Effects of moguisteine on the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve in guinea pigs

The study aimed to further demonstrate the peripheral antitussive properties of moguisteine. Firstly, the antitussive effect of moguisteine on the cough reflex induced by inhalation of citric acid aerosol was evaluated in conscious guinea pigs. Secondly, the effects of both moguisteine and codeine on the centrally mediated cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve were investigated in anesthetized guinea pigs. Moguisteine (2.5-10 mg/kg, intravenously, i.v.) reduced the cough reflex induced by 7.5% citric acid aerosol in a dose-dependent manner, with an ED50 value of 0.55 mg/kg. Both i.v. (0.5-4 mg/kg) and intracerebroventricular (i.c.v., 5-20 microg) injection of codeine dose dependently inhibited the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve; the ED50 values were 0.91 mg/kg and 7.90 microg, respectively. The inhibitory effect of codeine (4 mg/kg i.v.) was abolished by pretreatment with naloxone (2 mg/kg intraperitoneally). In contrast to codeine, neither i.v. (4 and 20 mg/kg) nor i.c.v. (20 microg) injection of moguisteine affected the cough reflex. These results suggest that the antitussive effect of codeine is mediated by central opioid mechanisms, whereas the antitussive effect of moguisteine is mediated by peripheral mechanisms.     

Antinociception produced by an ascending spino-supraspinal pathway

Studies in mice and rats have shown that antinociception produced by intrathecal (i.t.) administration of opioids can be partially inhibited by intracerebroventricular (i.c.v.) administration of naloxone. In this study we tested the hypothesis that this inhibition by i.c.v. naloxone results from antagonism of supraspinal endogenous opioid-mediated antinociception produced by the action of i.t. opioids on an ascending antinociceptive pathway. In rats lightly anesthetized with urethane/alpha-chloralose, i.t. DAMGO, i.t. lidocaine, or spinal transection at T5-T6 all attenuated the trigeminal jaw opening reflex (JOR) (i.e., were antinociceptive), an effect that was antagonized in each case by i.c.v. naloxone. These findings support the suggestion that there exists a pathway that ascends from the spinal cord to a supraspinal site that tonically inhibits antinociception mediated by supraspinal opioids. When activity in this ascending pathway is suppressed (e.g., by i.t. opioids or local anesthetics or by spinal cord transection), antinociception mediated by supraspinal opioids is disinhibited. To determine the supraspinal site(s) at which endogenous opioid-dependent antinociception is evoked by i.t. opioids, we microinjected naloxone methiodide into several supraspinal sites. Microinjection of naloxone methiodide into nucleus accumbens but not into the rostral ventral medulla (RVM) or the periaqueductal gray matter (PAG) antagonized the suppression of the JOR produced by i.t. DAMGO or lidocaine. The possibility that this ascending pathway may represent a source of spinal input to mesolimbic circuitry involved in setting the state of sensorimotor reactivity to noxious stimuli is discussed.     

Antinociceptive properties of propofol: involvement of spinal cord gamma-aminobutyric acid(A) receptors

In this study, we investigated the interaction of propofol (a compound used widely as an intravenous anesthetic) with gamma-aminobutyric acid(A) (GABA(A)) and delta opioid receptors at the level of the spinal cord. Nociceptive thresholds were measured in rats through the use of electrical current testing (ECT) and tail-flick latency. Full recovery from sedation occurred 36.3 +/- 1.7 min (mean +/- S.E.M.; n = 20) after 40 mg/kg propofol i.p. Forty minutes after administration, there was residual antinociception when assessed by ECT but not when assessed by noxious heat. The ECT antinociceptive effects of propofol at tail but not neck sites were suppressed by intrathecal injection of the GABA(A) antagonists bicuculline and SR-95531 and the delta opioid antagonist naltrindole. These results suggest that there is an interaction between propofol and antagonists at receptors in the caudal segments of the spinal cord responsible for tail innervation. Antagonist dose-response curves were compared with those for suppression of intrathecal midazolam-induced antinociception. All intrathecal antagonists reversed the antinociceptive effect of propofol with the same dose-response curves as those previously obtained for suppression of the effect of intrathecal midazolam. We conclude that propofol, when given intraperitoneally, produces antinociception in rats through an interaction with spinal GABA(A) receptors. This combination leads to activation of a spinal cord system involving a delta opioid receptor; the same mechanisms involved with midazolam-induced spinal antinociception.     

Acetate-free biofiltration versus bicarbonate haemodialysis in the treatment of patients with diabetic nephropathy: a cross-over multicentric study

BACKGROUND: Recent evidence suggests that the spinal cord is an important site of anesthetic action that produces surgical immobility. Inhalation anesthetics depress the Hoffmann's reflex (H reflex) and F wave, indicating spinal motoneuron suppression. The aim of this study was to assess the correlation between isoflurane-induced immobility and H- and F-wave suppression. METHODS: The baseline H reflex and F wave were measured before anesthesia in 15 adult patients. After induction, 1% end-tidal isoflurane was maintained for 20 min before the H and F waves were reelicited. Using an electric stimulus applied to the forearm and grading the response as movement or no movement, the authors increased or decreased the isoflurane concentration in 0.1% steps, depending on the movement responses. The H and F waves were recorded 20 min after each change of isoflurane concentration. The correlation between H- and F-wave suppression and surgical immobility was analyzed using a paired t test with Bonferroni correction. RESULTS: H-reflex amplitude (2.74 +/- 1.63 mV) and F-wave persistence (70.69 +/- 26.19%) at the highest isoflurane concentration that allowed movement response to a stimulus are different (P < 0.01) from these (1.97 +/- 1.46 mV; 43.16 +/- 22.91%) at the lowest isoflurane concentration that suppressed response. At 0.8% isoflurane, the H-reflex amplitude was 3.69 +/- 1.83 mV with movement and 1.01 +/- 1.14 mV without movement (P < 0.01); F-wave amplitude was 0.29 +/- 0.15 mV with movement and 0.11 +/- 0.06 mV without movement (P < 0.01); F-wave persistence was 80 +/- 22.36% with movement and 34.9 +/- 25.75% without movement (P < 0.01). CONCLUSIONS: The degree of H- and F-wave amplitude and F-wave persistence suppression correlates with movement response, suggesting that isoflurane-suppressive action in the spinal cord plays a significant role in producing surgical immobility.     

Effect of imipramine and ftoracizin on platelet aggregation and smooth muscle contraction of the ureter

The influence of the tricyclic antidepressants imipramine and ftoracizin on platelet aggregation and smooth muscle contractility was investigated in comparison with action of known smooth muscle relaxant and platelet aggregation inhibitor, papaverine. It has been shown that the tricyclic antidepressants possess potent spasmolytic activity but unlike papaverine have no effect on platelet aggregation. The biochemical mechanisms of the non-specific action of tricyclic antidepressants as well as some other structurally related-drugs are discussed.     

Effects of posterior teeth replacement on temporomandibular joint sounds: a preliminary report

Previous reports have shown the prevalence of jaw clicking to be significantly higher in a population with missing posterior teeth compared with an dentulous population. This study presents a 2- to 5-year assessment of the effects of posterior teeth replacement on the amplitude of jaw clicking in subjects who were asymptomatic in all respects except jaw clicking. Patients requiring removable partial dentures (RPDs) were clinically and anamnestically examined and temporomandibular joint (TMJ) sounds were recorded using a modified stethoscope attached to an adjustable headgear. Amplified signals were displayed on a strip chart recorder. The amplitude of TMJ sounds at preinsertion of RPDs were 27.5 +/- 17.7 dB at opening, and 11.1 +/- 12.7 dB at closing. Similar values after prosthesis insertion were 15.8 +/- 17.0 dB and 7.4 +/- 7.5 dB, respectively. Paired t test analyses showed significant differences in the amplitude of sound for opening and closing before inserting the prosthesis (p = 0.003) and for opening before and after treatment (p = 0.014). Following replacement of posterior teeth, the clicking amplitude decreased in 68% of recordings, remained unchanged in 11%, and increased in 21%.     

Chronic desipramine treatment desensitizes the rat to anesthetic and antinociceptive effects of the alpha2-adrenergic agonist dexmedetomidine

INTRODUCTION: The effects of long-term administration of the tricyclic antidepressant agent desipramine on the hypnotic, antinociceptive, anesthetic-sparing, and central norepinephrine turnover suppressant action of short-term dexmedetomidine, a highly selective alpha2-adrenergic agonist, were studied in rats. METHODS: Rats were given a 3- or 4-week course of twice daily administration of desipramine, 10 mg/kg, or saline. The effect of a hypnotic dose of dexmedetomidine, 250 microg/kg given intraperitoneally, on the duration of loss of righting reflex was determined. The tail flick latency response was determined before and after 50 microg/kg dexmedetomidine. The minimum anesthetic concentration of halothane and the central norepinephrine turnover rate were determined before and after administration of 30 microg/kg dexmedetomidine. Changes in the affinity and density of the alpha2-adrenergic receptor in locus coeruleus and spinal cord also were determined. RESULTS: Treatment with desipramine decreased dexmedetomidine-induced loss of righting reflex duration by 67% and eliminated the antinociceptive effect of dexmedetomidine. Dexmedetomidine produced a 55% decrease in minimum anesthetic concentration in the control group but no reduction in desipramine-treated rats. Desipramine did not change the receptor density or binding affinity of alpha2 receptors at the site for hypnotic (locus coeruleus) or antinociceptive (spinal cord) responses. No decrement in the central norepinephrine turnover rate was noted in the locus coeruleus of dexmedetomidine after 3 weeks of treatment with desipramine. The alpha1-adrenergic antagonist prazosin at 1 or 5 mg/kg completely (minimum anesthetic concentration reduction), almost completely (antinociceptive), or partially (hypnotic) restored responsiveness to normal. CONCLUSIONS: These data indicate that treatment with desipramine induces hyporesponsiveness to the hypnotic, analgesic, and minimum anesthetic concentration-reducing, but not to the suppression of central norepinephrine turnover, properties of dexmedetomidine. The hyporesponsiveness appears to involve an alpha1-adrenergic mechanism.     

Intracisternal antisense oligodeoxynucleotides to the thyrotropin-releasing hormone receptor blocked vagal-dependent stimulation of gastric emptying induced by acute cold in rats

Cold exposure increases TRH gene expression in hypothalamic and raphe nuclei and results in a vagal activation of gastric function. We investigated the role of medullary TRH receptors in cold (4-6 C, 90 min)-induced stimulation of gastric motor function in fasted conscious rats using intracisternal injections of TRH receptor (TRHr) antisense oligodeoxynucleotides (100 microg twice, -48 and -24 h). The gastric emptying of a methyl-cellulose solution was assessed by the phenol red method. TRH (0.1 microg) or the somatostatin subtype 5-preferring analog, BIM-23052 (1 microg), injected intracisternally increased basal gastric emptying by 34% and 47%, respectively. TRHr antisense, which had no effect on basal emptying, blocked TRH action but did not influence that of BIM-23052. Cold exposure increased gastric emptying by 64%, and the response was inhibited by vagotomy, atropine (0.1 mg/kg, i.p.), and TRHr antisense (intracisternally). Saline or mismatched oligodeoxynucleotides, injected intracisternally under similar conditions, did not alter the enhanced gastric emptying induced by cold or intracisternal injection of TRH or BIM-23052. These results indicate that TRH receptor activation in the brain stem mediates acute cold-induced vagal cholinergic stimulation of gastric transit, and that medullary TRH may play a role in the autonomic visceral responses to acute cold.     

Clinical, neurophysiological and hemodynamic effects of a new nondepolarizing myorelaxant mivacurium in heart surgery patients]

Thirty patients aged 23 to 65 years with ASA class III operated on the heart under total intravenous anesthesia were examined after the Good Clinical Practice protocol. Mivacurium in bolus dose of 0.2 mg/kg was injected for intubation of the trachea; neuromuscular blocking (NMB) was maintained by a repeated injection of the drug in a dose of 0.15 mg/kg, after which it was infused at a rate of 1 to 10 micrograms/kg/min. Accelerometric control of neuromuscular conduction was carried out by the Organon (Belgium) TOF-Guard device. Central and peripheral hemodynamics was monitored. Side effects of the drug were recorded. Bolus injection of mivacurium in a dose of 0.2 mg/kg caused T1 suppression (90%) after 2.6 +/- 0.7 min. Maximal (97.7 +/- 4.5%) suppression was observed after 4.17 +/- 2.5 min. The conditions of intubation of the trachea after 3.9 +/- 1.8 min in the presence of 78 to 100% T1 suppression (97.7 +/- 4.5%) were considered excellent or good in 96.6% of cases. Clinically and neurophysiologically sufficient muscle relaxation after the first injection of the drug persisted for 27.7 +/- 7.3 min. Minimal rate of infusion for maintaining the NMB at 95 +/- 4% level of T1 suppression was 6.3 +/- 1.7 micrograms/kg/min. Bolus injection of mivacurium in a dose of 0.2 mg/kg for 60 sec involved a 1-3-min drop of the mean arterial pressure by 10.5% and a 10.3% decrease of heart rate. Repeated bolus injection of the drug in a dose of 0.15 mg/kg and its infusion did not change the peripheral and central hemodynamics. The most typical side effect of the drug in a dose of 0.2 mg/kg is short-term reversible reddening of the skin of the face and neck, observed in 20% of patients. The results permit us to consider mivacurium as an effective, safe, and controllable agent, which can be used in cardiosurgical patients.     

Suppression of an inhibitory jaw reflex by the anticipation of pain in man

Electromyographic recordings (EMGs) were made from the active masseter muscle, of the inhibitory reflex evoked by application of electrical stimuli to the skin of the upper lip in 15 human subjects. In control sequences, the reflex had a mean latency and duration (+/- S.E.M.) of 45.4 +/- 1.3 msec and 47.9 +/- 2.8 msec, respectively. Significant decreases in the reflex as well as increases in heart rate and anxiety levels assessed by a visual analogue scale, occurred when the subjects were stressed by the anticipation of receiving painful electrical stimuli above the ankle (P < 0.00005; Student's t-tests). During such sequences, the magnitude of the reflex measured by integration of the EMG, was reduced by 47.7 +/- 5.6%. This effect involved a reduction in both the duration and depth of the inhibitory wave. It occurred regardless of whether the painful stimuli were applied during or after the recording of the reflex and of whether the baseline activity in the muscle was inadvertently raised or lowered during the stressful sequences. It is concluded that stress induced by the anticipation of pain, can markedly reduce an inhibitory jaw reflex in man by exerting an influence on the reflex pathway prior to the motoneurones.     

Effects of viloxazine, an antidepressant agent, on biogenic amine uptake mechanisms and related activities

The effects of viloxazine, a clinically effective antidepressant, on noradrenaline (NA) and 5-hydroxytryptamine (5-HT) uptake and various related pharmacological activities were determined and compared to those of the tricyclic antidepressants desimipramine, imipramine, and amitriptyline. Viloxazine inhibitied [3H]NA uptake in the mouse and rat heart, being maximally about one half as potent as imipramine with a similar onset, but shorter duration of action than imipramine. The drug did not inhibit [3H]NA uptake in rat medulla or hypothalamus in contrast to desimipramine and imipramine, but it did alter [3H]NA metabolites in a similar manner. Viloxazine, like desimipramine, was a weak blocker of mouse brain 5-HT uptake, but differed from desimipramine as it poteniated 5-HT-mediated functions in the mouse and rat, as did imipramine and amitriptyline, the latter drugs being relatively potent blockers of 5-HT uptake. Viloxazine potentiated the L-DOPA behavioural syndrome in the mouse, antagonized reserpine-induced ptosis and hypothermia in the mouse, and inhibited gastric acid secretion in the rat, but was less potent than the tricyclic antidepressants. No appreciable in vivo inhibition of monoamine oxidase (EC 1.4.3.4.) activity in the mouse was exhibited. Like imipramine, the drug potentiated the ocular effects of L-adrenaline in the rabbit. It was similar to imipramine in potency in potentiating the apomorphine-induced gnawing in the mouse. The drug antagonized oxotremorine-induced hypothermia in the mouse but differed from the tricyclic antidepressants in not exhibiting the anticholinergic effects of blocking the tremors, salivation and lacrimation. Thus, viloxazine exhibits activities related to the biogenic amines both similar to and different from the tricyclics desimipramine, imipramine, and amitriptyline. These actions appear to be of relevance with respect to the antidepressant action of this drug.     

Morphine administered in the substantia gelatinosa of the spinal trigeminal nucleus caudalis inhibits nociceptive activities in the spinal trigeminal nucleus oralis

The present study investigates the effects of morphine microinjection into the spinal trigeminal nucleus caudalis (Sp5C) or the spinal trigeminal nucleus oralis (Sp5O) on C-fiber-evoked activities of Sp5O convergent neurons, after supramaximal percutaneous electrical stimulation in halothane-anesthetized rats. When it was microinjected into the Sp5O, morphine (2.5 microg in 0. 25 microl) never depressed the C-fiber-evoked responses of Sp5O convergent neurons (n = 13), whereas these neurons were responsive to the inhibitory effects of systemic morphine (6 mg/kg, i.v.) in a naloxone-reversible manner. On the contrary, morphine microinjected into the Sp5C produced a naloxone-reversible inhibition of the C-fiber-evoked responses of Sp5O neurons (n = 14). The magnitude and the time course of this effect varied according to the location of the injection sites. After microinjection into the superficial laminae (n = 7), a strong depressive effect of morphine (7 +/- 5% of control) on the C-fiber-evoked responses was apparent as soon as 5 min after the injection and could always be reversed by naloxone, administered either intravenously (0.4 mg/kg) or locally (2.5 microg in 0.6 microl) at the same site as morphine. After microinjection into deeper laminae (V-VI), a significant depressive effect (34 +/- 5% of control) of morphine could be detected only 20 min after the injection and was reversed only by intravenous administration of naloxone. These results suggest that morphine exerts its antinociceptive action on Sp5O convergent neurons by blocking the C-fiber inputs that relay in the Sp5C substantia gelatinosa. The mechanisms that underlie the activation of Sp5O convergent neurons by C-fibers and the inhibition of C-fiber-evoked responses of Sp5O convergent neurons by morphine microinjected into the Sp5C are discussed.     

Clinical evaluation of a posterior composite 10-year report

OBJECTIVE: To determine if the long-term use of continuously infused intrathecal baclofen (ITB) over a 1-year period will control spastic-dystonic hypertonia in patients with traumatic brain injury (TBI). SETTING: Tertiary care outpatient and inpatient rehabilitation center directly attached to a university hospital. SUBJECTS: Persons with TBI and intractable spasticity and dystonia for more than 6 months' duration recruited in a consecutive manner. DESIGN: TBI patients were admitted to the study after screening via a bolus injection of either intrathecal normal saline or 50 microg of baclofen. Data for Ashworth rigidity scores, spasm scores, and deep tendon reflex scores were collected for both the upper extremities (UE) and lower extremities (LE). Patients whose LE Ashworth scores decreased an average of 2 points were then offered implantation of a computer-controlled pump for continuous ITB. Changes over time were assessed statistically via Friedman's analysis for ordinal data and ANOVA for linear data. Differences between set points in time were also assessed via Wilcoxon signed rank. DATA SET: Seventeen patients (average age 29+/-11 yrs) with spasticity and/or dystonia treated over 1 year via a computer-controllable intrathecal delivery system for the delivery of ITB. RESULTS: After 1 year of continuous ITB treatment the average LE Ashworth score decreased from 3.5+/-1.3 (SD) to 1.7+/-0.9 (p < .0001), spasm score from 1.8+/-1.3 to 0.2+/-0.5 (p< .0001), and reflex score from 2.5+/-1.1 to 0.1+/-0.3 (p < .0001). The average UE Ashworth score decreased from 2.9+/-1.5 to 1.6+/-1.0 (p < .0001), spasm score from 1.2+/-1.5 to 0.2+/-0.6 (p < 0.0001), and reflex score from 2.2+/-0.5 to 1.0+/-0.8 (p < .0001). The average ITB dose required to attain these effects at 1 year was 302 microg continuously infused per day. CONCLUSION: Continuous intrathecal infusion of baclofen is capable of maintaining a reduction in spasticity and dystonia in both the upper and lower extremities of TBI patients.     

Absence of antinociceptive tolerance to improgan, a cimetidine analog, in rats

Improgan, an analog of the histamine receptor antagonist cimetidine, produces highly effective analgesia following intraventricular injection. The present study examined changes in the antinociceptive effects of improgan following once daily intraventricular injections. Improgan (100-150 microg) produced near maximal antinociception 10 and 30 min after daily administration on all 4 test days, whereas comparable morphine treatments (50 microg) induced considerable tolerance. Thus, improgan produced highly effective analgesia without the development of tolerance.     

The inhibitory effect of nociceptin on the micturition reflex in anaesthetized rats

1. We have investigated the effect of nociceptin on the micturition reflex evoked by distension or topical application of capsaicin on the urinary bladder of urethane-anaesthetized rats. 2. Nociceptin produced a dose-dependent (3-100 nmol kg(-1) i.v.) transient suppression of the distension-evoked micturition reflex: its effect was not modified by guanethidine (68 micromol kg(-1) s.c.) nor by bilateral cervical vagotomy, alone or in combination, and by naloxone (1.2 micromol kg(-1) i.v.). 3. Nociceptin (100 nmol/kg i.v.) slightly (about 30%) inhibited the contractions of the rat bladder produced by pre- or postganglionic electrical stimulation of the pelvic nerve. 4. Nociceptin almost totally abolished the reflex component of the response to topical capsaicin (1 microg in 50 microl). 5. In the rat isolated bladder, submaximal contractions produced by electrical field stimulation were slightly reduced (25+/-4% inhibition) by 1 microM nociceptin. Nociceptin did not affect the contraction of the rat bladder induced by acetylcholine (10 microM) or ATP (1 mM). 6. These findings indicate that nociceptin exerts a naloxone-resistant suppression of the volume-evoked micturition reflex which involves inhibition of transmitter release from postganglionic bladder nerves. An inhibitory effect on bladder afferent nerves is also suggested.     

Pharyngo-UES contractile reflex in patients with posterior laryngitis

BACKGROUND: Earlier studies have shown that stimulation of the human pharynx by injection of minute amounts of water stimulates the pharyngo-UES contractile reflex. It has been suggested that this reflex may be activated during pharyngeal reflux of gastric and/or esophageal content, thus increasing the UES pressure and possibly preventing further entry of the refluxate into the pharynx. However, the integrity of this reflex in patients with posterior laryngitis has not been studied. AIM: Evaluate the pharyngo-UES contractile reflex in a group of patients with objective findings of posterior laryngitis. METHODS: Fourteen consecutive patients with posterior laryngitis (mean age, 48+/-6 y) and 13 healthy volunteers (mean age, 53+/-6 y) were studied by concurrent pharyngeal water stimulation and UES manometry. RESULTS: The threshold volume required to evoke the pharyngo-UES contractile reflex in the laryngitis group (0.4+/-0.05 mL) was significantly higher than that of the control (0.2+/-0.04 mL) (P < .05). Following stimulation of the pharyngo-UES contractile reflex, the maximum postinjection pressure in patients (75+/-6 mm Hg) was similar to that of the controls (78+/-6 mm Hg). The percent increase in UES pressure following stimulation of the reflex in the laryngitis group (99%+/-15%) was significantly higher than that of controls (55%+/-11%) (P < .05). CONCLUSIONS: Compared with normal controls, a significantly larger volume of liquid is required to trigger this reflex in patients with posterior laryngitis. When triggered, the maximum UES pressure induced by the pharyngo-UES contractile reflex is similar between the two groups. These findings suggest an altered afferent sensory limb of this reflex in patients with posterior laryngitis.     

The localisation of TPPS4 in some organs and its possible nephrotoxicity in rats

Endogenous opioids have been implicated in the mechanism of action of antidepressant drugs. In this study, we evaluated effects of single and repeated imipramine administration on proenkephalin and prodynorphin gene expression in the rat nucleus accumbens and striatum. In situ hybridization study showed that single imipramine injection (10 mg/kg, i.p.) decreased the level of proenkephalin (by ca. 20%) and prodynorphin (by ca. 25%) mRNA to the same extent in both structures. Repeated imipramine administration (10 mg/kg i.p. twice daily for 10 days) had no effect on proenkephalin mRNA level, whereas the prodynorphin gene expression was regulated differently. At 3 h after the last dose of imipramine the prodynorphin mRNA level was decreased (by ca. 25%) in the striatum, but not in the nucleus accumbens, whereas at 24 h an up-regulation (by ca. 27%) of prodynorphin mRNA level could be observed in the nucleus accumbens only. In the light of involvement of opioids in mood regulation, these adaptive changes may participate in neurochemical mechanisms of antidepressant therapy.     

The rate zonal separation of organelles from dilute suspensions: the problem of a large sample volume

We previously showed that preoperative nicorandil, a hybrid potassium channel opener and nitrate compound, conferred cardioprotective effects in a hypoxia/reoxygenation model of isolated human atrial muscle by using functional recovery as an end point, and that ischaemic preconditioning surprisingly abolished the protection afforded by nicorandil. In view of this paradoxic result, this study was undertaken to assess whether ischaemic preconditioning influences any protective effect of nicorandil by using infarct size as an end point. In addition, we investigated the underlying mechanisms of the protective action of nicorandil. Rabbits underwent a midline sternotomy under anaesthesia. A left coronary branch was occluded for 30 min followed by 120 min of reperfusion. Nicorandil (100 microg/kg bolus + 10 microg/kg/min) was given intravenously 30 min before coronary occlusion and continued to the time of reperfusion (early treatment) or 5 min before reperfusion and continued throughout reperfusion (late treatment). Ischaemic preconditioning was achieved by a single episode of 5-min coronary occlusion followed by 10-min reperfusion before the 30-minute occlusion in the presence or absence of nicorandil. Risk volume and infarct volume were determined by fluorescent microspheres and tetrazolium staining, respectively. Early treatment with nicorandil conferred a significant decrease in percentage of infarct size within the risk zone (24.9 +/- 2.9%) when compared with control (39.2 +/- 4.3%; p < 0.01). Late treatment with nicorandil had no effect on infarct size (43.5 +/- 3.4%). Ischaemic preconditioning also resulted in significant reduction in infarct size (13.4 +/- 4.3%; p < 0.01 vs. control). The combination of ischaemic preconditioning with nicorandil (early treatment) showed an intermediate protective efficacy between early treatment with nicorandil alone and ischaemic preconditioning alone (18.1 +/- 4.2%; p < 0.01 vs. control). Nitroglycerin (10 microg/kg bolus + 1 microg/kg/kg/min, i.v.) given before and during ischaemia tended to reduce infarct size, but the effect was not statistically significant (28.9 +/- 2.9%; p > 0.05 vs. control). Although an adenosine triphosphate (ATP)-sensitive potassium channel blocker, 5-hydroxydecanoate (5 mg/kg, i.v.) by itself had no effect on infarct size (38.8 +/- 3.6%), the protective effect of nicorandil was abolished by 5-hydroxydecanoate (37.7 +/- 5.8%; p < 0.05 vs. early treatment of nicorandil). There were no differences in area at risk or haemodynamics between groups. Our results show that nicorandil has a protective effect against myocardial infarction in our rabbit model when infused before and during ischaemia, but not during reperfusion, and the protective effect is abolished by an ATP-sensitive potassium channel blocker. Furthermore, the addition of ischaemic preconditioning does not detrimentally influence the effect of nicorandil. This suggests that nicorandil can confer an infarct-limiting effect by opening of ATP-sensitive potassium channels with or without intermittent ischaemia, as may happen in patients with unstable angina.     

Recovery of growth hormone release from suppression by exogenous insulin-like growth factor I (IGF-I): evidence for a suppressive action of free rather than bound IGF-I

To determine the time course of recovery of GH release from insulin-like growth factor I (IGF-I) suppression, 11 healthy adults (18-29 yr) received, in randomized order, 4-h i.v. infusions of recombinant human IGF-I (rhIGF-I; 3 microg/kg-h) or saline (control) from 25.5-29.5 h of a 47.5-h fast. Serum GH was maximally suppressed within 2 h and remained suppressed for 2 h after the rhIGF-I infusion; during this 4-h period, GH concentrations were approximately 25% of control day levels [median (interquartile range), 1.2 (0.4-4.0) vs. 4.8 (2.8-7.9) microg/L; P < 0.05]. A rebound increase in GH concentrations occurred 5-7 h after the end of rhIGF-I infusion [7.6 (4.6 -11.7) vs. 4.3 (2.5-6.0) microg/L; P < 0.05]. Thereafter, serum GH concentrations were similar on both days. Total IGF-I concentrations peaked at the end of the rhIGF-I infusion (432 +/- 43 vs. 263 +/- 44 microg/L; P < 0.0001) and remained elevated 18 h after the rhIGF-I infusion (360 +/- 36 vs. 202 +/- 23 microg/L; P = 0.001). Free IGF-I concentrations were approximately 140% above control day values at the end of the infusion (2.1 +/- 0.4 vs. 0.88 +/- 0.3 microg/L; P = 0.001), but declined to baseline within 2 h after the infusion. The close temporal association between the resolution of GH suppression and the fall of free IGF-I concentrations, and the lack of any association with total IGF-I concentrations suggest that unbound (free), not protein-bound, IGF-I is the major IGF-I component responsible for this suppression. The rebound increase in GH concentrations after the end of rhIGF-I infusion is consistent with cessation of an inhibitory effect of free IGF-I on GH release.     

Possible role of nitric oxide in the antinociceptive action of intraventricular bradykinin in mice

The i.c.v. administration of bradykinin (4, 8 and 16 micrograms) induced antinociception in mice which was resistant to naloxone; furthermore, the induction of tolerance to morphine by a single s.c. injection (100 mg/kg, 24 h before test doses of the peptide) did not affect antinociception. Since bradykinin is known to increase nitric oxide (NO) in peripheral tissues, we studied the possibility that its antinociceptive action may be related to NO effects in the central nervous system. Bradykinin effects were antagonized by previous treatment with NG-nitro-L-arginine or concomitant i.c.v. administration of bradykinin and methylene blue. The immediate precursor of NO, L-arginine, which by itself produces analgesia, also reduced bradykinin effects; moreover, tolerance to L-arginine significantly decreased the response to the peptide. These results suggest that NO is involved in antinociception induced by i.c.v. administration of bradykinin.