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Results for “augmented feedback”

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PubMed2000

Action potential propagation in inhomogeneous cardiac tissue: safety factor considerations and ionic mechanism.

Heterogeneity of myocardial structure and membrane excitability is accentuated by pathology and remodeling. In this study, a detailed model of the ventricular myocyte in a multicellular fiber was used to compute a location-dependent quantitative measure of conduction (safety factor, SF) and to determine the kinetics and contribution of sodium current (I(Na)) and L-type calcium current [I(Ca(L))] during conduction. We obtained the following results. 1) SF decreases sharply for propagation into regions of increased electrical load (tissue expansion, increased gap junction coupling, reduced excitability, hyperkalemia); it can be <1 locally (a value indicating conduction failure) and can recover beyond the transition region to resume propagation. 2) SF and propagation across inhomogeneities involve major contribution from I(Ca(L)). 3) Modulating I(Na) or I(Ca(L)) (by blocking agents or calcium overload) can cause unidirectional block in the inhomogeneous region. 4) Structural inhomogeneity causes local augmentation of I(Ca(L)) and suppression of I(Na) in a feedback fashion. 5) Propagation across regions of suppressed I(Na) is achieved via a I(Ca(L))-dependent mechanism. 6) Reduced intercellular coupling can effectively compensate for reduced SF caused by tissue expansion but not by reduced membrane excitability.

Action Potentials↗

PubMed2004

Effects of bilateral vestibular nucleus lesions on cardiovascular regulation in conscious cats.

The vestibular system participates in cardiovascular regulation during postural changes. In prior studies (Holmes MJ, Cotter LA, Arendt HE, Cas SP, and Yates BJ. Brain Res 938: 62-72, 2002, and Jian BJ, Cotter LA, Emanuel BA, Cass SP, and Yates BJ. J Appl Physiol 86: 1552-1560, 1999), transection of the vestibular nerves resulted in instability in blood pressure during nose-up body tilts, particularly when no visual information reflecting body position in space was available. However, recovery of orthostatic tolerance occurred within 1 wk, presumably because the vestibular nuclei integrate a variety of sensory inputs reflecting body location. The present study tested the hypothesis that lesions of the vestibular nuclei result in persistent cardiovascular deficits during orthostatic challenges. Blood pressure and heart rate were monitored in five conscious cats during nose-up tilts of varying amplitude, both before and after chemical lesions of the vestibular nuclei. Before lesions, blood pressure remained relatively stable during tilts. In all animals, the blood pressure responses to nose-up tilts were altered by damage to the medial and inferior vestibular nuclei; these effects were noted both when animals were tested in the presence and absence of visual feedback. In four of the five animals, the lesions also resulted in augmented heart rate increases from baseline values during 60 degrees nose-up tilts. These effects persisted for longer than 1 wk, but they gradually resolved over time, except in the animal with the worst deficits. These observations suggest that recovery of compensatory cardiovascular responses after loss of vestibular inputs is accomplished at least in part through plastic changes in the vestibular nuclei and the enhancement of the ability of vestibular nucleus neurons to discriminate body position in space by employing nonlabyrinthine signals.

Adaptation, Physiological↗

PubMed2004

Puberty, ovarian steroids, and stress.

Puberty is accompanied by a number of changes, among them increased risk for development of major depression. The most common etiology of major depression is stressful life events, being present in approximately 90% of first episodes of depression. The hypothalamic-pituitary-adrenal (HPA) axis is one of the major systems involved in responses to stress, and this system is clearly influenced by ovarian hormones. Normal women demonstrate resistance to negative feedback of both cortisol in the fast-feedback paradigm and dexamethasone in the standard delayed-feedback paradigm. Depressed premenopausal women show greater increases in baseline cortisol than postmenopausal depressed women and than depressed men. Studies in rodents suggest a similar resistance to glucocorticoid feedback but suggest that estradiol can function to inhibit stress responsiveness. Studies of premenopausal depressed women demonstrate lower estradiol, which suggests that there is less inhibitory feedback of estradiol on the HPA axis, while normal progesterone continues to augment stress responses further. The onset of these reproductive hormonal changes modulating stress systems at puberty may sensitize girls to stressful life events, which become more frequent at the transition to puberty and young adulthood.

Animals↗

PubMed1983

Variable effects of testosterone on dopamine activity in several microdissected regions in the preoptic area and medial basal hypothalamus.

We have observed previously that systemic treatments or local implants of testosterone (T) suppress dopamine (DA) turnover in the preoptic area-anterior hypothalamus of male rats. In the present study, we sought to identify discrete regions innervated by the incertohypothalamic DA system and the tuberoinfundibular DA system which respond to T replacement. Adult male rats were orchidectomized and immediately treated with either empty (controls) or T-containing Silastic implants. After 14 days, animals from each group were treated with alpha-methylparatyrosine and killed 0, 45, and 90 min later for analysis of DA turnover in eight microdissected brain regions. The T implants produced an increase in serum T and 5 alpha-dihydrotestosterone and reduced serum LH to concentrations observed in intact male rats without affecting serum PRL levels. Serum levels of T within the physiological range caused a profound decrease in the DA turnover rate in the medical preoptic nuclei and anterior hypothalamic nuclei without influencing DA activity in the periventricular nuclei, the site of perikarya for these DA projections. In contrast, DA turnover in the median eminence was increased 3-fold by T treatment, while DA activity in the arcuate nuclei, the locus of cell bodies of the tuberoinfundibular DA system, was not affected. These studies reveal disparate effects of T on the terminal fields of the two DA systems. While augmentation in the median eminence DA activity may participate in the negative feedback effects of T on gonadotropin secretion, the T-induced suppression of DA turnover in the medial preoptic nuclei and anterior hypothalamic nuclei may well be involved in androgen-dependent aggression and copulatory behavior.

Animals↗

PubMed2001

Signaling lymphocytic activation molecule expression and regulation in human intracellular infection correlate with Th1 cytokine patterns.

Induction of Th1 cytokines, those associated with cell-mediated immunity, is critical for host defense against infection by intracellular pathogens, including mycobacteria. Signaling lymphocytic activation molecule (SLAM, CD150) is a transmembrane protein expressed on lymphocytes that promotes T cell proliferation and IFN-gamma production. The expression and role of SLAM in human infectious disease were investigated using leprosy as a model. We found that SLAM mRNA and protein were more strongly expressed in skin lesions of tuberculoid patients, those with measurable CMI to the pathogen, Mycobacterium leprae, compared with lepromatous patients, who have weak CMI against M. leprae. Peripheral blood T cells from tuberculoid patients showed a striking increase in the level of SLAM expression after stimulation with M. leprae, whereas the expression of SLAM on T cells from lepromatous patients show little change by M. leprae stimulation. Engagement of SLAM by an agonistic mAb up-regulated IFN-gamma production from tuberculoid patients and slightly increased the levels of IFN-gamma in lepromatous patients. In addition, IFN-gamma augmented SLAM expression on M. leprae-stimulated peripheral blood T cells from leprosy patients. Signaling through SLAM after IFN-gamma treatment of Ag-stimulated cells enhanced IFN-gamma production in lepromatous patients to the levels of tuberculoid patients. Our data suggest that the local release of IFN-gamma by M. leprae-activated T cells in tuberculoid leprosy lesions leads to up-regulation of SLAM expression. Ligation of SLAM augments IFN-gamma production in the local microenvironment, creating a positive feedback loop. Failure of T cells from lepromatous leprosy patients to produce IFN-gamma in response to M. leprae contributes to reduced expression of SLAM. Therefore, the activation of SLAM may promote the cell-mediated immune response to intracellular bacterial pathogens.

Antibodies↗

PubMed1999

Mice with IFN-gamma receptor deficiency are less susceptible to experimental autoimmune myasthenia gravis.

IFN-gamma can either adversely or beneficially affect certain experimental autoimmune diseases. To study the role of IFN-gamma in the autoantibody-mediated experimental autoimmune myasthenia gravis (EAMG), an animal model of myasthenia gravis in humans, IFN-gammaR-deficient (IFN-gammaR-/-) mutant C57BL/6 mice and congenic wild-type mice were immunized with Torpedo acetylcholine receptor (AChR) plus CFA. IFN-gammaR-/- mice exhibited significantly lower incidence and severity of muscle weakness, lower anti-AChR IgG Ab levels, and lower Ab affinity to AChR compared with wild-type mice. Passive transfer of serum from IFN-gammaR-/- mice induced less muscular weakness compared with serum from wild-type mice. In contrast, numbers of lymph node cells secreting IFN-gamma and of those expressing IFN-gamma mRNA were strongly augmented in the IFN-gammaR-/- mice, reflecting a failure of negative feedback circuits. Cytokine studies by in situ hybridization revealed lower levels of lymphoid cells expressing AChR-reactive IL-1beta and TNF-alpha mRNA in AChR + CFA-immunized IFN-gammaR-/- mice compared with wild-type mice. No differences were found for AChR-reactive cells expressing IL-4, IL-10, or TGF-beta mRNA. These results indicate that IFN-gamma promotes systemic humoral responses in EAMG by up-regulating the production and the affinity of anti-AChR autoantibodies, thereby contributing to susceptibility to EAMG in C57BL/6-type mice.

Animals↗

PubMed2000

A facet-based system for computer-assisted instruction in pain management for elderly patients.

DIANA2, a web-based interactive tutor for pain management (see www.talariainc.com), was more effective than conventional methods of learning (such as reading articles that contain the same type of information) in making the principles of pain management for the elderly more easily accessible to learners. DIANA2 was similarly effective for different types of health care providers (students, nurses, and residents), and the study participants were excited by their experience with a different mode of learning. DIANA is based on interactive facet-based learning principles that guide learners to reflect on their understanding of the situation and to modify and augment their understanding in response to real-time facet-specific feedback.

Aged↗

PubMed1995

Effective teaching behaviours of rural family medicine preceptors.

OBJECTIVE: To describe effective teaching behaviours of rural family medicine preceptors. DESIGN: Descriptive qualitative study using the critical incident technique. SETTING: Rural Manitoba community practices affiliated with the University of Manitoba's 8-week family medicine/community medicine rotation (clinical clerkship). PARTICIPANTS: All family medicine preceptors and fourth-year medical students involved in two family medicine rotations from Mar. 11 to June 14, 1991. During the first rotation all 12 students and 21 preceptors participated. During the second rotation 12 of the 13 students and 20 of the 21 preceptors participated. The overall response rate was 97%. OUTCOME MEASURES: Effective and less effective preceptor teaching behaviours. RESULTS: During 120 telephone interviews (48 with the students and 72 with the preceptors) 275 critical teaching incidents were elicited. Over 800 teaching behaviours were identified, and seven main categories describing effective teaching behaviours of preceptors were formed: (a) actively involves the student, providing adequate supervision and appropriate independence, (b) develops and fosters a supportive interpersonal relationship with the student to facilitate learning, (c) emphasizes problem solving and the understanding of general principles, (d) balances clinical and teaching responsibilities, (e) demonstrates clinical and professional competence, (f) uses an organized approach, including goal setting and summation, and (g) provides the student with ongoing feedback, assessments and evaluations. CONCLUSION: The teaching behaviours described in this study augment and corroborate findings from previous studies on clinical teaching and provide a better understanding of effective teaching behaviours. The findings suggest a curriculum for a faculty-development program for rural family medicine preceptors.

Canada↗

PubMed1994

A quantitative study of dopamine control in the rat striatum.

The control of dopamine release by negative feedback via dopaminergic autoreceptors has been well established. Using previously derived mathematical equations, we have incorporated this feedback component into a mass-action binding model in which the rate of ligand release is a function of the quantity that is bound. A consequence of this model is that competitive antagonists augment release, whereas competing agonists reduce such release. In order to obtain values of the parameters needed in the feedback equations, in vivo microdialysis was used to deliver drugs locally to the rat striatum and to monitor the resulting changes in extracellular dopamine levels. The dopamine agonists apomorphine and quinpirole and the antagonists haloperidol and sulpiride were individually infused into the rat striatum via the microdialysis probe, and the effect of each on extracellular dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic levels was recorded. The data obtained from the microdialysis experiments were used to construct dopamine's control curve, a new quantitative concept that describes the feedback control of the dopaminergic system. Once known, the ligand's control curve has predictive value that may be useful in the design of efficient drug tests. Alterations of dopamine's control curve, which may occur with aging, drug addiction and pathological states, can now be studied and may provide new insights for potential therapeutic strategies.

Animals↗

PubMed1990

Role of gastric juice in feedback regulation of rat pancreatic secretion by luminal proteases.

The role of gastric juice in the intestine on the pancreatic secretory response to intraduodenal infusion of trypsin inhibitors or to diversion of bile and pancreatic juice from the intestine was studied in conscious rats with pylorus ligation and gastric juice drainage. In absence of gastric juice in the intestine, diversion of bile and pancreatic juice from the intestine stimulated pancreatic secretion, but the incremental protein and fluid secretory responses to diversion of bile and pancreatic juice were increased approximately 2.9-fold and 2.5-fold, respectively, by intraduodenal infusion of HCl (60 microEq/h). Intraduodenal infusion of HCl (240 microEq/h) had no effect on the pancreatic secretory response to infusion of lima bean trypsin inhibitor (20 mg). These results support the hypothesis that the inhibitory effect of atropine on the pancreatic secretory response to diversion of pancreatic juice or bile and pancreatic juice is secondary to inhibition of gastric acid secretion. The lack of effect of HCl on the pancreatic response to trypsin inhibitor contradicts the hypothesis that acid in the intestine is important or necessary for the feedback response to loss of intraluminal protease activity. It is proposed that acid in the intestine augments the pancreatic response to diversion of pancreatic juice or bile and pancreatic juice by reducing intraluminal pH and thereby inactivating residual pancreatic proteases.

Animals↗

PubMed1982

Direct enhancement of gonadotropin-stimulated ovarian estrogen biosynthesis by estrogen and clomiphene citrate.

The biosynthesis of ovarian aromatases and hence estrogen production are under the control of the gonadotropins, FSH and LH. Using a primary culture of rat granulosa cells, we now report that estrogens (diethylstilbestrol and 17 beta-estradiol) augment the stimulation of aromatase activity by FSH and LH. Moreover, clomiphene citrate, a drug widely used to induce ovulation in anovulatory women, also enhances gonadotropin-stimulated aromatase activity. These in vitro findings suggest that estrogens within the microenvironment of the ovarian follicles may exert a local autoregulatory effect on their own production via an ultra-short loop, positive feedback mechanism. In addition, the clinical efficacy of clomiphene citrate may derive partially from its direct augmentation of the gonadotropin-stimulated estrogen production at the ovarian level.

Animals↗

PubMed2006

Switching feedback mechanisms realize the dual role of MCIP in the regulation of calcineurin activity.

Calcineurin (CaN) assists T-cell activation, growth and differentiation of skeletal and cardiac myocytes, memory, and apoptosis. It also activates transcription of the nuclear factor of activated T-cells (NFAT) family including hypertrophic target genes. It has been reported that the modulatory calcineurin-interacting protein (MCIP) inhibits the CaN activity and thereby reduces the hypertrophic response. However, it has been shown that MCIP facilitates or permits the hypertrophic response under some stress conditions such as isoproterenol infusion or pressure overload by transverse aortic constriction. As there is no direct experimental evidence that can explain these paradoxical phenomena, there has been a controversy concerning the functional role of MCIP in developing the hypertrophic response. It is therefore crucial to establish a hypothesis that can clearly explain these phenomena. Towards this end, we propose in this paper a hypothesis that is based on available experimental evidence as well as mathematical modeling and computer simulations. We hypothesize that there is a threshold in the nuclear NFAT concentration above which MCIP is switched on. Below this threshold, the inhibition of active CaN by MCIP is negligible, while the activated protein kinase increases the dissociation rate of the CaN/MCIP complex. This leads to an augmentation of active CaN. This mechanism realizes the positive effect (i.e., removing any negative feedback) of MCIP in the hypertrophic response. On the other hand, the over-expression of active CaN increases nuclear NFAT to values above the threshold, while CaN is inhibited through binding of MCIP (expressed by the nuclear NFAT). This mechanism realizes the introduction of a negative feedback mechanism. To unravel this switching feedback mechanism, we have developed a mathematical model for which computer simulations are in agreement with the existing experimental data. The simulations demonstrate how the apparently paradoxical behavior can emerge as a result of cellular conditions.

Animals↗

PubMed1983

Spontaneous helper factor production by nonadherent rabbit lymphoid cells and its feedback regulation by adherent cells.

Normal, unstimulated rabbit lymphoid cells, when depleted of adherent cells, produced soluble helper factor activity that augmented antibody formation by rabbit spleen cells primed against sheep red blood cells (SRBC). Adherent cells inhibited the production of the helper factor by nonadherent cells via a soluble product. Thus unseparated (adherent cell-containing) appendix, lymph node, and spleen cell cultures did not produce the helper factor. On the other hand, the activity of the helper factor required the presence of adherent cells in the assay cultures. Peritoneal exudate cells, predominantly esterase positive, also inhibited the production of the helper factor if they were first exposed to the helper factor-containing culture supernatant. These results imply that a helper factor may participate in the feedback regulation of its own production via an adherent cell population.

Animals↗

PubMed2005

Acute effects of glucocorticoids on ATP-induced Ca2+ mobilization and nitric oxide production in cochlear spiral ganglion neurons.

Rapid, non-genomic effects of glucocorticoids on extracellular adenosine 5'-triphosphate (ATP)-induced intracellular Ca(2+) concentration ([Ca(2+)](i)) changes and nitric oxide (NO) production were investigated in type I spiral ganglion neurons (SGNs) of the guinea-pig cochlea using the Ca(2+)-sensitive dye fura-2 and the NO-sensitive dye 4,5-diaminofluorescein (DAF-2). Pretreatment of SGNs with 1 microM dexamethasone for 10 min, a synthetic glucocorticoid hormone, enhanced the ATP-induced [Ca(2+)](i) increase in SGNs. RU 38486, a competitive glucocorticoid receptor antagonist eliminated the effects of dexamethasone on the ATP-induced [Ca(2+)](i) increase in SGNs. These acute effects of dexamethasone were dependent on the presence of extracellular Ca(2+), thereby suggesting that dexamethasone may rapidly enhance the Ca(2+) influx through the activation of ionotropic P2X receptors which may interact with glucocorticoid-mediated membrane receptors. Extracellular ATP increased the intensity of DAF-2 fluorescence, indicating NO production in SGNs. The ATP-induced NO production was mainly due to the Ca(2+) influx through the activation of P2 receptors. S-nitroso-N-acetylpenicillamine, a NO donor, enhanced the ATP-induced [Ca(2+)](i) increase in SGNs while L-N(G)-nitroarginine methyl ester (L-NAME), a NO synthesis inhibitor, inhibited it. Dexamethasone enhanced the ATP-induced NO production in SGNs. The augmentation of dexamethasone on ATP-induced NO production was abolished in the presence of l-NAME. It is concluded that the ATP-induced [Ca(2+)](i) increase induces NO production which enhances a [Ca(2+)](i) increase in SGNs by a positive-feedback mechanism. Dexamethasone enhances the ATP-induced [Ca(2+)](i) increase in SGNs which results in the augmentation of NO production. The present study suggests that NO may play an important role in auditory signal transduction. Our results also indicate that glucocorticoids may rapidly affect auditory neurotransmission due to a novel non-genomic mechanism.

Adenosine Triphosphate↗

PubMed2002

Hypersecretion of FSH in infant boys and girls born small for gestational age.

Prenatal growth restraint, as reflected in a low birthweight for gestational age, is a risk factor for postpubertal FSH hypersecretion and for reduced gonadal size. The ontogeny of the low-birthweight effect on the FSH-inhibin B feedback loop is unknown. Infancy is an episode of choice to study the possibility of an early low-birthweight effect on the FSH-inhibin B loop because this phase is characterized by high activity within the gonadal axis. We assessed serum concentrations of FSH and inhibin B in 46 infants [26 girls and 20 boys; mean age, 4 months; range, 3-6 months; 17 appropriate for gestational age (AGA), 29 small for gestational age (SGA); mean birthweight, 3.2 kg for AGA vs. 2.3 kg for SGA], together with circulating levels of LH, E2, and free androgen index. In SGA girls and boys, serum FSH levels were 2- and 4-fold higher (P < 0.001), respectively, than in AGA controls of the same gender (7.3 +/- 0.9 vs. 3.8 +/- 0.4 IU/ml and 2.9 +/- 0.5 vs. 0.7 +/- 0.2 IU/ml). Serum LH, inhibin B, and free androgen index/E2 concentrations were similar in AGA and SGA infants. In conclusion, prenatal growth restraint was found to be followed by elevated serum FSH concentrations in infant girls and boys. SGA infants seem to need an augmented FSH drive to fulfill inhibin B requirements on the afferent side of the feedback loop. The late-endocrine correlates of early growth restraint are herewith extended to include the main axis of reproduction in both genders. It remains to be studied whether FSH hypersecretion in infancy is a marker of subsequent subfertility.

Cohort Studies↗

PubMed1992

Effects of dorsal root entry zone lesion on spinal cord potentials evoked by segmental, ascending and descending volleys.

The spinal cord potentials (SCPs) were recorded from the dorsal root entry zone (DREZ) and posterior epidural space in patients before and after dorsal root entry zone lesion (DREZL) during general anaesthesia. The SCPs from the DREZ activated by segmental, ascending and descending volleys were basically the same in fundamental waveform as those recorded from the posterior epidural space. Segmentally activated slow negative (N1) wave, reflecting synchronized activities of dorsal horn neurones, and positive (P2) wave, thought to indicate primary afferent depolarization, were affected by DREZL in all 4 subjects tested, even by contralateral stimulation, suggesting that these components of the segmental SCPs in man partly reflect the activities of the contralateral dorsal horn. The spike-like potentials activated by ascending volleys were not affected by DREZL, while the subsequent slow components were decreased in the lesioned level. This may indicate that ascending spinal cord tracts are not affected by the operation, and suggests that the origin of the slow components by ascending volleys lies at least in part in the segmental dorsal horn. The slow negative and positive components, recorded at a remote segment from DREZL, in response to the descending volleys, were augmented after DREZL, suggesting that activation of ascending or descending inhibition through a feedback loop via the supraspinal structures might occur at least transiently following DREZL. All components of the SCPs activated by descending volleys were decreased or disappeared in recording from the lesioned level, as expected. Thus, intra-operative recording of the SCPs during DREZL might be beneficial for monitoring and studying human spinal cord function.

Afferent Pathways↗

PubMed2000

Effects of prestimulus respiratory levels on inhibitory respiratory response by nociceptive muscular afferents.

We have previously shown that the inhibitory respiratory response, which we call post-stimulus suppression, is induced by nociceptive muscular afferents. This phenomenon is thought to be caused by a negative feedback induced by excessive afferent inputs. In the present study, we investigated whether augmented levels of prestimulus respiration would influence the magnitude of poststimulus suppression by recording the phrenic nerve discharges in chloralose-urethane anesthetized, vagotomized, paralyzed and artificially ventilated cats. The respiratory level was augmented by means of either hypercapnia, hypoxia or naloxone administration, all of which markedly facilitated the peak amplitude (PK) of integrated phrenic discharges, neural tidal volume. When the electrical stimulation of thin-fiber muscular afferents was performed at these augmented PK levels, the magnitude of poststimulus suppression in the PK was markedly attenuated without consistently altering the facilitatory response during the stimulation period. It seems that the facilitatory component of the augmented level of resting respiration may reduce the inhibitory component of poststimulus suppression. The results indicate that prestimulus respiratory activity is an important factor in determining the magnitude of poststimulus suppression.

Animals↗

PubMed1992

Protein kinase C activation modulates tumour necrosis factor-alpha priming of human neutrophils for zymosan-induced leukotriene B4 release.

Neutrophil (PMN) activation by the yeast component zymosan involves the complement receptor type 3 (CD11b/CD18). Recombinant human tumour necrosis factor-alpha (rhTNF-alpha) augmented the zymosan-stimulated leukotriene B4 (LTB4) release from PMN, reaching a fourfold increase at 10(-9) M. Co-incubation of PMN with 10(-9) M rhTNF-alpha and staurosporine resulted in a further dose-dependent increase, which became significantly greater than a purely additive effect at a staurosporine concentration of 10 nM. This synergy was maintained at all doses of staurosporine tested. In addition, doses of phorbol 12-myristate 13-acetate (PMA) that do not activate protein kinase C (PKC) (below 10(-9) M) also augmented the zymosan-stimulated release of LTB4. However, doses of PMA above 10(-9) M progressively inhibited the response to levels below that of zymosan alone. Staurosporine at 50 nM completely prevented, and 10(-9) M rhTNF-alpha partially but significantly (P less than 0.02 at 10(-8) M PMA, P less than 0.01 at 10(-7) M PMA) reversed, this high-dose PMA inhibition. PKC activation thus opposes the priming effect of rhTNF-alpha on neutrophils, while PKC inhibition may enhance the ability of rhTNF-alpha to prime PMN for zymosan activation. The combined effect of rhTNF-alpha and staurosporine suggests an intracellular synergy rather than simply a direct action due to increased zymosan receptor expression. Thus there appear to be mechanisms whereby the responses of neutrophils may be augmented without activating PKC. Indeed, kinase activation may even exert a degree of feedback control that is antagonized by rhTNF-alpha treatment.

Alkaloids↗