjected bilaterally into the NTS produced hypotension and bradycardia. The same doses of nicardipine intravenously injected did not change either parameter. Previous administration of the beta-adrenoceptor blocking drug, tertatolol (50 micrograms/kg i.v.), prevented the nicardipine-induced bradycardia and hypotension after injection into the NTS. These data suggest that part of the central cardiovascular effects of nicardipine result from an interaction with DHP sites within the NTS leading to a withdrawal of the sympathetic tone.

Intracerebroventricular injections of nicardipine (10 micrograms/kg) to SHR induced hypotension which was suppressed by pretreatment with 6-OHDA. This hypotension was also inhibited by a previous injection of naloxone (100 micrograms/kg i.c.v.) whereas the hypotension induced by intravenously injected nicardipine (10 micrograms/kg) was not changed. It is suggested that the release of endogenous opioids is involved in the sympatho-inhibitory effect of centrally administered dihydropyridine calcium channel antagonists.

The authors review structural aberrations of the X chromosome in women. The correlation of their occurrence with clinical experience has led to a better understanding of the syndromes they provoke as well as of the gene content and mode of action of the X chromosome.