Short-lasting Decrease Research Articles

Exploration of driver stress when resuming control from highly automated driving in an emergency situation

IntroductionIn a highly automated vehicle, the resumption of manual control often takes place in emergency situations automation cannot handle. Time pressure may increase driver stress and lead to risky behaviors. For safety purposes, this study examines the impacts of emergency takeovers on driver stress. MethodThe impacts of emergency takeovers on driver stress were explored through heart rate, pupil diameter and perceived stress, gathered from 36 drivers in a driving simulator. Three degrees of emergency were used: non–, moderate, and extreme emergency. ResultsThe results indicate a pupil dilation, high levels of perceived stress and a long-lasting increase in heart rate when drivers had to resume control in moderate and extreme emergency situations. The results also show a lower perceived stress level and a bi-phasic cardiac pattern—composed of a short-lasting decrease in heart rate prior to long-lasting increase in heart rate—when drivers were warned to regain control (moderate emergency) compared to when they were not warned (extreme emergency). ConclusionThe results (1) suggest that time urgency is a key factor in the induction of driver stress during takeovers, (2) support the existence of a warning-induced preparatory response—characterized by a short-lasting decrease in heart rate—and previously observed in research on defensive behaviors, and (3) support the hypothesis that the preparatory response is a means of reducing driver stress. Overall, the results provide valuable information about cognitive preparation for emergency takeovers, and more generally about driver stress in emergency situations.

Cannabidiol Affects the Bezold-Jarisch Reflex via TRPV1 and 5-HT3 Receptors and Has Peripheral Sympathomimetic Effects in Spontaneously Hypertensive and Normotensive Rats.

Cannabidiol (CBD) is a nonpsychotropic constituent of Cannabis sativa L. It is suggested to be useful in hypertension. Under in vitro conditions, it activates vanilloid TRPV1 and inhibits serotonin 5-HT3 receptors, i.e., receptors involved in the Bezold-Jarisch reflex stimulation. The aim of our study was to compare the cardiovascular effects of CBD in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Experiments were performed on conscious, urethane-anesthetized, and pithed rats. In pithed SHR and WKY, CBD increased heart rate (HR) and systolic blood pressure (SBP) and decreased diastolic BP (DBP) in a manner insensitive to adrenalectomy. Propranolol strongly impaired the CBD-induced increases in HR and SBP without affecting the decreases in DBP. Desipramine also reduced the CBD-induced effects on HR and SBP and further increased its effects on DBP. In anesthetized rats, bolus i.v. injection of single doses of CBD induced short-lasting decreases in HR, SBP, and DBP, stronger in SHR than in WKY and prevented by bilateral vagotomy. The CBD-induced fall in HR but not in BP was diminished by the TRPV1 receptor antagonist capsazepine and almost completely abolished if CBD was re-injected after previous administration. CBD reduced the Bezold-Jarisch reflex elicited by the 5-HT3 receptor agonist phenylbiguanide but not that evoked by the TRPV1 agonist capsaicin. In conscious rats, CBD did not affect cardiovascular parameters. In isolated left atria, CBD decreased contractile force. Conclusions: Cannabidiol (1) induces the Bezold-Jarisch reflex likely via TRPV1 receptors (which undergo tachyphylaxis) more markedly in SHR than in WKY; (2) inhibits the Bezold-Jarisch reflex induced by activation of 5-HT3 but not TRPV1 receptors; (3) has peripheral sympathomimetic, (4) vasodilatory, and (5) negative inotropic effects. The above properties of CBD should be taken under consideration when CBD is used for therapeutic purposes.

Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability

BackgroundTranscranial static magnetic field stimulation (tSMS) was recently added to the family of inhibitory non-invasive brain stimulation techniques. However, the application of tSMS for 10–20 min over the motor cortex (M1) induces only short-lasting effects that revert within few minutes. ObjectiveWe examined whether increasing the duration of tSMS to 30 min leads to long-lasting changes in cortical excitability, which is critical for translating tSMS toward clinical applications. MethodsThe study comprised 5 experiments in 45 healthy subjects. We assessed the impact of 30-min-tSMS over M1 on corticospinal excitability, as measured by the amplitude of motor evoked potentials (MEPs) and resting motor thresholds (RMTs) to single-pulse transcranial magnetic stimulation (TMS) (experiments 1–2). We then assessed the impact of 30-min-tSMS on intracortical excitability, as measured by short-interval intracortical facilitation (SICF) and short-interval intracortical inhibition (SICI) using paired-pulse TMS protocols (experiments 2–4). We finally assessed the impact of 10-min-tSMS on SICF and SICI (experiment 5). Results30-min-tSMS decreased MEP amplitude compared to sham for at least 30 min after the end of the stimulation. This long-lasting effect was associated with increased SICF and reduced SICI. 10-min-tSMS –previously reported to induce a short-lasting decrease in MEP amplitude– produced the opposite changes in intracortical excitability, decreasing SICF while increasing SICI. ConclusionsThese results suggest a dissociation of intracortical changes in the consolidation from short-lasting to long-lasting decrease of corticospinal excitability induced by tSMS. The long-lasting effects of 30-min-tSMS open the way to the translation of this simple, portable and low-cost technique toward clinical trials.

P148 Dose–effect of transcranial static magnetic field stimulation on excitatory and inhibitory intracortical circuits

Question Transcranial static magnetic field stimulation (tSMS) is a new low-cost, non-invasive brain stimulation (NIBS) technique. When tSMS is applied for 10–15 min over the motor cortex, it leads to a short-lasting decrease of cortical excitability in healthy subjects, as measured by a decreased amplitude of motor-evoked potentials (MEPs), associated with an increase of short-latency intracortical inhibition (SICI). Here we aimed to test the effects of a longer application of tSMS (30 min) on excitatory and inhibitory intracortical circuits. Methods We performed 3 randomized double-blind sham-controlled experiments in a total of 31 right-handed healthy subjects. In experiment 1 we assessed MEP amplitudes before and after tSMS (or sham) applied for 30 min to the non-dominant motor cortex. In experiment 2 we tested the effects of 30 min of tSMS on SICI and I wave interaction. In experiment 3 we evaluated the effects of 10 min of tSMS on SICI and on the first peak of I wave interaction (short-latency intracortical facilitation, SICF). Results Prolonged application of tSMS (30 min) significantly decreased MEP amplitudes compared to sham till 30 min after the end of tSMS and, surprisingly, reduced SICI while increasing SICF. By applying tSMS for only 10 min, we found a significant and short-lasting increase of SICI with reduction of SICF. Conclusions We found that a prolonged application of tSMS leads to a long-lasting reduction in motor cortex excitability, similar to those typically induced by continuous theta-burst stimulation (cTBS) and cathodal transcranial direct current stimulation (tDCS). Moreover, SICI and SICF could be modulated in a bidirectional way by tSMS, depending on the application time, revealing a dose–effect of tSMS on excitatory and inhibitory intracortical circuits.

Contribution of the nitric oxide donor molsidomine and the antiparkinsonian drug l-DOPA to the modulation of the blood pressure in unilaterally 6-OHDA-lesioned rats.

Interaction between dopaminergic and nitrergic neurotransmission in the brain plays a crucial role in the control of motor function and in the regulation of blood pressure (BP). In Parkinson's disease (PD), dopaminergic denervation of the striatum leads to disturbances in the nitrergic system in the basal ganglia. Recently, it has been demonstrated that addition of a low dose of the nitric oxide donor molsidomine to l-DOPA therapy improves dopaminergic neurotransmission in the denervated nigrostriatal system and weakens dyskinesias in rodent models of the disease. The aim of the present study was to examine the impact of chronic administration of molsidomine (2mg/kg) and l-DOPA (25mg/kg), alone and in combination, on systolic (SBP) and diastolic (DBP) blood pressure in the anesthetized, unilaterally 6-OHDA-lesioned rats. The measurement of SBP and DBP was performed 24h after the penultimate and immediately after the last drug doses. In 6-OHDA-lesioned rats receiving saline, spontaneous, small decreases in SBP and DBP were observed during the measurements lasting 60min. Administration of molsidomine alone or in combination with l-DOPA distinctly decreased the BP in 6-OHDA-lesioned rats already after 10min compared to those treated with saline or l-DOPA alone, respectively. In both groups, the molsidomine-mediated declines in BP persisted till the end of measurement but they disappeared after 24h. Our results indicate that in this PD model molsidomine evokes a short-lasting decrease in BP in contrast to conventional antihypertensive drugs that maintain long-term effect and worsen orthostatic hypotension in parkinsonian patients.

DOSE-FINDING STUDY AND PHARMACODYNAMIC ASSESSMENT OF PROPOFOL FOR (SEMI-)ELECTIVE INTUBATION IN NEONATES

IntroductionThe optimal propofol dose and its safety for procedural sedation in neonates is controversial. The aim of this study was to perform a prospective propofol dose-finding study with pharmacodynamic (PD) assessment during (semi-)elective intubation in neonates.MethodsPatients were stratified in 4 groups by postmenstrual and postnatal age. The first patient in each group received 1 mg/kg intravenous propofol bolus. Dosing for the next patient was determined using the up-and-down method. Propofol ED50 doses [effective dose for successful intubation (as well as extubation in INSURE -intubation, surfactant, extubation-cases) in 50% of patients] were calculated, with simultaneous assessment of clinical scores, continuous vital sign monitoring and propofol blood concentrations (3 and 12h after dosing).ResultsThirty-five neonates (weight 540–3290 g) were included. Using initial and total propofol dose ranges of 0.5–2 and 0.5–4.5 mg/kg respectively, median propofol ED50 range for preterm neonates <10 days was 0.480–1.287 mg/kg. Clinical recovery was not attained at the end of the scoring period (21 minutes). A median decrease in mean arterial blood pressure (MABP) between −29.41% and −39.09% from baseline, and a short-lasting decrease in peripheral (SaO2) and regional cerebral (rScO2) oxygen saturation was documented. Variability in MABP, SaO2 and rScO2 was not explained by weight, age or propofol concentrations.ConclusionsLow propofol doses sufficiently sedate neonates for intubation, but clinical recovery takes time and is accompanied by permissive hypotension. Propofol ED50 doses are provided and need integration in a prospective validation approach. Finally, feasibility of continuous monitoring for neonatal pharmacodynamic research was demonstrated.

Modulation of non-painful phantom sensation in subjects with spinal cord injury by means of rTMS.

We aimed in this study to investigate whether repetitive transcranial magnetic stimulation (rTMS), given as theta burst stimulation (TBS), can interfere with non-painful phantom sensations in subjects with spinal cord injury (SCI). In double-blind, sham-controlled experiments in five subjects with cervical or thoracic traumatic SCI, we evaluated the effects of a single session of inhibitory (continuous) TBS, excitatory (intermittent) TBS, or placebo TBS, on simplex and complex non-painful phantom sensations. The interventions targeted the contralateral primary motor cortex (M1), the primary sensory cortex (S1) and the posterior parietal cortex (PPC). Measurements were carried out at baseline (T0), 5 min (T1) and 30 min later (T2) after the intervention. Descriptive evaluation of results shows that non-painful phantom sensations were not affected by rTMS applied over M1. Continuous (inhibitory) TBS over S1 induced a short-lasting decrease of simple non-painful phantom sensations, while continuous TBS over PPC induced a short-lasting decrease of both simple and complex phantom sensations. Intermittent (excitatory) TBS over PPC induced a slight increase of non-painful phantom sensations. Tests for significance confirm these observations, but must be interpreted with caution because of the small sample size. In conclusion, non-painful phantom sensations may be associated to a hyperexcitability of PPC and to a lesser extent of S1, which can be normalized by inhibitory rTMS. Our preliminary findings provide further evidence that neuromodulatory techniques are able to reverse phantom sensations not only after limb amputation but also in other conditions characterized by deafferentation such as SCI.

Motor and parietal cortex stimulation for phantom limb pain and sensations

Limb amputation may lead to chronic painful sensations referred to the absent limb, ie phantom limb pain (PLP), which is likely subtended by maladaptive plasticity. The present study investigated whether transcranial direct current stimulation (tDCS), a noninvasive technique of brain stimulation that can modulate neuroplasticity, can reduce PLP. In 2 double-blind, sham-controlled experiments in subjects with unilateral lower or upper limb amputation, we measured the effects of a single session of tDCS (2mA, 15min) of the primary motor cortex (M1) and of the posterior parietal cortex (PPC) on PLP, stump pain, nonpainful phantom limb sensations and telescoping. Anodal tDCS of M1 induced a selective short-lasting decrease of PLP, whereas cathodal tDCS of PPC induced a selective short-lasting decrease of nonpainful phantom sensations; stump pain and telescoping were not affected by parietal or by motor tDCS. These findings demonstrate that painful and nonpainful phantom limb sensations are dissociable phenomena. PLP is associated primarily with cortical excitability shifts in the sensorimotor network; increasing excitability in this system by anodal tDCS has an antalgic effect on PLP. Conversely, nonpainful phantom sensations are associated to a hyperexcitation of PPC that can be normalized by cathodal tDCS. This evidence highlights the relationship between the level of excitability of different cortical areas, which underpins maladaptive plasticity following limb amputation and the phenomenology of phantom limb, and it opens up new opportunities for the use of tDCS in the treatment of PLP.

P.1.c.049 Cinnarizine, a calcium channel antagonist, attenuates changes of parkinsonian-type induced in rat by the proteasome inhibitor lactacystin

The effects of intranigral injections of Spantide II, a novel tachykinik antagonist, on extracellular dopamine, and dihydroxyphenylacetic acid (DOPAC) levels in the rat striatum were studied using in vivo microdialysis. The ability of Spantide II to inhibit intranigral substance P or neurokinin A stimulation of striatal dopamine levels was also studied. A unilateral injection (all substances were injected in a volume of 0.2 μl) of Spantide II (0.7 nmol) intot he substantia nigra, pars reticulata (SNR) of halothane anaesthetized rats produced a short-lasting decrease in dopamine levels in the spsilateral striatum. Striatal DOPAC levels showed no change after Spantide II. A unilateral injection of substance P (0.07 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was prevented when substance P was co-administered with Spantide II (0.7 nmol). A unilateral injection of neurokinin A (0.09 nmol) into the SNR produced an increase in ipsilateral striatal dopamine levels, which was not modified when neurokinin A was co-administered with Spantide II (0.7 nmol). Immunohistochemical analysis using antisera to tyrosine hydroxylase and neuropeptide K, as well as Cresyl violet staining, revealed that intranigral injections of Spantide II (0.7 nmol) did not produce significant damage in the substantia nigra. The results indicate that Spantide II is not ‘neurotoxic’ when injected intranigrally, and that it is a selective antagonist of substance P in the substantia nigra. Furthermore, the reduction of striatal dopamine levels after intranigral Spantide II injections suggests that nigrostriatal dopamine projection is tonically stimulated by striatonigral substance P.

Effects of Lung Recruitment Maneuvers on Splanchnic Organ Perfusion During Endotoxin-Induced Pulmonary Arterial Hypertension

Lung recruitment maneuvers (RMs), used to reopen atelectatic lung units and to improve oxygenation during mechanical ventilation, may result in hemodynamic impairment. We hypothesize that pulmonary arterial hypertension aggravates the consequences of RMs in the splanchnic circulation. Twelve anesthetized pigs underwent laparotomy and prolonged postoperative ventilation. Systemic, regional, and organ blood flows were monitored. After 6 h (= baseline), a recruitment maneuver was performed with sustained inflation of the lungs. Thereafter, the pigs were randomly assigned to group C (control, n = 6) or group E with endotoxin-induced pulmonary arterial hypertension (n = 6). Endotoxemia resulted in a normotensive and hyperdynamic state and a deterioration of the oxygenation index by 33%. The RM was then repeated in both groups. Pulmonary artery pressure increased during lipopolysaccharide infusion from 17 ± 2 mmHg (mean ± SD) to 31 ± 10 mmHg and remained unchanged in controls (P < 0.05). During endotoxemia, RM decreased aortic pulse pressure from 37 ± 14 mmHg to 27 ± 13 mmHg (mean ± SD, P = 0.024). The blood flows of the renal artery, hepatic artery, celiac trunk, superior mesenteric artery, and portal vein decreased to 71% ± 21%, 69% ± 20%, 76% ± 16%, 79% ± 18%, and 81% ± 12%, respectively, of baseline flows before RM (P < 0.05 all). Organ perfusion of kidney cortex, kidney medulla, liver, and jejunal mucosa in group E decreased to 65% ± 19%, 77% ± 13%, 66% ± 26%, and 71% ± 12%, respectively, of baseline flows (P < 0.05 all). The corresponding recovery to at least 90% of baseline regional blood flow and organ perfusion lasted 1 to 5 min. Importantly, the decreases in regional blood flows and organ perfusion and the time to recovery of these flows did not differ from the controls. In conclusion, lipopolysaccharide-induced pulmonary arterial hypertension does not aggravate the RM-induced significant but short-lasting decreases in systemic, regional, and organ blood flows.

Assessment of human brain temperature by 1H MRS during visual stimulation and hypercapnia

Brain temperature is determined by the interplay between the cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF). In this study, single-voxel 1H nuclear MRS, with an accuracy of +/-0.2 degrees C for temperature determination, was used at 3 T to measure human brain temperature during visual stimulation (which increases both CBF and CMRO2) and hypercapnia (which increases CBF only). Visual stimulation had no detectable effect on brain temperature in the parenchyma showing blood oxygenation level dependent activation. Hypercapnia, leading to an increase in the end tidal CO2 by 8 +/- 2 mm Hg above the baseline, caused a short-lasting decrease in brain temperature of 0.30 +/- 0.33 degrees C. These results indicate that increased CBF may be a key factor, bringing about a small decrease in brain temperature during brain activation. However, the increase in CBF is not sufficient to lower brain temperature in the presence of a concomitant increase in endogenous heat production.

Episodic Dural Stimulation in Awake Rats: A Model for Recurrent Headache

To model, in rats, the development of chronic trigeminal nociceptive hypersensitivity seen in patients with recurrent headache. Pathophysiology studies suggest that patients with recurrent migraine headache experience repeated bouts of dural nociceptor activation. In some patients, the severity and frequency of headache attacks increase over time. Patients with recurrent headache are hypersensitive to nitric oxide donors, such as glyceryl trinitrate (GTN). Current trigeminal pain models do not reflect the repeated episodic nature of dural nociceptor activation in patients with recurrent headache. Repeated nociceptor activation creates long-lasting changes in the periphery and brain due to activity-dependent neuronal plasticity. An animal model of repeated activation of dural nociceptors will facilitate the study of the physiological changes caused by repeated, episodic pain and the factors important for the transition of episodic to chronic migraine. We induced dural inflammation by infusing an inflammatory soup (IS) through a cannula on the dura in awake behaving rats. This was repeated 3 times per week for up to 4 weeks. Periorbital pressure sensory testing was used to monitor the change in trigeminal sensitivity. Rats were challenged with GTN to test the hypothesis that many dural stimulations are required to model the hypersensitivity of migraine patients. Quantitative trigeminal sensory testing and microdialysis in the trigeminal nucleus caudalis (TNC) were used to measure GTN hypersensitivity. Multiple infusions of IS (>8), over weeks, induced a long-lasting decrease in periorbital pressure thresholds that lasted >3 weeks after the last infusion. In contrast, IS infusion in IS-naive rats and those that received 3 IS infusions produced only short-lasting decreases in periorbital pressure thresholds. Rats that received more than 8 IS infusions showed a marked increase in their neurochemical and behavioral responses to GTN. In these rats, GTN induced a decrease in periorbital von Frey thresholds that lasted >5 hours. In contrast, in rats that received only 3 IS infusions, GTN caused a threshold decrease for 1.5 hour. In vivo microdialysis in the TNC showed that GTN increased extracellular glutamate levels in rats with more than 8 IS infusions to 7.7 times the basal levels. In IS-naive rats and those that received only 3 IS infusions, the extracellular glutamate levels rose to only 1.7 and 1.9 times the basal level, respectively. Repeated IS stimulation of the dura produces a chronic state of trigeminal hypersensitivity and potentiates the response to GTN. This hyperresponsiveness outlasts the last IS infusion and is the basis of our rat model of recurrent headache. This model can be used to study the changes in the brain and periphery induced by repeated trigeminovascular nociceptor activation and has the potential to elucidate the mechanisms for the transition of episodic to chronic headache.

Involvement of peripherally released substance P and calcitonin gene-related peptide in mediating mechanical hyperalgesia in a traumatic neuropathy model of the rat

We hypothesized that neuropeptides released from the peripheral terminals of primary afferents play an important role in mechanical hyperalgesia after peripheral nerve injury. Nerve injury was performed on rats with lumbar 5 spinal nerve lesion (L5 SNL), which was preceded by L5 dorsal rhizotomy (L5 DR) to avoid the potential central effects induced by L5 SNL through the L5 dorsal root. L5 DR produced a short-lasting (<6 days) decrease in paw withdrawal threshold (PWT) while the following L5 SNL produced a persistent (>42 days) PWT decrease. When intraplantar injection to the affected hind paw was given immediately before L5 SNL, antagonists for both neurokinin 1 (NK1) and calcitonin gene-related peptide 1 (CGRP1) receptors delayed the onset of the PWT decrease for 2–4 days. However, when the same injection was given after L5 SNL, CGRP1, but not NK1, receptor antagonist reversed the decreased PWT for 105 min. It is suggested that peripherally released neuropeptides contribute to the generation of neuropathic pain, with substance P and CGRP contributing to its induction phase, but only CGRP to its maintenance phase.

Blood pressure effects of intravenous apomorphine in conscious deoxycorticosterone-acetate salt-hypertensive rats.

The present study reports the effects of apomorphine (APO) on blood pressure and the principal site of action of this agonist in 4-week deoxycorticosterone-acetate (DOCA)-hypertensive conscious rats. In these preprations, intravenous (i.v.) administration of APO (0.50-1 mg/kg) induced short-lasting and dose-dependent decreases in mean arterial pressure. The hypotensive response to APO (0.3 mg/kg) was reversed into a significant pressor effect by i.v. hexamethonium (30 mg/kg), whereas it was enhanced by i.v. pretreatment with the vasopressor antagonist of arginine vasopressin (AVP) d(CH2)5Tyr(Me)AVP (10 microg/kg) and/or prazosin (1 mg/kg). This depressor effect was suppressed by the central and peripheral dopamine D2 receptor antagonist metoclopramide (5 mg/kg i.v.), unaffected by the selective dopamine D1 receptor antagonist SCH 23390 (0.2 mg/kg i.v.), partly reduced by intrathecal domperidone (40 microg per rat at T9-T10 level), a dopamine D2 receptor antagonist which does not cross the blood-brain barrier, and reversed into a significant pressor effect by i.v. domperidone (0.5 mg/kg). The latter pressor effect was fully abolished by combined i.v. pretreatment with the vasopressor antagonist of AVP and prazosin. These results show that, in conscious DOCA salt-hypertensive rats, APO induced a brief, initial depressor effect, which is opposed to a central pressor component. The depressor component is related to an inhibition of norepinephrine transmission through activation of dopamine D2 receptors, some of which are located in the spinal cord and some of which are located in the peripheral circulation. The central pressor component, which became manifest after peripheral dopamine D2 receptor blockade, appears to be related to an increase in vasopressin release and sympathetic tone through activation of brain dopamine D2 receptors.

Role of the nitric oxide/cyclic GMP pathway and extracellular environment in the nitric oxide donor-induced increase in dopamine secretion from PC12 cells: a microdialysis in vitro study.

In vitro microdialysis was used to investigate the mechanism of nitric oxide (NO) donor-induced changes in dopamine (DA) secretion from PC12 cells. Infusion of the NO-donor S-nitroso-N-acetylpenicillamine (SNAP, 1.0 mm) induced a long-lasting increase in DA and 3-methoxytyramine (3-MT) dialysate concentrations. SNAP-induced increases were inhibited either by pre-infusion of the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazolo[4,3]quinoxalin-1-one (ODQ, 0.1 mm) or by Ca2+ omission. Ca2+ re-introduction restored SNAP effects. SNAP-induced increases in DA + 3-MT were unaffected by co-infusion of the l-type Ca2+ channel inhibitor nifedipine. The NO-donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3, 1.0 mm) induced a short-lasting decrease in dialysate DA + 3-MT. Ascorbic acid (0.2 mm) co-infusion allowed NOR-3 to increase dialysate DA + 3-MT. ODQ pre-infusion inhibited NOR-3 + ascorbic acid-induced DA + 3-MT increases. Infusion of high K+ (75 mm) induced a 2.5-fold increase in dialysate DA + 3-MT. The increase was abolished by NOR-3 co-infusion. Conversely, co-infusion of ascorbic acid (0.2 mm) with NOR-3 + high K+ restored high K+ effects. Co-infusion of nifedipine inhibited high K+-induced DA + 3-MT increases. These results suggest that activation of the NO/sGC/cyclic GMP pathway may be the underlying mechanism of extracellular Ca2+-dependent effects of exogenous NO on DA secretion from PC12 cells. Extracellular Ca2+ entry may occur through nifedipine-insensitive channels. NO effects and DA concentrations in dialysates largely depend on both the timing of NO generation and the extracellular environment in which NO is generated.

Excitatory and inhibitory responses of dopamine neurons in the ventral tegmental area to nicotine.

In the present electrophysiological study the mechanisms by which nicotine activates dopamine neurons in the ventral tegmental area in anesthetized Sprague-Dawley rats were analyzed. Intravenous administration of nicotine caused a dose-dependent increase in firing rate and percentage of spikes fired in bursts of ventral tegmental area dopamine neurons. However, this activation was preceded by an instantaneous but short-lasting inhibition of the firing rate. The excitation of dopamine neurons by nicotine (1.5-400 microg/kg i.v.) was antagonized and even reversed into an inhibitory response by elevated levels (four-fold) of the endogenous glutamate receptor antagonist kynurenic acid, as induced by a potent inhibitor of kynurenine 3-hydroxylase (PNU 156561A, 40 mg/kg, i.v., 5-9 h). The antagonistic action induced by PNU 156561A pretreatment was prevented by administration of D-cycloserine (128 mg/kg, i.v., 5 min). Administration of the GABA(B)-receptor antagonist CGP 35348 (200 mg/kg, i.v., 3 min) facilitated the nicotine-induced increase in burst firing activity of dopamine neurons and antagonized the short-lasting decrease in firing rate by nicotine. The results of the present study show that nicotine produces both inhibition and excitation of ventral tegmental area dopamine neurons, actions that appear to be related to the release of GABA and glutamate, respectively. Whereas the excitatory action of nicotine may be associated with motivational processes underlying learning and cognitive behavior, the inhibitory action of the drug may play a more prominent role in the situation of a profound dysregulation of the mesocorticolimbic dopamine system and may help to explain the high prevalence of tobacco-smoking in schizophrenics.

Identification, synthesis and pharmacological activity of moxonidine metabolites

The metabolism of moxonidine, 4-chloro- N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, LY326869, in rats, mice, dogs, and humans has been examined. At least 17 metabolites were identified or tentatively identified in the different species by HPLC, LC/MS and LC/MS/MS. The identities of seven of the major metabolites have been verified by independent synthesis. The metabolites are generally derived from oxidation and conjugation pathways. Oxidation occurred at the imidazolidine ring as well as the methyl at the 2 position of the pyrimidine ring. All seven metabolites were examined in the spontaneously hypertensive rats (3 mg kg −1, i.v.) for pressure and heart rate. Only one, 2-hydroxymethyl-4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxypyrimidine, exerted a short-lasting decrease in blood pressure, albeit attenuated in magnitude compared to moxonidine.

Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats.

In anaesthetized rats activation of vanilloid receptors on sensory vagal nerves elicits rapid bradycardia and hypotension (Bezold-Jarisch reflex). Recent in vitro experiments revealed that the endogenous cannabinoid ligand anandamide acts as an agonist at the vanilloid VRI receptors. The present study was aimed at examining whether vanilloid VR1 receptors are involved in the cardiovascular effects of anandamide in the anaesthetized rat. Intravenous injection of anandamide, its stable analogue methanandamide and the vanilloid receptor agonist capsaicin produced a dose-dependent immediate and short-lasting decrease in heart rate and blood pressure with the following rank order of potencies: capsaicin > methanandamide > anandamide. This bradycardia was dose-dependently diminished by the selective vanilloid receptor antagonist capsazepine (0.3-3 micromol/kg) and the nonselective inhibitor of these receptors, ruthenium red (1-10 micromol/kg). Both antagonists reduced or tended to reduce the hypotension stimulated by the agonists. Following this bradycardia and hypotension (presumably evoked by the Bezold-Jarisch reflex; phase I), capsaicin, anandamide and methanandamide led to a brief vasopressor effect (phase II). Subsequently both anandamides, but not capsaicin, induced a more prolonged decrease in blood pressure (phase III). Capsazepine and ruthenium red (at doses up to 3 tmol/kg and 10 micromol/kg, respectively) failed to affect these changes in blood pressure. The cannabinoid CB1 receptor antagonist SR 141716 at 3 micromol/kg abolished the prolonged decrease in blood pressure (phase III) induced by anandamide and methanandamide, but had no effect on the reflex bradycardia and hypotension (phase I) and on the subsequent vasopressor effect (phase II) evoked by capsaicin, anandamide and methanandamide. In conclusion, the endogenous cannabinoid receptor agonist anandamide and its stable analogue methanandamide induce reflex bradycardia and hypotension (phase I) by activating the vanilloid VRI receptor. Whereas the mechanism underlying the brief vasopressor effect (phase II) is unknown, the prolonged hypotension (phase III) results from stimulation of the cannabinoid CB1 receptor.

Avoidance of allergens and air pollutants in respiratory allergy

Avoidance of allergens and air pollutants in respiratory allergy

Short-term cardiovascular responses to rapid whole-body tilting during exercise.

Our objective was to characterize the responses of heart rate (HR) and arterial blood pressure (BP) to changes in posture during concomitant dynamic leg exercise. Ten men performed dynamic leg exercise at 50, 100, and 150 W and were rapidly and repeatedly tilted between supine (0 degrees ) and upright (80 degrees ) positions at 2-min intervals. Continuous recordings of BP and HR were made, and changes in central blood volume were estimated from transthoracic impedance. Short-lasting increases in BP were observed immediately upon tilting from the upright to the supine position (down-tilt), averaging +18 mmHg (50 W) to +31 mmHg (150 W), and there were equally short-lasting decreases in BP, ranging from -26 to -38 mmHg upon tilting from supine to upright (up-tilt). These components occurred for all pressure parameters (systolic, mean, diastolic, and pulse pressures). We propose that these transients reflect mainly tilt-induced changes in total peripheral resistance resulting from decreases and increases of the efficiency of the venous muscle pump. After 3-4 s (down-tilt) and 7-11 s (up-tilt) there were large HR transients in a direction opposite to the pressure transients. These HR transients were larger during the down-tilt (-15 to -26 beats. min(-1)) than during the up-tilt (+13 to +17 beats. min(-1)), and increased in amplitude with work intensity during the down-tilt. The tilt-induced HR fluctuations could be modelled as a basically linear function of an arterial baroreflex input from a site half-way between the heart and the carotid sinus, and with varying contributions of fast vagal and slow sympathetic HR responses resulting in attenuated tachycardic responses to hypotensive stimuli during exercise.