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PubMed2005

Augmented breath phase volume and timing relationships in the anesthetized rat.

Augmented breaths (ABs), or sighs, are airway protective reflexes and part of the normal repertoire of respiratory behaviors. ABs consist of two phases, where phase I volume and timing resembles preceding eupnic breaths, and phase II is an augmenting motor pattern and occurs at the end of phase I. Recent evidence suggest multiple respiratory motor patterns can occur following dynamic functional reconfiguration of one respiratory neural network. It follows that the response of the respiratory network to modulatory inputs also may undergo dynamic reconfiguration. We hypothesized that lung-volume related feedback during ABs would alter AB timing differentially during phase I and II. We measured phase I and II volumes and durations in urethane anesthetized rats with decreased lung volume secondary to three models of varying phrenic motor impairment (spinal injury alone, unilateral phrenicotomy, and combined injuries). AB phase I and II inspired volume were decreased after phrenic motor impairment (p<0.05). In contrast, only phase I duration following injury was altered compared to controls. Phase II duration remaining unchanged despite the greatest effect of injury on volume occurring during phase II. Thus, sigh volume-timing relationships differ between phases of an augmented breath suggesting that the response of the respiratory network to modulatory inputs has changed. These data support the hypothesis that multiple respiratory behaviors occur following dynamic reconfiguration of the respiratory neural network.

Anesthesia, General↗

PubMed1997

Studies on the release and extracellular metabolism of endogenous ATP in rat superior cervical ganglion: support for neurotransmitter role of ATP.

The release of endogenous ATP, measured by the luciferin-luciferase assay, and the release of [3H]acetylcholine from the isolated superior cervical ganglion of the rat loaded with [3H]choline were studied simultaneously. Electrical field stimulation enhanced the release of endogenous ATP and acetylcholine in a [Ca2+]o-dependent manner. The Na+ channel blocker, tetrodotoxin (1 microM) inhibited the stimulation-evoked release of endogenous ATP and of [3H]acetylcholine, but did not change the resting release. The release of ATP was dependent on the frequency of stimulation between 2 and 10 Hz. when the number of shocks was kept constant (360 shocks), while acetylcholine was not released in a frequency-dependent fashion. Ten days after cutting of the preganglionic nerve of the superior cervical ganglion the stimulation-evoked release of acetylcholine and ATP was abolished and the uptake of [3H]choline was significantly reduced but not inhibited. Hexamethonium, (100 microM) a nicotinic acetylcholine receptor antagonist, significantly reduced the release of both acetylcholine and ATP, indicating a positive feedback modulation of ACh and ATP release. 8-Cyclopentyl-1,3-dipropylxanthine (10 nM), the selective A1-adenosine receptor antagonist exhibited similar effect on the release of ATP and acetylcholine: both of them were augmented, showing that the stimulation-evoked release of ATP and acetylcholine are under the inhibitory control of A1-adenosine receptors. When the temperature was reduced to 7 degrees C to inhibit carrier-mediated processes, the resting and stimulated release of acetylcholine was not changed. Conversely, the release of ATP in response to stimulation was reduced by 79.9 +/- 5.6%, and the basal release was also almost completely blocked. Carbamylcholine by itself was able to release ATP, but not acetylcholine, in a hexamethonium-inhibitable manner, even from ganglia whose preganglionic nerve had been cut 10 days prior to experiments, suggesting that ATP release can occur in response to nicotinic receptor stimulation of postsynaptic cells. The breakdown of ATP or AMP by superior cervical ganglion was measured by high performance liquid chromatography combined with UV detection. ATP and AMP, added to the tissues, were readily decomposed: the Km (apparent Michaelis constant) and Vmax (apparent maximal velocity) were 475 +/- 24 microM and 3.50 +/- 0.18 nmol/min per mg for ectoATPase and 1550 +/- 120 microM and 14.5 +/- 0.9 nmol/min per mg tissue for 5'-nucleotidase. In addition, by using electron microscopic enzyme histochemistry, the presence of ectoATPase was also shown in the superior cervical ganglion. It is concluded that endogenous ATP and acetylcholine are released simultaneously in response to stimulation of preganglionic nerve terminals in the superior cervical ganglion in a [Ca2+]o-dependent, tetrodotoxin-sensitive manner and is metabolized by ectoenzymes present in the tissue. The dissociation of the release of ATP and acetylcholine at different stimulation frequencies and temperatures shows that the release-ratio of acetylcholine and ATP can vary upon the condition of stimulation: this can reflect either the different composition of synaptic vesicles in the preganglionic nerve terminals or a significant contribution of non-exocytotic, carrier-mediated type of release of ATP to the bulk release.

Adenosine Triphosphate↗

PubMed1997

Influence of chronic Naltrexone treatment on growth hormone and insulin secretion in obese subjects.

OBJECTIVE: Recent studies have demonstrated the restoration of a normal 24 h GH profile induced by a reduction of insulinaemia after weight loss, suggesting a reciprocal relationship between plasma insulin and GH concentrations. We aimed to clarify if an opiate-induced reduction in plasma insulin could affect GH secretion in obesity. DESIGN: We have studied the insulin response to an oral glucose tolerance test (OGTT) and the GH response to GHRH before and after prolonged treatment with Naltrexone (NTX). C-peptide, IGF-I, IGFBP-3 plasma levels and the IGF-I/IGFBP-3 molar ratio were also determined. SUBJECTS: Twelve obese women (aged 25-41 y; Body mass index (BMI): 31-39 kg/m2) and six lean normal women (aged 25-38; BMI: 19.8-23.1 kg/m2). MEASUREMENT: GH was determined by the IRMA method; insulin, C-peptide, IGF-I and IGFBP-3 were assayed by the RIA method. For molar comparison between IGF-I and IGFBP-3 we have considered 30.5 kDa the molar weight of IGFBP-3. Results are expressed as mean +/- s.e.m. RESULTS: We observed a significant decrease in basal concentration of both insulin (230.1 +/- 34.9 vs 133.2 +/- 16.9 pmol/L; P < 0.005) and C-peptide (3.7 +/- 0.3 vs 2.4 +/- 0.1 micrograms/L; P < 0.02). No modifications in the insulin secretory response to the OGTT were observed. A significant increase of the GHRH-induced GH peak response (7.7 +/- 1.4 vs 19.7 +/- 3.1 micrograms/L; P < 0.01) and GH-AUC (533 +/- 151 vs 1415 +/- 339 micrograms/L/120 min; P < 0.01) was found after NTX treatment. A negative correlation was found between basal insulin and GH peak values, both before (r = -0.641, P = 0.027) and after NTX (r = -0.714, P = 0.013). No modifications were found in IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio. Moreover, NTX affected neither the insulin response to OGTT or IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio in a group of six lean controls. Conversely, NTX significantly reduced the GH response to GHRH, when expressed as both peak and AUC values. CONCLUSIONS: The opiate antagonist significantly reduced basal insulin concentrations and augmented the GH response to GHRH in obese subjects. In the absence of modifications in IGF-I and IGFBP-3 plasma levels and their molar ratio, we propose that insulin may exert a negative feedback on GH secretion.

Adult↗

PubMed1992

Modulation of evoked contractions in rat arteries by ryanodine, thapsigargin, and cyclopiazonic acid.

The contribution of sarcoplasmic reticulum (SR) Ca2+ release to evoked tension in rat arterial rings was studied by comparing the effects of ryanodine (an SR Ca2+ channel opener) and thapsigargin and cyclopiazonic acid (CPA) (two Ca(2+)-ATPase inhibitors). Isometric tension was evoked by serotonin (5-HT), 30-50 mM external K+, and 10 mM caffeine in rings of aorta and a small (second-order) branch of the superior mesenteric artery (SMA). Resting tension was unaffected by 10 microM ryanodine or 1-5 microM thapsigargin, but 20 microM CPA raised resting tension in aortic rings and evoked spontaneous contractions in some SMA rings. Ryanodine (10 microM) or 1-5 microM thapsigargin partially depleted the SR Ca2+ stores (indicated by reduced caffeine-evoked contractions) and attenuated 5-HT- and high K(+)-evoked contractions in aortic rings but augmented 5-HT- and high K(+)-evoked contractions in SMA. Caffeine completely emptied the SR Ca2+ stores in the presence of ryanodine but not thapsigargin in both the aorta and SMA; thus, thapsigargin may selectively affect one component of a heterogeneous SR. When the aortic Ca2+ stores were empty (i.e., caffeine contractions were abolished), the 5-HT- and high K(+)-evoked contractions in the aorta were also augmented. CPA rapidly emptied the SR Ca2+ stores in both the aorta and SMA. CPA augmented the 5-HT-evoked contractions in the SMA and in five of nine aortic rings but attenuated evoked contractions in the remaining aortic rings. The attenuation or abolition of the caffeine contractions implies that ryanodine, thapsigargin, and CPA all deplete the SR Ca2+ stores. The attenuated responses to 5-HT and high K+ observed when the aortic SR Ca2+ stores were only partially depleted are consistent with the idea that evoked SR Ca2+ release is a large component of the Ca2+ transient in the aorta. The augmentation of 5-HT- and high K(+P)-evoked responses after partial (SMA) or complete (aorta) depletion of the SR Ca2+ stores suggests that evoked release of SR Ca2+ normally regulates Ca2+ entry by negative feedback and/or that the SR normally buffers the evoked rise in cytosolic Ca2+.

Animals↗

PubMed1977

Activation and function of human Hageman factor. The role of high molecular weight kininogen and prekallikrein.

The activation and function of surface-bound Hageman factor in human plasma are dependent upon both high molecular weight (HMW) kininogen and prekallikrein. HMW kininogen does not affect the binding of Hageman factor to surfaces, but it enhances the function of surface-bound Hageman factor as assessed by its ability to activate prekallikrein and Factor XI. The initial conversion of prekallikrein to kallikrein by the surface-bound Hageman factor in the presence of HMW kininogen is followed by a rapid enzymatic activation of Hageman factor by kallikrein. The latter interaction is also facilitated by HMW kininogen. Kallikrein therefore functions as an activator of Hageman factor by a positive feedback mechanism and generates most of the activated Hageman factor during brief exposure of plasma to activating surfaces. HMW kininogen is a cofactor in the enzymatic activation of Hageman factor by kallikrein and it also augments the function of the activated Hageman factor generated. The stoichiometry of the Hagman factor interaction with HMW kininogen suggests that it enhances the activity of the active site of Hageman factor. Since HMW kininogen and prekallikrein circulate as a complex, HMW kininogen may also place the prekallikrein in an optimal position for its reciprocal interaction with Hageman factor to proceed. The surface appears to play a passive role upon which bound Hageman factor and the prekallikrein-HMW kininogen complex can interact.

Binding Sites↗

PubMed1982

Cardiopulmonary coupling during exercise.

Muscular exercise imposes the most potent sustained stress to cellular energetics. At work rates below the anaerobic threshold (i.e. no sustained lactic acidosis), the ventilatory and cardiovascular responses regulate arterial PCO2, [H+] and PO2 at or close to their resting levels in the steady state. However, dynamic forcing and systems-analytic techniques reveal two phases of the non-steady-state response dynamics. In the first phase, increased gas flow to the lungs results solely from increased pulmonary blood flow, with alveolar gas tensions being maintained at their resting levels by a coupled increase in ventilation (VE): evidence for cardiopulmonary coupling being provided by experimentally-altered in man and dog. Arterial chemoreception does not impose humoral feedback control in this phase. Rather, rapid feedforward mechanisms operate, with both intrathoracic (largely cardiac) and exercising-limb mechanoreception proposed as afferent sources. In the second phase, cardiogenic gas flow to the lungs is augmented by altered mixed venous blood gas contents; ventilation responding exponentially with a time constant (tau) which is an inverse function of carotid body gain. The close dynamic coupling of VE with CO2 output (tau VE tau TVCO2) in this phase results in arterial PCO2 and [H+] being maintained close to their resting levels. However, the kinetic dissociation between VE and O2 uptake, with tau VE much greater than tau VO2, leads to an appreciable transient fall of arterial PO2. The respiratory compensation for the sustained lactic acidosis at higher work rates is predominantly mediated by the carotid bodies in man: the aortic bodies subserving no discernible role. Control of the respiratory and circulatory responses to exercise is therefore mediated by both neural and humoral mechanisms: and an important control link appears to couple the responses, via feedforward ventilatory control of cardiac origin.

Animals↗

PubMed1992

[Changes in beta-endorphin and its messenger RNA in pituitary, hypothalamus, lymphocytes and blood plasma during cold acclimation of rats].

Changes of beta-endorphin (beta-EP) and its mRNA in pituitary (P), hypothalamus (HT), lymphocytes (LC) and blood plasma (BP) during cold acclimation of SD male rats were studied by beta-EP mRNA dot blot, RP-HPLC and beta-EP radio-immunoassay (RIA). Experimental results showed: (1) After cold-exposure for 1 week pituitary beta-EP mRNA increased significantly with the appearance of stimulated cellular immune function. (2) beta-EP mRNA in hypothalamic immune center and peripheral LC increased when cold acclimation of animals was established for a cold exposure of 2 weeks (C2W). (3) From C2W onward, plasma beta-EP also continued to increase, indicating an augmented state of cellular immune function. As LC and plasma beta-EP product continued to show increase, pituitary beta-EP mRNA content recovered to control level from C2W onward possibly due to a feedback mechanism through LC-P-HT axis.

Acclimatization↗

PubMed1980

Whither the WBC differential?--some alternatives.

Most efforts to automate the WBC differential have involved the use of devices to identify and enumerate WBC types, the underlying assumption being that the cell type percentages constitute the important end results. A different assumption exists. It is that the clinical usefulness of this procedure derives primarily from the fact that a trained morphologist has conducted a detailed examination of the slide. Based on this second assumption, a different approach to automation was investigated. This involved the use of a computer system to augment the morphologist in the slide examination process. This augmentation was accomplished by: 1. Determination of linked abnormalities on 117,000 WBC counts and presentation of linkages to the morphologist when a particular abnormality was identified on the hemogram or the slide. 2. Information feedback which compared each technologist with others in the laboratory performing similar tasks. 3. Varying the number of cells examined per slide, based on the apparent abnormality of the slide. The linkage patterns found, their clinical usefulness, and the impact on technologist performance and test quality are discussed.

Computers↗

PubMed2005

Increased intracellular pH at the macula densa activates nNOS during tubuloglomerular feedback.

BACKGROUND: The macula densa senses increasing NaCl concentrations in tubular fluid and increases afferent arteriole tone by a process known as tubuloglomerular feedback (TGF). Nitric oxide (NO) production by macula densa neuronal nitric oxide synthase (nNOS) is enhanced by increasing NaCl in the macula densa lumen, and the NO thus formed inhibits TGF. Blocking apical Na(+)/H(+) exchange with amiloride augments TGF and mimics the effect of nNOS inhibition. We hypothesized that increasing NaCl in the macula densa lumen raises macula densa intracellular pH (pH(i)) and activates nNOS. METHODS: The thick ascending limb and a portion of the distal tubule with intact macula densa plaque adherent to the glomerulus were microdissected and perfused. Macula densa perfusate was changed from a low (10 mmol/L) to high NaCl solution (80 mmol/L) to mimic the conditions that induce TGF. Osmolality of both solutions was 180 mOsm, so that changing the solutions did not alter cell volume. RESULTS: Macula densa pH(i) increased significantly from 7.0 +/- 0.5 to 7.8 +/- 0.6 when the perfusate was changed from low to high (P < 0.05; N= 5). When amiloride was added to inhibit Na(+)/H(+) exchange, the increase in pH(i) during TGF was blocked (N= 5). Fluorescence intensity of DAF-2, an NO-sensitive dye, increased by 28.8 +/- 4.1% after increasing luminal NaCl (N= 5), indicating an increase in NO production. In the presence of the Na(+)/H(+) exchanger inhibitor amiloride or the nNOS inhibitor 7-NI, the increase in NO induced by switching the macula densa perfusate from low to high was blunted. To study whether changes in pH(i) can directly alter NO production, we used nigericin, a K(+)/H(+) ionophore, to equilibrate luminal and intracellular pH. When macula densa pH was raised from 7.3 to 7.8 in the presence of 10(-5) mol/L nigericin in the low NaCl solution, fluorescence of DAF-2 in the macula densa increased by 17.9 +/- 1.3% (P < 0.01; N= 5). In the presence of 7-NI, the increase in NO induced by raising pH(i) was blocked (N= 5). CONCLUSION: We concluded that macula densa pH(i) increases during TGF, and this increase in pH(i) activates nNos.

Amiloride↗

PubMed2005

Enhancement of excitatory synaptic integration by GABAergic inhibition in the subthalamic nucleus.

The activity patterns of subthalamic nucleus (STN) neurons, which are intimately related to normal movement and abnormal movement in Parkinson's disease (PD), are sculpted by feedback GABAergic inhibition from the reciprocally connected globus pallidus (GP). To understand the principles underlying the integration of GABAergic inputs, we used gramicidin-based patch-clamp recording of STN neurons in rat brain slices. Voltage-dependent Na+ (Nav) channels actively truncated synthetic IPSPs and were required for autonomous activity. In contrast, hyperpolarization-activated cyclic nucleotide-gated and class 3 voltage-dependent Ca2+ channels contributed minimally to the integration of single or low-frequency trains of IPSPs and autonomous activity. Interestingly, IPSPs modified action potentials (APs) in a manner that suggested IPSPs enhanced postsynaptic Nav channel availability. This possibility was confirmed in acutely isolated STN neurons using current-clamp recordings containing IPSPs as voltage-clamp waveforms. Tetrodotoxin-sensitive subthreshold and spike-associated Na+ currents declined during autonomous spiking but were indeed transiently boosted after IPSPs. A functional consequence of inhibition-dependent augmentation of postsynaptic excitability was that EPSP-AP coupling was dramatically improved when IPSPs preceded EPSPs. Because STN neuronal activity exhibits coherence with cortical beta-oscillations in PD, we tested how rhythmic sequences of cortical EPSPs were integrated in the absence and presence of feedback inhibition. STN neuronal activity was consistently entrained by EPSPs only in the presence of feedback inhibition. These observations suggest that feedback inhibition from the GP is critical for the emergence of coherent beta-oscillations between the cortex and STN in PD.

Animals↗

PubMed1992

The roles of cell Ca2+, protein kinase C and the Na(+)-H+ antiport in the development of hypertension and insulin resistance.

There is evidence that the cytosolic free Ca2+, protein kinase C, and the Na(+)-H+ antiport cross-communicate with one another through positive and negative feedback mechanisms, thereby maintaining cellular Ca2+ and pH homeostasis. This triumvirate may play a role in the development of insulin resistance--a common characteristic of both essential hypertension and non-insulin-dependent diabetes mellitus. Circulating cells from patients with essential hypertension and non-insulin-dependent diabetes mellitus demonstrate elevated cytosolic free Ca2+, increased protein kinase C activity, or both, and these perturbations are associated with augmented activity of the Na(+)-H+ antiport. If present in other cells (e.g., striated muscle cells and adipocytes), these alterations could underlie insulin resistance in essential hypertension and non-insulin-dependent diabetes mellitus.

Animals↗

PubMed2004

GABAergic integration of progesterone and androgen feedback to gonadotropin-releasing hormone neurons.

Steroid feedback regulates GnRH secretion and previous work has implicated gamma-aminobutyric acid (GABA)ergic neurons as a mediator of these effects. We examined GABAergic postsynaptic currents (PSCs) in green fluorescent protein-identified GnRH neurons from mice exposed to different steroid milieus in vivo. Adult mice were ovariectomized and treated with estradiol (OVX+E, controls) or E plus progesterone (P, OVX+E+P). P decreased PSC frequency, a presynaptic effect, and PSC size, which could be via pre- and/or postsynaptic mechanisms. In contrast, dihydrotestosterone (DHT, OVX+E+DHT) increased both GABAergic PSC frequency and size in GnRH neurons. Tetrodotoxin (TTX), which eliminates action-potential-dependent presynaptic effects, did not alter frequency, suggesting DHT may have increased PSC frequency by increasing connectivity between GABAergic and GnRH neurons. TTX reduced PSC size below control values, indicating DHT may augment presynaptic GABA release but inhibits the postsynaptic GnRH neuron response. In mice treated with both P and DHT (OVX+E+P+DHT), PSC frequency and size were similar to controls, suggesting these steroids counteract one another. These results demonstrate GABAergic neurons participate in integrating and conveying steroid feedback to GnRH neurons, defining a potential central mechanism for steroid regulation of GnRH neurons during the reproductive cycle, and providing one possible mechanism for increased activity of these cells in hyperandrogenic females.

Androgens↗

PubMed1998

Inhibitors of transcription, proteasome inhibitors, and DNA-damaging drugs differentially affect feedback of p53 degradation.

Mutations of the p53 gene are the most common abnormalities in human cancer. In contrast to mutant p53, wild-type (wt) p53 protein is present at low levels due to rapid degradation by proteasome. We demonstrated that wt p53 protein stabilization following DNA damage or proteasome inhibition did not abolish the wild-type conformation. DNA damage did not cause accumulation of ubiquitinated forms of wt p53, suggesting abrogation of ubiquitination. Consistent with this, the E6 oncoprotein which targets p53 for ubiquitination abolished stabilization of p53 protein by DNA-damaging drugs but not by proteasome inhibitors. In contrast to the effects on wt p53, inhibitors of proteolysis downregulated mutant p53. Regulation of p53 levels can be explained by a feedback mechanism where wt p53 transcriptionally induces "sensor" proteins (Mdm-2, as an example) and these, in turn, target p53 for degradation. Like p53, Mdm-2 is degraded by proteasome. Therefore, inhibition of proteasome caused accumulation of Mdm-2, leading to degradation of mutant p53 by the remaining proteolytic activity of the cell. We propose that inhibition of transcription should increase wt p53 protein due to inhibition of Mdm-2 synthesis. An inhibitor of transcription, alpha-amanitin, dramatically induced wt p53 protein, whereas Mdm-2 protein was downregulated. Moreover, alpha-amanitin increased p53 protein levels in E6-transfected cells. Although inhibitors of transcription, such as actinomycin D, also damage DNA, reduction of Mdm-2 or other putative "sensor" proteins may contribute to their p53-stabilizing activity. Similarly, antimetabolites augment accumulation of wt p53 due to interference with RNA synthesis.

Cysteine Endopeptidases↗

PubMed1978

Beta-adrenoceptors modulate noradrenaline release from axonal sprouts in cultured rat superior cervical ganglia.

Superior cervical ganglia of rats grown in organ culture were used to study the effect of beta-receptor stimulants and antagonists on 3H-noradrenaline release in response to stimulation by KC1 (75 mM). (--)-Isoprenaline 1X 10(-9)--1 X 10(-7) M) increased 20--25% the release of 3H-noradrenaline from cultured ganglia exposed to KC1. Isoprenaline did not modify either the spontaneous (non-calcium dependent) release of 3H-noradrenaline from cultured ganglia, or the KC1-stimulated release from fresh ganglia. The effect of (--)-isoprenaline was blocked by (--)-propranolol 5 X 10(-9) -- 1 X 10(-8) M and by butoxamine 10(-6) M, but not by (+)-propranolol (1 -- 5 X 10(-8) M), practolol (1 X 10(-8) -- 1 X 10(-6) M), or sotalol (1 X 10(-7) -- 1 X 10(-6) M). Isoprenaline induced augmentation of 3H-noradrenaline release and its antagonism by (--)-propranolol still occurred in the presence of DMI. It is suggested that presynaptic beta-receptors in sympathetic nerve terminals may be involved in a positive feedback of noradrenaline release.

Adrenergic beta-Antagonists↗

PubMed2002

Women's sexual desire--disordered or misunderstood?

A new model of women's sexual response moves the focus from spontaneous drive with its markers of sexual thoughts, fantasies, and conscious urge to be sexual to an inherently responsive cycle. The model reflects intimacy-based sexual motivation, processing of sexual stimuli to arousal, cognitive, and affective appraisal of that arousal. Sexual desire to continue the physical experience is accessed later. Providing that the outcome is emotionally and physically satisfying, emotional intimacy with the partner is increased. Any spontaneous sexual drive augments this intimacy-based cycle. Analysis of one or many breaks in the cycle has therapeutic implications.

Affect↗

PubMed1981

Histamine secretion from human leucocytes stimulated by basophil-derived platelet-activating factor.

Crude preparations of platelet-activating factors (PAF) derived by methanolic extraction of supernatants from antigen-challenged basophils generally stimulated the secretion of histamine from human peripheral blood leucocytes when co-incubated with these cells in the absence of an additional stimulator. When these crude preparations were analysed by a preparative thin-layer chromatography technique established for the isolation of purified native PAF, multiple lipid components were identified. The component that migrated in accordance with native PAF, and which activated platelets to aggregation/secretion, was responsible for the induction of histamine release previously seen with the crude PAF preparations and could augment histamine secretion from leucocytes undergoing stimulation with either the biologically active peptide F-Met-Leu-Phe or with antigen E. These data suggest that basophil-derived PAF may serve as an important endogenous feedback mechanism during basophil activation in addition to its modulatory role upon the platelet.

Basophils↗

PubMed1977

The two pools of pituitary gonadotropin: regulation during the menstrual cycle.

Information on the relative activity and on the functional relationships between the acutely releasable (1st) and reserve (2nd) pools of pituitary LH during the course of the normal menstrual cycle was obtained via a 4 h LRF infusion (0.2 mug/min X 4 h). This was immediately followed by 3 pulses of LRF (10 mug at 2 h intervals) to assess further the size of the acutely releasable pool after activation of the reserve pool by the infusion. Our observations indicate that two functional pools of LH are present in all phases of the menstrual cycle and that comparative pool size or activity is influenced profoundly by ovarian steroid feedback as well as by the pattern of input of hypothalamic LRF. From the early to the late follicular phase, in synchrony with the rising levels of E2, the size of the 2nd pool is preferentially augmented. A small increase in the 1st pool activity is not apparent until the late follicular phase when a 5-fold increase in the size of the 2nd pool is also attained. During the mid-luteal phase and in association with relatively high progesterone (P) and E2, th large 2nd pool is maintained as in the late follicular phase but the 1st pool is strikingly smaller. Activation of the 2nd pool of LH by the LRF infusion (priming) increases the acutely releasable LH (1st pool) in all three phases of the cycle, as evidenced by an enhanced response to the 1st but not subsequent pulses of LRF at the end of the infusion as compared with non-infused controls. This priming effect is likely a reflection of activation or "shifting" of LH from the larger 2nd pool to the smaller 1st pool. It is found that this priming effect is greatest during the mid-luteal phase as compared to other phases of the cycle. During the days of mid-cycle LH surge, a dramatic reversal of the relative activity of the two pools in observed and this is manifested by an enormous increase in the activity of the 1st relative to the 2nd pool. In contrast to other phases of the cycle, the release of LH from the 2nd pool is not sustained and this premature decline in LH release despite continuous LRF infusion appears to be due to pituitary depletion of LH as evidenced by the failure of the pituitary response to pulses of LRF immediately following the infusion...

Estradiol↗

PubMed1980

The effect of pargyline pretreatment on the enhancement of the exocytotic release of norepinephrine during nerve stimulation which is induced by a benzoquinolizine compound with reserpine-like properties.

Pretreatment of guinea pigs with paragyline (100 mg/kg i.p., 18 hr before sacrifice) resulted in a significant depression in the overflow of endogenous norepinephrine (NE), total 3H, [3H]NE and dopamine beta-hydroxylase associated with stimulation of the sympathetic nerves to the isolated heart. The depression was pronounced at 5 Hz. At 10 Hz, pargyline pretreatment was without effect. The effect on dopamine beta-hydroxylase output was not as great as that on total 3H, [3H]NE or endogenous NE release, suggesting the possibility that more than one mechanism is responsible for the depressant effect of monoamine oxidase (MAO) inhibition on sympathetic neurotransmission. A benzoquinolizine compound with reserpine-like properties, 2-hydroxy-2-ethyl-3-isobutyl-9, 10-dimethoxy,1,2,3,4,6,7-hexahydro-11b-H-benzo[alpha]quinolizine (RO 4-1284), increased the nerve stimulation-mediated overflow of all the measured indices of neurotransmitter release, in addition to producing a significant increase in the spontaneous overflow of 3H from hearts of untreated guinea pigs. The augmentation of nerve-stimulated NE release by RO 4-1284 was even greater in hearts from pargyline pretreated guinea pigs. These results would tend to eliminate a causal role for a deaminated metabolite of NE in the augmenting effect on release seen with RO 4-1284. Conversely, the inhibition of neurotransmitter release associated with MAO inhibition is not mediated by the blockade in the formation of deaminated catecholamine metabolites. Enhancement in the negative feedback mechanism on release and the accumulation of false transmitter probably account for the local effects of MAO inhibitors on neurally mediated norepinephrine release.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗