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PubMed1991

Ventricular wall motion and NE release in post-ischemic reperfused myocardium.

To clarify the relationship between post-ischemic myocardial dysfunction and local cardiac sympathetic nerve function, we measured regional myocardial length and norepinephrine (NE) release during sympathetic nerve stimulation in 32 mongrel dogs. Coronary occlusion was produced by balloon occluder for 15 min and reperfused for 60 min. Dogs were divided into 3 groups as follows; Group 1 (n = 14): Sympathetic nerve stimulation, Group 2 (n = 9): Pre-treatment with yohimbine hydrochloride (0.2 mg/kg) and sympathetic nerve stimulation, Group 3 (n = 9): Exogenous NE administration. Sympathetic nerve stimulation or NE infusion were performed before occlusion and after reperfusion. In group 1, the extent of the increase in systolic shortening during sympathetic nerve stimulation (delta - shortening) lowered at 5 min after reperfusion and augmented progressively. But, delta-shortening at an early reperfusion period did not reduce in group 2 and 3. NE release from the ischemic myocardium decreased in group 1 and did not recover for 60 min. When the cardiac sympathetic nerve was denervated with 90% phenol solution, NE release further decreased in group 1. On the other hand, NE release did not decrease in group 2. These results indicate that the response to sympathetic nerve stimulation decreased in post-ischemic reperfused myocardium and this was due to diminished NE release. It was considered that sympathetic nerve conduction was not completely impaired in post-ischemic myocardium and pre-synaptic alpha-2 receptor mediated negative feedback mechanism would play an important role in these diminished NE release.

Animals↗
PubMed2002

Enhancement of plasminogen activation by surfactin C: augmentation of fibrinolysis in vitro and in vivo.

The reciprocal activation of plasminogen and prourokinase (pro-u-PA) is an important mechanism in the initiation and propagation of local fibrinolytic activity. We have found that a bacterial lipopeptide compound, surfactin C (3-20 microM), enhances the activation of pro-u-PA in the presence of plasminogen. This effect accompanied increased conversions of both pro-u-PA and plasminogen to their two-chain forms. Surfactin C also elevated the rate of plasminogen activation by two-chain urokinase (tcu-PA) while not affecting plasmin-catalyzed pro-u-PA activation and amidolytic activities of tcu-PA and plasmin. The intrinsic fluorescence of plasminogen was increased, and molecular elution time of plasminogen in size-exclusion chromatography was shortened in the presence of surfactin C. These results suggested that surfactin C induced a relaxation of plasminogen conformation, thus leading to enhancement of u-PA-catalyzed plasminogen activation, which in turn caused feedback pro-u-PA activation. Surfactin C was active in enhancing [125I]fibrin degradation both by pro-u-PA/plasminogen and tcu-PA/plasminogen systems. In a rat pulmonary embolism model, surfactin C (1 mg/kg, i.v.) elevated 125I plasma clot lysis when injected in combination with pro-u-PA. The present results provide first evidence that pharmacological relaxation of plasminogen conformation leads to enhanced fibrinolysis in vivo.

Animals↗
PubMed1985

Activity and synapse elimination at the neuromuscular junction.

The neuromuscular junction undergoes a loss of synaptic connections during early development. This loss converts the innervation of each muscle fiber from polyneuronal to single. During this change the number of motor neurons remains constant but the number of muscle fibers innervated by each motor neuron is reduced. Evidence indicates that a local competition among the inputs on each muscle fiber determines which inputs are eliminated. The role of synapse elimination in the development of neuromuscular circuits, other than ensuring a single innervation of each fiber, is unclear. Most evidence suggests that the elimination plays little or no role in correcting for errant connections. Rather, it seems that connections are initially highly specific, in terms of both which motor neurons connect to which muscles and which neurons connect to which particular fibers within these muscles. A number of attempts have been made to determine the importance of neuromuscular activity during early development for this rearrangement of synaptic connections. Experiments reducing neuromuscular activity by muscle tenotomy, deafferentation and spinal cord section, block of nerve impulse conduction with tetrodotoxin, and the use of postsynaptic and presynaptic blocking agents have all shown that normal activity is required for normal synapse elimination. Most experiments in which complete muscle paralysis has been achieved show that activity may be essential for the occurrence of synapse elimination. Furthermore, experiments in which neuromuscular activity has been augmented by external stimulation show that synapse elimination is accelerated. A plausible hypothesis to explain the activity dependence of neuromuscular synapse elimination is that a neuromuscular trophic agent is produced by the muscle fibers and that this production is controlled by muscle-fiber activity. The terminals on each fiber compete for the substance produced by that fiber. Inactive fibers produce large quantities of this substance; on the other hand, muscle activity suppresses the level of synthesis of this agent to the point where only a single synaptic terminal can be maintained. Inactive muscle fibers would be expected to be able to maintain more nerve terminals. The attractiveness of this scheme is that it provides a simple feedback mechanism to ensure that each fiber retains a single effective input.

Animals↗
PubMed1976

Modification by sex steroids of LHRH response in the polycystic ovary syndrome.

Exogenously administered oestradiol or progesterone was found to induce augmentation of LH and FSH release in response to LHRH administration in patients with the polycystic ovary (PCO) syndrome. The effect of oestradiol upon LH release in the patients was significantly less than the augmented release induced in normal women (P less than 0-02). In contrast, progesterone induced a significantly greater LH release in PCO patients than normal women studied during the early follicular phase (P less than 0-001) but less than that in normal women studied during the mid-follicular phase of the cycle (P less than 0-01). The effects on FSH release in the PCO patients were less marked but similar to those in normal women with comparable basal steroid levels. The results suggest that both oestradiol and progesterone can modify the hypothalamic-pituitary axis in the PCO syndrome in a manner similar to that observed in normal women and a failure of these 'positive feedback' mechanisms does not appear to be the cause of the ovulatory deficiency in this syndrome.

Clinical Trials as Topic↗
PubMed1976

The functional changes of the pituitary gonadotrophs during the menstrual cycle.

Submaximal doses of LRF, administered over a period of several hours, either by repeated pulses (10 mug at 2 h intervals X 5) or by constant infusion (0.2 mug/min X 4 h), have permitted the assessment of changes in the releasable gonadotropin during the menstrual cycle. Quantitations in the acute releasable and ultimately releasable gonadotropins were made which represent, respectively, the sensitivity and reserve of the gonadotrophs. The functional expression of these two components of gonadotropin release exhibited profound changes during the menstrual cycle and were in synchrony with the cyclicity of ovarian steroid levels; during the early follicular phase, both sensitivity and reserve were at a minimum, but with increasing levels of E2, a preferential increase in reserve over sensitivity (P less than 0.005) was found. Although both sensitivity and reserve increased dramatically near the midcycle, the relative change in these two components was reversed from the late follicular phase to the midcycle surge. The presence of this phenomenon may be causally related to the development of a self-priming effect of LRF at this time, as evidenced by an augmentation of gonadotropin release to the 2nd pulse of LRF. Thus, a build-up in pituitary store consequent to the greater increase in reserve than in sensitivity, together with the appearance of the self-priming effect of LRF induced by progressively rising levels of E2, may constitute the essential dynamics required for the development of the midcycle gonadotropin surge. Pituitary sensitivity and reserve continued to be high during the early luteal phase but reduced progressively thereafter. In all studied, FSH responses were less obvious but showed remarkable parallelism to the pattern of LH responses. We have concluded that the functional capacity of the gonadotrophs exhibits a remarkable cyclic change and that the adenohypophysis represents a critical feedback site in the development of pre-ovulatory gonadotropin surge.

Adult↗
PubMed1993

Enhancement of N- and L-type calcium channel currents by protein kinase C in frog sympathetic neurons.

The effect of protein kinase C (PKC) stimulation on Ca2+ channels was studied in frog sympathetic neurons. 12,13-Phorbol dibutyrate (PDBu) consistently augmented Ca2+ channel currents in whole-cell recordings. This enhancement was blocked by staurosporine and PKC(19-31), but not produced by 4 alpha-phorbol 12,13-didecanoate, indicating that PDBu acts via PKC. Both N- and L-type currents, as isolated pharmacologically, were increased. PKC enhancement was independent of the extent of G protein activation, indicating that it was not caused by removal of tonic G protein inhibition. In unitary recordings PDBu produced dramatic increases in single N- and L-type channel activity by sharply decreasing closed time intervals between adjacent openings, but did not alter the unitary current size or mean open time. This up-modulation by PKC may constitute a positive feedback mechanism in the regulation of neuronal Ca2+ channel activity.

Alkaloids↗
PubMed2005

MAP kinase phosphatase 1 controls innate immune responses and suppresses endotoxic shock.

Septic shock is a leading cause of morbidity and mortality. However, genetic factors predisposing to septic shock are not fully understood. Excessive production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha, and the resultant severe hypotension play a central role in the pathophysiological process. Mitogen-activated protein (MAP) kinase cascades are crucial in the biosynthesis of proinflammatory cytokines. MAP kinase phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAP kinase. Thus, we hypothesize that knockout of the Mkp-1 gene results in prolonged MAP kinase activation, augmented cytokine production, and increased susceptibility to endotoxic shock. Here, we show that knockout of Mkp-1 substantially sensitizes mice to endotoxic shock induced by lipopolysaccharide (LPS) challenge. We demonstrate that upon LPS challenge, Mkp-1-/- cells exhibit prolonged p38 and c-Jun NH2-terminal kinase activation as well as enhanced TNF-alpha and interleukin (IL)-6 production compared with wild-type cells. After LPS challenge, Mkp-1 knockout mice produce dramatically more TNF-alpha, IL-6, and IL-10 than do wild-type mice. Consequently, Mkp-1 knockout mice develop severe hypotension and multiple organ failure, and exhibit a remarkable increase in mortality. Our studies demonstrate that MKP-1 is a pivotal feedback control regulator of the innate immune responses and plays a critical role in suppressing endotoxin shock.

Animals↗
PubMed2002

Glomerulotubular balance, dietary protein, and the renal response to glycine in diabetic rats.

The glomerular filtration rate (GFR) normally increases during glycine infusion, which is a test of "renal reserve." Renal reserve is absent in diabetes mellitus. GFR increases after protein feeding because of increased tubular reabsorption, which reduces the signal for tubuloglomerular feedback (TGF). Dietary protein restriction normalizes some aspects of glomerular function in diabetes. Renal micropuncture was performed in rats 4-5 wk after diabetes was induced by streptozotocin to determine whether renal reserve is lost as a result of altered tubular function and activation of TGF, whether 10 days of dietary protein restriction could restore renal reserve, and whether this results from effects of glycine on the tubule. TGF activation was determined by locating single-nephron GFR (SNGFR) in the early distal tubule along the TGF curve. The TGF signal was determined from the ionic content of the early distal tubule. In nondiabetic rats, SNGFR in the early distal tubule increased during glycine infusion because of primary vasodilation augmented by increased tubular reabsorption, which stabilized the TGF signal. In diabetic rats, glycine reduced reabsorption, thereby activating TGF, which was largely responsible for the lack of renal reserve. In protein-restricted diabetic rats, the tubular response to glycine remained abnormal, but renal reserve was restored by a vascular mechanism. Glycine affects GFR directly and via the tubule. In diabetes, reduced tubular reabsorption dominates. In low-protein diabetes, the vascular effect is enhanced and overrides the effect of reduced tubular reabsorption.

Animals↗
PubMed1992

Time-dependent reduction and potentiation of growth hormone (GH) responsiveness to GH-releasing factor induced by exogenous GH: role for somatostatin.

Exogenous GH is known to exert a negative feedback effect on its own responsiveness to GH-releasing factor (GRF); however, the mechanism is not known. In the present study we examined the time course of effects of a single sc administration of recombinant human (rh) GH on GH responsiveness to GRF and investigated the possible involvement of somatostatin (SRIF) in this response. Free-moving adult male rats were administered 200 micrograms rhGH, sc, at 0800 h and subsequently challenged with 1 microgram GRF-(1-29)NH2, iv, at times of spontaneous peaks (1100 and 1500 h) and troughs (1300 h) in GH secretion during a 6-h (1000-1600 h) sampling period. H2O-injected control rats exhibited the typical cyclic responsiveness to GRF stimulation, with GRF-induced GH release significantly greater during peak compared to trough periods of the GH rhythm. Pretreatment with rhGH 3 h before GRF injection markedly inhibited the GH response to GRF at a peak time [integrated GH release over 30 min, 1135 +/- 271 vs. 6372 +/- 1185 ng/ml.30 min in H2O-injected controls (mean +/- SE); P less than 0.01]. In striking contrast, 5 h after rhGH administration, there was a 6-fold augmentation of GH responsiveness to GRF compared to that in H2O-injected controls at a trough time (7032 +/- 1622 vs. 1128 +/- 216 ng/ml.30 min; P less than 0.01). High GH responsiveness to GRF was preserved 7 h after rhGH injection. Passive immunization of rhGH-treated rats with SRIF antiserum reversed the rhGH-induced blunted GH response at 3 h (7985 +/- 366 vs. 1705 +/- 431 ng/ml.30 min in rhGH-treated control rats given normal sheep serum; P less than 0.01) and completely restored GH responsiveness to levels as high as those in H2O-injected controls. These results demonstrate that 1) a single sc injection of rhGH markedly attenuates GH responsiveness to GRF acutely for about 3 h, but subsequently enhances somatotroph sensitivity to the stimulatory actions of GRF; and 2) the short term blunting of GRF-induced GH release by rhGH is due at least in part to increased release of endogenous SRIF. The subsequent potentiation of GH responsiveness to GRF is probably due to a SRIF-mediated build-up of pituitary GH stores in a readily releasable pool. Such a mechanism of GH autofeedback may play a physiological role in the genesis of pulsatile GH secretion.

Animals↗
PubMed1987

Hormonal regulation of inhibin production by cultured Sertoli cells.

The hormonal regulation of inhibin production by cultured rat Sertoli cells was examined using a specific radioimmunoassay (RIA) which detects the N-terminal portion of the porcine inhibin alpha chain. FSH, but not hCG or prolactin caused a dose-dependent increase in inhibin production (EC50 for FSH = 2.4 ng/ml); both secreted and intracellular levels of inhibin were increased, but the secreted form represented one-half to two-thirds of the total. The FSH-stimulated production of inhibin was augmented by addition of a phosphodiesterase inhibitor, and could be mimicked by cholera toxin, forskolin, or dibutyryl cAMP, all of which are known to increase intracellular cAMP levels. Inclusion of either dihydrotestosterone or estradiol in the cultures had no effect on inhibin production, both in the presence and absence of FSH. Examination of the conditioned media from forskolin-treated Sertoli cells by gel filtration chromatography revealed a single peak of bioactive and immunoreactive inhibin, at a molecular weight of approximately 32,000, similar to that observed for the porcine and bovine follicular fluid inhibins. Thus, FSH activated the cAMP pathway to stimulate Sertoli cell production of inhibin which in turn suppresses pituitary FSH release to form a closed-loop feedback system.

Animals↗
PubMed2005

PKC-induced ERK1/2 interactions and downstream effectors in ovine cerebral arteries.

Both protein kinase C (PKC) and extracellular signal-regulated kinases (ERK1/2) are involved in mediating vascular smooth muscle contraction. We tested the hypotheses that in addition to PKC activation of ERK1/2, by negative feedback ERKs modulate PKC-induced contraction, and that their interactions modulate both thick and thin myofilament pathways. In ovine middle cerebral arteries (MCA), we measured isometric tension and intracellular free calcium concentration ([Ca(2+)](i)) responses to PKC stimulation [phorbol 12,13-dibutyrate (PDBu), 3 x 10(-6) M] in the absence or presence of ERK1/2 inhibition (U-0126, 10(-5) M). After PDBu +/- ERK1/2 inhibition, we also examined by Western immunoblot the levels of total and phosphorylated ERK1/2, caldesmon(Ser789), myosin light chain(20) (MLC(20)), and CPI-17. PDBu induced significant increase in tension in the absence of increased [Ca(2+)](i). PDBu also increased phosphorylated ERK1/2 levels, a response blocked by U-0126. In turn, U-0126 augmented PDBu-induced contractions. PDBu also was associated with significant increases in phosphorylated caldesmon(Ser789) and MLC(20) levels, each of which peaked at 5 to 10 min. PDBu also increased phosphorylated CPI-17 levels, which peaked at 2 to 3 min. Rho kinase inhibition (Y-27632, 3 x 10(-7) M) did not alter PDBu-induced contraction. These results support the idea that PKC activation can increase CPI-17 phosphorylation to decrease myosin light chain phosphatase activity. In turn, this increases MLC(20) phosphorylation in the thick filament pathway and increases Ca(2+) sensitivity. In addition, ERK1/2-dependent phosphorylation of caldesmon(Ser789) was not necessary for PDBu-induced contraction and appears not to be involved in the reversal of caldesmon's inhibitory effect on actin-myosin ATPase.

Animals↗
PubMed2006

Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element.

Asef (herein called Asef1) was identified as a Rac1-specific exchange factor stimulated by adenomatous polyposis coli (APC), contributing to colorectal cancer cell metastasis. We investigated Asef2, an Asef1 homologue having a similar N-terminal APC binding region (ABR) and Src-homology 3 (SH3) domain. Contrary to previous reports, we found that Asef1 and Asef2 exchange activity is Cdc42 specific. Moreover, the ABR of Asef2 did not function independently but acted in tandem with the SH3 domain to bind APC. The ABRSH3 also bound the C-terminal tail of Asef2, allowing it to function as an autoinhibitory module within the protein. Deletion of the C-terminal tail did not constitutively activate Asef2 as predicted; rather, a conserved C-terminal segment was required for augmented Cdc42 GDP/GTP exchange. Thus, Asef2 activation involves APC releasing the ABRSH3 from the C-terminal tail, resulting in Cdc42 exchange. These results highlight a novel exchange factor regulatory mechanism and establish Asef1 and Asef2 as Cdc42 exchange factors, providing a more appropriate context for understanding the contribution of APC in establishing cell polarity and migration.

Adenomatous Polyposis Coli Protein↗
PubMed2004

Estradiol supplementation modulates growth hormone (GH) secretory-burst waveform and recombinant human insulin-like growth factor-I-enforced suppression of endogenously driven GH release in postmenopausal women.

The present study tests the mechanistic postulate that estrogen confers resistance to negative feedback by systemic IGF-I. To this end, eight postmenopausal women received a constant iv infusion of recombinant human (rh)IGF-I (10 micro g/kg.h x 6 h) and saline in randomized order on the 10th day of supplementation with oral estradiol (E(2)) and placebo (Pl). GH secretion was quantitated by 10-min blood sampling, immunochemiluminometry assay, and deconvolution analysis. Administration of E(2) compared with Pl followed by saline infusion: 1) stimulated pulsatile GH secretion ( micro g/liter.6 h), viz., 12 +/- 3.3 (Pl) and 18 +/- 4.6 (E(2)) (mean +/- SEM, paired comparison, P < 0.05); 2) halved the time latency (min) to achieve peak GH secretion after GHRH injection, 24 +/- 2.2 (Pl) and 12 +/- 2.1 (E(2)) (P < 0.01); and 3) did not alter the mass of GH secreted ( micro g/liter) in response to a maximally effective dose of GHRH, 30 +/- 7.2 (Pl) and 37 +/- 11 (E(2)). Exposure to E(2) compared with Pl followed by rhIGF-I infusion: 1) accelerated the rate of decline of GH concentrations by 3.3-fold, viz., absolute slope ( micro g/liter.1000 min), 3.8 (range, 2.5-5.0) (Pl) and 12 (range, 10-14) (E(2)) (P < 0.001); 2) augmented the algebraic decrement in GH concentrations ( micro g/liter) enforced by rhIGF-I infusion, 0.73 +/- 0.21 (Pl) and 1.6 +/- 0.25 (E(2)) (P < 0.01); 3) halved the time delay (min) to peak GHRH-induced GH secretion, 20 +/- 1.2 (Pl) vs. 10 +/- 1.3 (E(2)) min (P < 0.01). In contradistinction, E(2) did not alter: 1) the capability of rhIGF-I to suppress GHRH-stimulated GH secretory burst mass significantly, viz., by 50 +/- 8% (Pl) and 52 +/- 14% (E(2)) (P < 0.05 each vs. saline); 2) the hourly rate of rise of infused (total) IGF-I concentrations; and 3) total and ultrafiltratably free IGF-I concentrations ( micro g/liter) attained at the end of the two rhIGF-I infusions. In summary, compared with Pl, E(2) supplementation in postmenopausal women: 1) amplifies endogenously driven GH secretory-burst mass; 2) initiates rapid onset of GHRH-stimulated GH release; and 3) potentiates IGF-I-dependent suppression of unstimulated GH concentrations. Based upon companion modeling data, we postulate that E(2) facilitates the upstroke and IGF-I enforces the downstroke of high-amplitude GH secretory bursts in estrogen-replete individuals.

Drug Interactions↗
PubMed1996

Acute administration of buspirone increases the escape of hypothalamic-pituitary-adrenal-axis hormones from suppression by dexamethasone in depression.

Recently, our laboratory found a significant enhancing effect of L-5-hydroxy-tryptophan (L-5-HTP) on post-dexamethasone (DST) plasma adrenocorticotropic hormone (ACTH) and cortisol levels in major-but not in minor-depression. To further elucidate the effects of central serotonin (5-HT) activity on the negative feedback of glucocorticoids on hypothalamic-pituitary-adrenal (HPA)-axis function in depression, this study investigates the effects of buspirone, a 5-HT1A receptor agonist, on post-DST ACTH and cortisol levels in 75 depressed subjects. Plasma post-DST ACTH and cortisol concentrations were significantly increased by the acute administration of buspirone (30 mg PO) compared to placebo. There were no differences in buspirone-induced post-DST ACTH or cortisol responses between minor and major depression. There were significant correlations between post-DST ACTH and cortisol, and between post-DST-buspirone ACTH and cortisol. The buspirone-induced post-DST cortisol responses were significantly higher in depressed women than men. It is concluded that buspirone may augment ACTH and, consequently, cortisol escape from suppression by dexamethasone in major as well as in minor depression.

Adrenocorticotropic Hormone↗
PubMed2002

Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog.

The influence of angiotensin II (ANGII) on the dynamic characteristics of renal blood flow (RBF) was studied in conscious dogs by testing the response to a step increase in renal artery pressure (RAP) after a 60 s period of pressure reduction (to 50 mmHg) and by calculating the transfer function between physiological fluctuations in RAP and RBF. During the RAP reduction, renal vascular resistance (RVR) decreased and upon rapid restoration of RAP, RVR returned to baseline with a characteristic time course: within the first 10 s, RVR rose rapidly by 40 % of the initial change (first response, myogenic response). A second rise began after 20-30 s and reached baseline after an overshoot at 40 s (second response, tubuloglomerular feedback (TGF)). Between both responses, RVR rose very slowly (plateau). The transfer function had a low gain below 0.01 Hz (high autoregulatory efficiency) and two corner frequencies at 0.026 Hz (TGF) and at 0.12 Hz (myogenic response). Inhibition of angiotensin converting enzyme (ACE) lowered baseline RVR, but not the minimum RVR at the end of the RAP reduction (autoregulation-independent RVR). Both the first and second response were reduced, but the normalised level of the plateau (balance between myogenic response, TGF and possible slower mechanisms) and the transfer gain below 0.01 Hz were not affected. Infusion of ANGII after ramipril raised baseline RVR above the control condition. The first and second response and the transfer gain at both corner frequencies were slightly augmented, but the normalised level of the plateau was not affected. It is concluded that alterations of plasma ANGII within a physiological range do not modulate the relative contribution of the myogenic response to the overall short-term autoregulation of RBF. Consequently, it appears that ANGII augments not only TGF, but also the myogenic response.

Angiotensin II↗
PubMed1998

Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin (PG) synthesis, augment production of tumor necrosis factor (TNF) in most experimental models. We investigated the effect of two NSAIDs, indomethacin and ibuprofen, on the production of TNF in the CNS induced by intracerebroventricular injection of lipopolysaccharide (LPS). Indomethacin and ibuprofen, administered intraperitoneally, augmented (three- to ninefold) the levels of TNF in serum and peripheral organs of mice injected intraperitoneally with LPS and in rats with adjuvant arthritis (up to a sevenfold increase). However, NSAIDs (intraperitoneally or intracerebroventricularly) did not increase brain TNF production induced by intravenous LPS. In fact, indomethacin decreased (1.4-1.8-fold) TNF levels in the spinal cord of rats with experimental autoimmune encephalomyelitis and in the cortex of rats with focal cerebral ischemia. Systemic administration of iloprost inhibited serum TNF levels after intraperitoneal LPS, whereas intracerebroventricular injection of iloprost or PGE2 did not inhibit brain TNF induced by intracerebroventricular LPS. Both peripheral and central TNF productions were inhibited by cyclic AMP level-elevating agents or dexamethasone. Thus, a PG-driven negative feedback controls TNF production in the periphery but not in the CNS.

Animals↗
PubMed1971

Drug-induced changes in the release of ( 3 H)-noradrenaline from field stimulated rat iris.

1. Isolated rat irides were incubated with [(3)H]-noradrenaline [(3)H-NA] (10(-7)M), superfused with buffer and then stimulated by an electrical field. The effect of desipramine, clonidine, phentolamine, phenoxybenzamine, GD131, normetanephrine and 4-tropolone-acetamide on the stimulation-induced overflow of [(3)H]-NA was tested by adding the drug to the superfusing buffer. The effect of pretreatment with phentolamine or phenoxybenzamine on the stimulation-induced overflow of [(3)H]-NA was also studied.2. The effect of desipramine, clonidine, phentolamine, phenoxybenzamine and GD131 on uptake of [(3)H]-NA in isolated irides was determined.3. Desipramine moderately increased the stimulation-induced overflow at concentrations which almost completely inhibited neuronal uptake. It was calculated that in the isolated rat iris 30-40% of the released [(3)H]-NA is inactivated by reuptake into the nerve terminal. This figure may represent the true reuptake percentage in this preparation. Desipramine-induced inhibition of [(3)H]-NA release from the nerve terminal, possibly via a negative feed-back mechanism, may also contribute to this low figure.4. Phentolamine and phenoxybenzamine, in concentrations or doses which did not inhibit neuronal uptake of [(3)H]-NA, consistently increased the stimulation-induced overflow. This increase was further augmented when neuronal uptake was inhibited.5. The alpha-adrenoceptor stimulating drug clonidine decreased the stimulation-induced overflow.6. GD131, normetanephrine and 4-tropolone-acetamide did not greatly affect the stimulation-induced overflow of [(3)H-NA].7. It is concluded that the increased [(3)H]-NA overflow obtained after alpha-adrenoceptor blockade is due to an increased [(3)H]-NA release from the nerve terminals.

Acetamides↗