Purification of a multimeric phospholipase A2 from rabbit renal cortex.
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Animals↗
Biomedical subjects
A R Morrison
Publications and source records attributed to A R Morrison.
Effect of the tyrosine kinase inhibitor, genistein, on interleukin-1 stimulated PGE2 production in mesangial cells.
Prostaglandin production and cAMP formation are two signaling pathways identified for IL-1, though neither adequately account for the multitude of effects of IL-1. To investigate the role of tyrosine phosphorylation in IL-1 signaling, we used the tyrosine kinase inhibitor, genistein. At 10-30 micrograms/ml, genistein blocked IL-1 stimulated prostaglandin production and induction of prostaglandin endoperoxide synthase (PES) in glomerular mesangial cells maintained in 10% serum. Addition of genistein hours after IL-1 addition also halted further PGE2 synthesis. Genistein failed to block PES activity in vitro, indicating it was not acting as a PES inhibitor. Overall these data suggest that tyrosine phosphorylation may be a required event for IL-1 stimulation of PGE2 and PES activity, either directly as part of IL-1 signaling, or indirectly as part of a serum/PDGF competence effect on mesangial cells.
Animals↗
REM sleep suppression by monoamine reuptake blockade: development of tolerance with repeated drug administration.
Drugs that block monoamine reuptake initially suppress rapid eye movement (REM) sleep in the cat and other species. Less is known about the effects of repeated drugs administration. Desipramine (DMI) and sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthylamine] (SER), which are relatively specific in blocking norepinephrine and serotonin reuptake, respectively, were each given to cats for approximately two and a half weeks. Six-hour sleep polygraphic records were obtained under the placebo condition, after acute drug administration, and again during chronic drug administration. DMI and SER both reduced REM sleep percentage acutely and in each case. Significant tolerance then developed. These actions of DMI and SER reflected changes in mean REM sleep episode duration as well as REM sleep episode number. Such differential effects of acute and chronic monoamine reuptake blockade on REM sleep behavior in the cat may ultimately be correlated with pharmacological changes at the receptor level.
1-Naphthylamine↗
Effects of monoamine reuptake blockade on ponto-geniculo-occipital wave activity.
Norepinephrine (NE) and serotonin (5HT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyl amine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features of hyperarousal; PGO wave suppression by antidepressant drugs may relate to clinical antidepressant actions.
1-Naphthylamine↗
Eicosanoid production by isolated glomeruli of rats with unilateral ureteral obstruction.
The production of PGE2 6-keto PGF1 alpha and TxB2 under basal conditions and after exposure to angiotensin II was examined in vitro in isolated glomeruli from sham-operated control rats and rats with unilateral ureteral obstruction of 24 hour duration, that were or were not pretreated with an inhibitor of the angiotensin I converting enzyme (ACE). Basal prostanoid production was greater in glomeruli from the obstructed kidney (OK) than in glomeruli from the contralateral kidney (CLK) of rats with obstruction or glomeruli from the kidneys of sham-operated rats. Glomeruli obtained from the CLK of rats with unilateral obstruction also produced more PGE2 and 6-keto PGF1 alpha than glomeruli obtained from kidneys of sham-operated rats. Administration of an ACE inhibitor to rats with unilateral obstruction in vivo returned basal prostanoid production in vitro to levels seen in glomeruli of sham-operated rats. The increase in prostanoid production in response to angiotensin II added in vitro was less in glomeruli from rats with unilateral obstruction than in glomeruli from sham-operated rats. However, the response was restored to that seen in glomeruli of sham-operated rats after blockade of angiotensin II synthesis in vivo in rats with unilateral obstruction. Blockade of angiotensin II synthesis in sham-operated rats did not affect prostanoid synthesis by their glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Role of ANG II in eicosanoid production by isolated glomeruli from rats with bilateral ureteral obstruction.
The production of prostaglandin (PG) E2, 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) under basal conditions and after exposure to angiotensin II (ANG II) or arginine vasopressin (AVP) was examined in vitro in isolated glomeruli. The glomeruli were obtained from control rats and rats with bilateral ureteral obstruction (BUO) of 24-h duration that were pretreated or not with an inhibitor of the angiotensin I converting enzyme (ACE). Basal prostanoid production was greater in isolated glomeruli from BUO rats than in controls. Administration of an ACE inhibitor, enalaprilat, given in vivo returned basal prostanoid production by isolated glomeruli of BUO rats to levels seen in glomeruli of control rats. The prostanoid production in response to addition of ANG II or AVP in vitro was blunted in glomeruli from BUO rats, but the response was restored to "normal" after blockade of ANG II synthesis in vivo in BUO rats. Blockade of ANG II synthesis in vivo did not affect prostanoid synthesis by isolated glomeruli of control rats. The prostanoid generation in response to addition of both ANG II and arachidonic acid in vitro compared with ANG II addition alone was not significantly stimulated in glomeruli from BUO rats. In contrast, it was significantly stimulated in glomeruli of control rats. The results indicate that endogenous ANG II has an important role in the increased synthesis of prostanoids found in isolated glomeruli of rats with BUO and that the in vitro prostanoid production in response to ANG II and AVP can be restored to normal when the synthesis of ANG II is inhibited in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Regulation of eicosanoid biosynthesis by phorbol ester in Madin Darby canine kidney cells.
We assessed the effects of the peptide agonist, bradykinin (BK), and phorbol myristate acetate (PMA) on prostaglandin E2 (PGE2) production, cyclooxygenase (COX) activity and mass, and arachidonic acid (AA) release in Madin Darby canine kidney (MDCK) cells. PMA stimulated PGE2 production by increasing both AA release and the activity of COX. Using [35S]methionine labeling and immunoprecipitation, we demonstrated that the increased COX activity is due to new COX synthesis. Actinomycin D and cycloheximide blocked the PMA-stimulated COX activity but not AA release. Both PMA-stimulated AA release and COX activity were reduced by the protein kinase C inhibitor staurosporine (STP). Glucocorticoids failed to alter PMA- or BK-stimulated PGE2 production was reduced by STP, indicating BK acts in part through protein kinase C activation. BK increased PGE2 production in PMA-treated cells, suggesting a protein kinase C-independent mechanism of action as well. BK did not stimulate any change in COX activity. We conclude that in MDCK cells PMA, but not BK, can stimulate both AA release and COX synthesis. Stimulation of COX synthesis requires either prolonged activation of protein kinase C and/or an additional nonprotein kinase C-mediated effect of PMA.
Animals↗
Startle-evoked changes in diaphragmatic activity during wakefulness and sleep.
Tonic inhibition of some respiratory muscles occurs as part of the generalized muscle atonia of rapid-eye-movement sleep (REMS). A second type of inhibition of the diaphragm during REMS, fractionations, consists of brief pauses in the diaphragmatic electromyogram (DIA EMG) in association with phasic events. Because motor inhibition can occur as part of the startle response, and the brain is highly activated during REMS, we hypothesized that the neural basis of the fractionations might be activation of a startle network. To test this hypothesis, tone bursts (100 dB, 20-ms duration at 15-s intervals) were applied to cats at a fixed inspiratory level in the DIA moving average during REMS, non-rapid-eye-movement sleep (NREMS), and wakefulness. Parallel sham studies (no tone applied) were obtained for each state. The response of the DIA EMG was averaged over 100 ms by using the tone pulse as a trigger, and the following parameters of the DIA EMG were measured: latency to peak and/or nadir, increment or decrement in activity, and duration of peak and/or nadir. After a tone, all five animals studied displayed a profound suppression of DIA activity during REMS (latency to nadir 42.4 +/- 10.0 ms, duration of suppression 35.9 +/- 17.6 ms). Similarly, DIA activity was suppressed in all cats during NREMS (latency to nadir 40.9 +/- 13.3 ms, duration 23.9 +/- 13.4 ms). An excitatory response was observed in only two cats during NREMS and wakefulness. The similarity of startle-induced DIA EMG pauses to spontaneous fractionations of DIA activity during REMS suggests that the latter result from activation of a central startle system.
Acoustic Stimulation↗
Mechanisms of seizure suppression during rapid-eye-movement (REM) sleep in cats.
REM sleep is the most antiepileptic state in the sleep-wake cycle for human generalized epilepsy, yet the neural mechanism is unknown. This study verified the antiepileptic properties of REM sleep in feline generalized epilepsy and also isolated the responsible factors. Conclusions are based on 20 cats evaluated for generalized EEG and motor seizure susceptibility before and after dissociation of specific REM sleep components. Bilateral electrolytic lesions of the medial-lateral pontine tegmentum created a syndrome of REM sleep without atonia. Systemic atropine created a syndrome of REM sleep without thalamocortical EEG desynchronization. Identical results were obtained in two seizure models, systemic penicillin epilepsy and electroconvulsive shock. (1) Normal REM sleep retarded the spread of EEG seizure discharges and had even more potent anticonvulsant effects. (2) Selective loss of 'sleep paralysis' (skeletal muscle atonia) during REM abolished REM sleep protection against myoclonus and convulsions without affecting generalized EEG paroxysms. (3) Conversely, selective loss of thalamocortical EEG desychronization abolished REM sleep protection against generalized EEG seizures without affecting clinical motor accompaniment. These results suggest that the descending brainstem pathways which mediate lower motor neuron inhibition also protect against generalized motor seizures during REM sleep. Protection against spread of EEG paroxysms is governed by a separate mechanism, presumably the ascending brainstem pathways mediating intense thalamocortical EEG desynchronization during REM sleep.
Animals↗
Bradykinin stimulated PGE2 production is independent of changes in intracellular calcium in MDCK cells.
In order to assess whether changes in intracellular Ca2+ are necessary for bradykinin stimulated activation of phospholipase A2 and PGE2 production, MDCK cells were treated with phorbol myristate acetate (PMA) and Lanthanum (La3+). 100 nM PMA reduced peak BK (1 uM) stimulated Ca2+ to 44.0 +/- 11.4% of control, while 1 mM LaC13 reduced peak Ca2+ to 43.5 +/- 12.2% of control. Addition of both PMA and LaC13 reduced the BK stimulated change in intracellular Ca2+ to 8.3 +/- 1.0% of control. In contrast, La3+ did not reduce PGE2 production in response to 10(-7) M to 10(-5) M BK. PMA stimulated PGE2 production, as shown previously. Addition of both PMA and La3+ at doses capable of reducing Ca2+ changes to less than 10% of normal, failed to block BK induced PGE2 production. Therefore, BK stimulated PLA2 activation and PGE2 production can be dissociated from changes in intracellular Ca2+ and suggest that BK activates PLA2 through a mechanism other than by increases in intracellular Ca2+.
Animals↗
Movement disorders during sleep in cats and dogs.
Spontaneous sleep movement disorders in 5 cats and 3 dogs were studied. Objective abnormalities during sleep were confirmed by electrographic or behavioral monitoring techniques in all animals. The cause of the disorder was CNS disease in 3 animals. A cause was not discovered in the other 5 animals, although at necropsy, 2 were found to have thyroid tumors. Many pharmacologic treatments were ineffectual, but trials with the benzodiazepine tranquilizer, clonazepam, suggested it will prove useful in controlling violent movements during rapid-eye-movement sleep.
Animals↗
Peptide hormones, cytosolic calcium and renal epithelial response.
We have reviewed the evidence that a number of hormones interact with renal tubular epithelial cells. The evidence suggests that in the mammalian renal tubule bradykinin and parathyroid hormone interact with cell surface receptors to initiate the hydrolysis of PIP2 leading to the formation of I 1,4,5P3 and diacylglycerol in the distal and proximal tubule, respectively. The activation of this second messenger system leads to the mobilization of Ca2+ from intracellular stores. Vasopressin does not activate this second messenger system in mammalian renal epithelial cells, and we cannot demonstrate I 1,4,5P3 formation and Ca2+ mobilization either in the rabbit papillary collecting tubules or in MDCK cells. There is evidence emerging, but not discussed here, that angiotensin II may also mediate some of its effects on the mammalian proximal tubule via the inositol polyphosphate second messenger system.
Animals↗
The effects of tones on PGO waves in slow wave sleep and paradoxical sleep.
Ponto-geniculo-occipital (PGO) waves are macropotential waveforms occurring spontaneously during paradoxical sleep (PS) in the pons, the lateral geniculate body (LGB), and the occipital cortex of the cat. In our earlier work (6, 20) tones elicited waves in the LGB and the occipital cortex during both slow wave sleep (SWS) and PS that resembled PGO waves in form and amplitude. Using a limited and variable number of trials, we observed that these elicited waveforms, which we term elicited PGO waves (PGOE), seemed to decline rapidly in amplitude and probability during SWS but not during PS. The present two experiments served as a more rigorous test of the hypothesis that the rate of habituation of PGOE would be more rapid in SWS. In a first experiment seven cats were studied in up to four sessions in PS and four in SWS; each session consisted of 32 1000-Hz, 90-dB SPL tones lasting 90 ms. We found that (i) the number of PGOE was significantly greater in PS; (ii) the mean amplitude of the waves was greater in PS; (iii) the probability of eliciting a wave tended to decline faster in SWS, but some decline also occurred in PS; and (iv) on the first trial, PGOE were more easily produced in SWS. Results of a second experiment with five cats suggested that the decline in the probability of PGOE in PS was not accounted for by differences in the ease of eliciting them at different times into a PS episode. The role of the dorsal raphe nucleus (DRN) in modulating state-dependent differences in PGOE is discussed.
Animals↗
Habituation of the startle reflex in posttraumatic stress disorder.
The authors investigated habituation of the eye-blink component of the startle reflex to repeated affectively neutral tactile and auditory stimuli in nine subjects with posttraumatic stress disorder and nine controls. Each group showed rapid habituation in both tactile and auditory modalities.
Acoustic Stimulation↗
Inhibition of bradykinin-induced increases of cytosolic Ca++ by a novel amiloride analog.
The present study was undertaken to determine whether activation of the Na+/H+ antiport regulates the bradykinin (BK)-induced Ca++ transient in Madin-Darby canine kidney cells. An amiloride analog, 5-N-N-ethyl[2-methoxy 5-nitrobenzyl]amiloride (L651,548), led to a dose-dependent inhibition of the BK-induced Ca++ transient (Ki = 9 microM), and this effect was eliminated in high external Na+. Zero external Na+ failed to inhibit the BK-induced Ca++ release, suggesting L651,548 is not acting through inhibition of the Na+/H+ antiport. Use of monovalent ionophores to adjust the intracellular pH demonstrated changes in peak Ca++ release by BK only over wide pH ranges. Furthermore, studies revealed L651,548 was much more potent at inhibiting pH recovery (Ki = 55 nM) than BK-induced Ca++ release. Studies in saponin-permeabilized cells demonstrated no effect of L651,548 on inositol trisphosphate-induced Ca++ release. Whole cell [3H] BK binding studies indicated a dose-dependent inhibition by L651,548. We conclude that the Na+/H+ antiport does not play a critical role in control of BK-induced Ca++ release in Madin-Darby canine kidney cells. Also, the amiloride analog L651,548 reduces BK Ca++ release by inhibition of BK receptor binding in Madin-Darby canine kidney cells.
Amiloride↗
Revising the differential diagnosis of the parasomnias in DSM-IIIR.
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Anxiety Disorders↗
Release of heat-loss responses in paradoxical sleep by thermal loads and by pontine tegmental lesions in cats.
Thermoregulatory heat-loss responses at high ambient temperatures were studied in intact cats and those with bilateral electrolytic lesions in the pontine tegmentum during wakefulness (W), slow-wave sleep (SWS), paradoxical sleep (PS) and PS without atonia induced by the lesions. Panting (respiratory rate greater than or equal to 90/min) was present during W, SWS, and in some cases, during PS. The percentage of the PS episodes with panting was directly related to ambient temperature. In intact cats at 30 degrees C, panting occurred in 8% of the PS episodes; at 35 degrees C, in 52%, and at 40 degrees C, in 77%. The percentage of PS episodes with panting was higher in the pontine-lesioned cats (90% at 35 degrees C), probably another indication of the altered thermoregulation of such animals. Thermoregulatory responses to heat load, and thermoregulation in general, have previously been shown to be suppressed in PS. Because hypothalamic thermosensitive neurons lack thermal responses during PS, the partial activation of heat-loss responses observed here may depend upon the function of extrahypothalamic brainstem areas.
Animals↗
Protein kinase C modulates phospholipase C and increases arachidonic acid release in bradykinin stimulated MDCK cells.
The tumor promoter phorbol ester (PMA) has been shown to stimulate protein kinase C (PKC) in MDCK cells. At the concentrations that produce stimulation of PKC, PMA (100 microM) inhibits BK-induced I1,4,5P3 (IP3) formation and calcium transients in these cells. 1-5-isoquinolinyl-2-methyl-piperazine (H7) a known inhibitor of PKC in MDCK cells reverses the effect of PMA on BK-stimulated IP3 formation and Ca2+ transients in these cells. PMA also stimulates arachidonate release which can be inhibited by preincubation with H7. A dual mechanism of regulation by PKC at the level of phospholipase C (down regulation) and phospholipase A2 (stimulation) is suggested in these cells.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗