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PubMed2002

Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism.

Constitutive activation of the BCR-ABL tyrosine kinase is fundamental to the pathogenesis of chronic myeloid leukemia (CML). STI571 inhibits this activity and modulates the transcription of several genes. It was shown by differential display that the suppressor of cytokine signaling-2 (SOCS-2) gene was down-regulated by STI571 treatment in 14 of 16 BCR-ABL-positive cell lines and in 2 BCR-ABL-transfected murine lines, but not in BCR-ABL-negative counterparts. The effect was maximal at 2 hours and persisted for at least 24 hours after exposure to 1 microM STI571, whereas SOCS-1 and SOCS-3 expression were unaffected. Baseline levels of SOCS-2 were significantly higher in BCR-ABL-positive as compared with BCR-ABL-negative cell lines. It was similar in leukocytes and CD34(+) cells from healthy persons (n = 44) and patients with CML in chronic phase (CP; n = 60) but significantly increased in patients with CML in blast crisis (BC; n = 20) (P <.0001). Mononuclear cells (MNCs) from 3 of 4 patients with CML in BC showed a 2-fold to 12-fold down-regulation of SOCS-2 levels on in vitro exposure to STI571; moreover, a 2-fold to 11-fold decrease in SOCS-2 was observed in MNCs from 7 of 8 patients with CML in BC who responded to treatment with STI571. Refractoriness to STI571 or relapse after initial response was accompanied by augmentation of SOCS-2 expression. Ectopic overexpression of SOCS-2 in 32Dp210 cells slowed growth, inhibited clonogenicity, and increased their motility and sensitivity to STI571. Overall, the results suggest that SOCS-2 is a component of a negative feedback mechanism; it is induced by Bcr-Abl but cannot reverse its overall growth-promoting effects in blastic transformation.

Alternative Splicing↗

PubMed1977

Hypothalamic control of the mammalian sexual maturation.

The attainment of sexual maturity is a complex process which requires maturation and interaction not only of gonads and reproductive tract but also of the pituitary and essentially of the neuroendocrine mechanisms which ultimately control gonadotropin secretion. One of the more attractive hypotheses of the sexual maturation presumes the existence of the sensitivity threshold of the regulating system to the negative feedback signal, which differentiates immaturity from maturity. As the subject matures this declines. In an attempt to examine further the maturational alterations of the male hypothalamo-pituitary-gonadal axis, investigations were carried out with regard to simultaneous changes of blood LH, FSH, testosterone and dihydrotestosterone levels during the course of 24 hr; augmentation of pituitary and blood LH and FSH concentrations under the stimulus of LH-RH as a function of time and age; synthesis and release of LH and FSH in the testosterone-blocked animals at various stages of sexual maturation; and in vitro biotransformation of testosterone to its 5 alpha-reduced metabolites by the pituitaries as a function of age. Evidence from the experimental data could be interpreted as a decrement of the feedback set-points during sexual maturatio as reflected by the transition of the responses obtained under various experimental signals. In parallel to these observations, new evidence was presented regarding not only quantitative but qualitative changes in the pituitary gonadotropins as response to the negative and positive feedback signals. This leads to new thinking with regard to the hypothesis of differential sensitivity.

Animals↗

PubMed2001

Regulation of GH secretion in acromegaly: reproducibility of daily GH profiles and attenuated negative feedback by IGF-I.

GH hypersecretion is a hallmark of acromegaly. It is unknown whether the secretory activity of somatotroph adenoma is autonomous or is still governed by central or peripheral mechanisms. In this study we investigated whether GH secretion in acromegaly 1) has a reproducible circadian pattern and 2) is inhibited by exogenous IGF-I. Eleven patients with newly diagnosed acromegaly were studied in 2 protocols. In protocol 1, peripheral blood was sampled every 10 min for 48 h in 6 patients for the determination of concordance between 24-h GH profiles. There was no significant day to day variability in mean 24-h output. There was, however, a significant time effect, and the 24-h GH secretion pattern was maintained between days. In protocol 2, 5 patients were sampled for GH every 10 min twice, once during infusion of normal saline and once during iv infusion of recombinant human IGF-I (10 microg/kg x h). The recombinant human IGF-I infusion increased plasma IGF-I to approximately 230% of the baseline concentration. This resulted in GH suppression (4220 +/- 1950 vs. 3223 +/- 1472 microg/liter.min; P = 0.001), but did not alter GH secretion pattern. There were highly significant cross-correlations for 10 of the 11 of the subjects in the two protocols when the lag was 0 min. By harmonic analysis, nocturnal augmentation of GH was maintained, and maximum daily GH occurred at approximately 2300 h. These data demonstrate that the pattern of GH secretion in acromegaly is not random, but is highly preserved with 24-h periodicity. In addition, negative feedback regulation by IGF-I is preserved, although the degree of negative feedback is grossly attenuated. Thus, secretory activity of somatotroph adenomas is not autonomous or haphazard, but is still subject to both feedback and feedforward regulatory mechanisms.

Acromegaly↗

PubMed2004

Dynamic properties of corticogeniculate excitatory transmission in the rat dorsal lateral geniculate nucleus in vitro.

The feedback excitation from the primary visual cortex to principal cells in the dorsal lateral geniculate nucleus (dLGN) is markedly enhanced with firing frequency. This property presumably reflects the ample short-term plasticity at the corticogeniculate synapse. The present study aims to explore corticogeniculate excitatory postsynaptic currents (EPSCs) evoked by brief trains of stimulation with whole-cell patch-clamp recordings in dLGN slices from DA-HAN rats. The EPSCs rapidly increased in amplitude with the first two or three impulses followed by a more gradual growth. A double exponential function with time constants 39 and 450 ms empirically described the growth for 5-25Hz trains. For lower train frequencies (down to 1Hz) a third component with time constant 4.8 s had to be included. The different time constants are suggested to represent fast and slow components of facilitation and augmentation. The time constant of the fast component changed with the extracellular calcium ion concentration as expected for a facilitation mechanism involving an endogenous calcium buffer that is more efficiently saturated with larger calcium influx. Concerning the function of the corticogeniculate feedback pathway, the different components of short-term plasticity interacted to increase EPSC amplitudes on a linear scale to firing frequency in the physiological range. This property makes the corticogeniculate synapse well suited to function as a neuronal amplifier that enhances the thalamic transfer of visual information to the cortex.

Animals↗

PubMed2001

Lowering total plasma insulin-like growth factor I concentrations by way of a novel, potent, and selective growth hormone (GH) receptor antagonist, pegvisomant (B2036-peg), augments the amplitude of GH secretory bursts and elevates basal/nonpulsatile GH release in healthy women and men.

The present clinical study implements a novel interventional strategy of short-term profound and selective blockade of GH receptors to reduce plasma insulin-like growth factor I (IGF-I) concentrations reversibly in healthy eumetabolic adults. Thereby, we examine the feedback role of systemic IGF-I on GH secretion without introducing the complex metabolic disarray that can otherwise accompany secondary IGF-I deprivation. To this end, we sampled blood at 10-min intervals for 10 h overnight in 8 men (aged 19-46 yr) and 4 women (aged 19-39 yr) to quantitate endogenous GH secretion and half-life 72 h after the prospective, randomly ordered, double blind, and within-subject cross-over administration of pegvisomant (1 mg/kg) or saline (0.5 mL) sc. Pegvisomant is an oligopegylated recombinant human GH peptide mutated to antagonize GH receptor-dependent signaling. Statistical analyses of paired plasma IGF-I concentrations and deconvolution-based quantitation of pulsatile GH secretion revealed that GH receptor blockade 1) suppressed fasting total IGF-I concentrations by 31%, viz. from (mean +/- SEM) 276 +/- 42 (placebo) to 190 +/- 20 microg/L (pegvisomant; P = 0.006) 84 h after drug injection; 2) increased the 10-h mean serum GH concentration by 71% from 1.4 +/- 0.33 (placebo) to 2.4 +/- 0.58 (pegvisomant; P = 0.024); 3) augmented the amplitude of underlying GH secretory bursts by 2.1-fold (i.e. from 0.13 +/- 0.032 to 0.27 +/- 0.076 microg/L.min; P = 0.0088); and 4) elevated the basal/nonpulsatile rate of GH secretion by 2.5-fold (from 2.3 +/- 0.77 to 5.07 +/- 1.8 microg/L.10 h; P = 0.022). The rise in the amplitude of GH secretory bursts correlated with the fall in plasma IGF-I concentrations (r = 0.603; P = 0.038). In contrast, IGF-I depletion did not alter GH secretory pulse frequency, half-duration, interpulse interval, percentage of pulsatile GH release, or half-life of endogenous GH. In summary, selective short-term reduction of systemic IGF-I concentrations in healthy eumetabolic adults drives GH secretion via the specific bipartite neuroregulatory mechanism of amplified GH secretory burst amplitude and elevated basal/nonpulsatile GH release. Endogenous GH half-life and frequency-related features of pulsatile GH secretion are not measurably affected, thus identifying a highly distinctive mode of IGF-I feedback-dependent control of GH output. As the increment in GH secretory burst amplitude correlated with the decrement in plasma IGF-I concentrations, we infer that variations in circulating IGF-I availability within the adult midphysiological range can influence pulsatile and basal GH production by way of negative feedback. Based on data in experimental animals, we speculate that the negative feedback actions of systemic IGF-I on GH secretion are mediated via increased hypothalamic somatostatin release, decreased GHRH (or GH-releasing peptide) secretion, and/or suppressed pituitary GH biosynthesis.

Adult↗

PubMed1993

Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: a microdialysis study.

The present study addressed the possibility that disinhibition of serotonin (5-HT) autoreceptor-mediated negative feedback might potentiate the elevation of nerve terminal 5-HT output induced by selective 5-HT reuptake blockade. To this end, rats were given citalopram and the 5-HT autoreceptor-blocking agents (S)-UH-301 (5-HT1A) and (-)-penbutolol (5-HT1A/1B), and the effect on extracellular 5-HT in the ventral hippocampus was monitored by means of in vivo microdialysis. Citalopram (5 mg/kg, s.c.) approximately doubled the 5-HT output, a response that was markedly augmented by (S)-UH-301 (3 mg/kg, s.c.) and (-)-penbutolol (8 mg/kg, s.c.) and by combined treatment with (S)-UH-301 (3 mg/kg, s.c.) plus (-)-penbutolol (1 microM; via the dialysis perfusion medium), but not by (-)-penbutolol (1 microM) alone. These findings provide evidence that 5-HT, in particular 5-HT1A, autoreceptor-mediated negative feedback mechanisms are pivotal in determining the nerve terminal 5-HT output level after 5-HT reuptake inhibition. These findings have important implications for the interplay between different processes controlling 5-HT transmission in vivo and might possibly offer a lead toward novel, therapeutically exploitable principles.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2003

Calcium signaling and uterine contractility.

Changes in Ca(2+) signals within the myometrium have important functional consequences, as they determine contractility. We show that the basic phasic nature of uterine contractions, which is essential for successful labor, is critically dependent on Ca(2+) influx through voltage-gated L-type Ca(2+) channels, and hence in turn, on membrane potential. Thus changes in ion channel expression around term will play an important role in governing uterine excitability and contractility. There remains uncertainty about which channels are present in human myometrium and the nature of the pacemaker mechanism that initiates the action potential. The sarcoplasmic reticulum may augment, to a small extent, the necessary increase in [Ca(2+)] for contraction when agonists stimulate the uterus, but its main role appears to be to control excitability, acting as a negative feedback mechanism to limit contractions. Myosin light chain kinase activity and phosphorylation of myosin are essential components in the pathway of uterine contraction, once Ca(2+) has been elevated. Modulation of myosin light chain phosphatase activity can also influence contractions, but the effects are small compared with those modulating myosin light chain kinase. Ca(2+)-sensitizing pathways may not be utilized much in modulating normal phasic uterine activity, and caution is needed in extrapolating from in vitro experiments to in vivo conditions, especially because there may be redundant pathways. There is a need to study appropriate physiologic preparations, but these are not always available (eg, preterm laboring myometrium) and to combine functional studies with modern molecular approaches, to advance our understanding to a new level, from which better therapeutics will be developed.

Animals↗

PubMed1988

Functional neuromuscular stimulation neuroprostheses for the tetraplegic hand.

Functional neuromuscular stimulation (FNS) of the C5 and C6 tetraplegic upper extremity has been shown to be a valid clinical tool for restoring controlled movement in the paralyzed hand. The current clinical system consists of a shoulder position transducer controlling an external microprocessor-based stimulator, which excites paralyzed muscle via the peripheral nerve using percutaneous leads or a multichannel, implantable stimulator. Tendon transfer surgery of paralyzed but innervated muscle may augment the neurologically deficient upper extremity by allowing the substitution of stronger motors or the addition of new motors where flaccid paralysis (dennervation) eliminates the usual muscle from a grasp pattern. Sensory feedback in the form of machine state and cognitive information can be provided to the normally innervated C5 dermatome skin by subcutaneous electrodes. C5- and C6-level tetraplegics using FNS can independently perform single-hand manipulative tasks at a level similar to that of subjects with intact C7 roots, although they lack the elbow control.

Electric Stimulation Therapy↗

PubMed1986

Restoration of impaired B- and T-lymphocyte subsets and functions in vitro by isoprinosine in prodromal homosexuals and AIDS patients.

Functional and phenotypical parameters demonstrated significant aberrations in both prodromal males and patients with the acquired immune deficiency syndrome (AIDS). Impaired B-cell functions as quantitated by Staphylococcus aureas Cowan Strain I (SAC) and pokeweed mitogen (PWM)-induced blastogenesis, intracytoplasmic immunoglobulins and spontaneous immunoglobulin were associated with a significant decrease in Leu3+ cells but unrelated to Leu2+ lymphocytes. The functional subsets of the latter were further defined by monoclonal antibodies (Leu8 and HLA-DR) applying dual color flow cytometry. Activated and effector-suppressor subsets with the phenotypes Leu2+ HLA-DR+ and Leu2+ Leu8- were elevated while both subsets of helper and suppressor-inducing helper lymphocytes, Leu3+ Leu8- and Leu3+ Leu8+, were depressed. These data demonstrated a broad spectrum of dysfunction involving all 3 stages of B-cell development in AIDS as well as possible defects in the feedback suppressor loop which regulates both the helper and suppressor T-lymphocyte system and B-cell functions. While in vitro incubation with isoprinosine had no modulative effect on SAC-induced blastogenesis (resting B-cell activities), it did modulate both PHA, PWM-induced transformation and the spontaneous secretion of immunoglobulins (partially and fully activated B-cell activities). In co-incubation with PWM, isoprinosine augmented the expression of inducer cells for helper functions while enhancing to normal level the number of suppressor-inducing helper cells. In addition, it reduced activated and effector-suppressor cells to near normal range in the PBL of high risk homosexuals. Only marginal modulation, however, was observed in suppressor subsets of AIDS subjects. This interference with the defective feedback loop may account for the selective clinical and immunoregulatory actions of this drug.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Prostaglandin F2alpha induces expression of prostaglandin G/H synthase-2 in the ovine corpus luteum: a potential positive feedback loop during luteolysis.

The primary role of prostaglandin (PG) F2alpha in regression of the corpus luteum has been clearly demonstrated in many mammalian species. We have used in vivo and in vitro approaches to investigate the possibility that exogenous PGF2alpha induces expression of prostaglandin G/H synthase-2 (PGHS-2; cyclooxygenase-2) and causes production of PGF2alpha in ovine luteal cells. Ewes received infusions into the ovarian artery of 1 ml PGF2alpha (1 micromol) or saline, and corpora lutea were collected at various times and analyzed for PGHS-2 mRNA using quantitative, competitive reverse transcription polymerase chain reaction. PGF2alpha dramatically increased the steady-state concentration of mRNA for PGHS-2 within 1 h, but basal concentration returned at 12 h posttreatment. In vitro studies using isolated ovine large luteal cells indicated that mRNA for PGHS-2 was induced by PGF2alpha, phorbol didecanoate, and ionomycin in a pattern similar to that observed in vivo. PGHS-2 protein was induced by all three treatments 4-12 h later, and accumulation of PGF2alpha in the culture media increased at 12 and 24 h posttreatment. In conclusion, we have provided evidence that PGF2alpha, probably acting through the protein kinase C/free intracellular calcium pathway, can stimulate large luteal cells to express PGHS-2 and produce PGF2alpha. This luteal PGF2alpha is likely to have an autocrine/paracrine function to augment the luteolytic effect of PGF2alpha of uterine origin.

Animals↗

PubMed2001

Concerted transcriptional activation of the low density lipoprotein receptor gene by insulin and luteinizing hormone in cultured porcine granulosa-luteal cells: possible convergence of protein kinase a, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase signaling pathways.

Insulin and insulin-like growth factor I (IGF-I) can amplify gonadotropin-stimulated steroidogenesis by augmenting the expression of key sterol regulatory genes in ovarian cells, viz. low density lipoprotein (LDL) receptor, steroidogenic acute regulatory protein, and P450 cholesterol side-chain cleavage enzyme (CYP11A). The mechanisms underlying the foregoing bihormonal interactions are not known. Accordingly, in relation to the LDL receptor gene, the present study tests the hypothesis that insulin/IGF-I and LH can act via concerted transcriptional control of promoter expression. To this end, we transiently transfected primary monolayer cultures of porcine granulosa-luteal cells with a reporter vector containing the putative 5'-upstream full-length (pLDLR1076/luc) regulatory region (-1076 to +11 bp) of the homologous LDL receptor gene driving firefly luciferase in the presence or absence of insulin (or IGF-I) and/or LH (each 100 ng/ml). Combined exposure to LH and insulin (or IGF-I) stimulated LDL receptor transcriptional activity maximally at 4 h by 8- to 20-fold, as normalized by coexpression of Renilla luciferase. Further analysis of multiple 5'-nested deletional constructs of the LDL receptor gene promoter showed that deletion of -139 bp upstream of the transcriptional start site virtually abolished basal expression and promoter responsiveness to LH and insulin/IGF-I. In contrast, full basal activity and 60-80% of maximal monohormonal and bihormonal drive were retained by the -255 to +11 bp fragment. As LDL receptor gene expression in other tissues is negatively regulated by the abundance of intracellular free cholesterol, we assessed the impact of concomitant pretreatment of granulosa-luteal cells with an exogenous soluble sterol (25-hydroxycholesterol, 1 and 10 microM). Excess sterol markedly (50-70%) attenuated bihormonally and, in lesser measure, LH-stimulated and basal LDL receptor promoter expression, thus affirming a feedback-sensitive sterol-repressive region in this gene. Non-LH receptor-dependent agonists of protein kinase A (PKA), 8-bromo-cAMP (1 mM), and forskolin (10 microM) with or without insulin/IGF-I costimulation likewise augmented LDL receptor promoter expression with similar strong dependency on the -255 to -139 bp 5'-upstream region. To assess more specific PKA-dependent mediation of LH's contribution to combined hormonal drive, the LDL receptor (-1076 to +11 bp) reporter plasmid was cotransfected with a full-sequence rabbit muscle protein kinase inhibitor (PKI) minigene driven constitutively by a Rous sarcoma virus promoter. Expression of the latter PKA antagonist blocked transcriptional stimulation by LH alone as well as that by LH combined with insulin (or IGF-I) by 70-85% without reducing basal transcriptional activity. Transfection of a mutant inactive (Arg to Gly) Rous sarcoma virus/PKI gene confirmed the specificity of the PKI effect. To investigate the convergent role of the insulin/IGF-I effector pathway mediating bihormonal stimulation of LDL receptor promoter expression, transfected granulosa-luteal cells were pretreated for 30 min with two specific inhibitors of phophatidylinositol 3-kinase, wortmannin (100 nM) and LY 294002 (10 microM), or of mitogen-activated protein kinase kinase, PD 98059 (50 microM), U0126 (10 microM), or the latter's inactive derivative, U0124 (10 microM). Both classes of antagonists impeded the ability of insulin or IGF-I to enhance LH-stimulated LDL receptor promoter expression by 60-80%. In conclusion, the present analyses indicate that LH and insulin (or IGF-I) can up-regulate LDL receptor transcriptional activity supraadditively in porcine granulosa-luteal cells 1) via one or more agonistic cis-acting DNA regions located between -255 and -139 bp 5'- upstream of the transcriptional start site, 2) without abrogating sterol-sensitive repressive of this promoter, and 3) by way of intracellular mechanisms that include the PKA, phophatidylinositol 3-kinase, and mitogen-activated protein kinase signaling pathways.

Animals↗

PubMed2002

Angiotensin II activates a nitric-oxide-driven inhibitory feedback in the rat paraventricular nucleus.

The hypothalamic paraventricular nucleus (PVN) has been shown to play major obligatory roles in autonomic and neuroendocrine regulation. Angiotensin II (ANG) acts as a neurotransmitter regulating the excitability of magnocellular neurons in this nucleus. We report here that ANG also activates a nitric-oxide-mediated negative feedback loop in the PVN that acts to regulate the functional output of magnocellular neurons. Thus in addition to its depolarizing actions on magnocellular neurons, ANG application results in an increase in the frequency of inhibitory postsynaptic potentials in a population of these neurons without effect on the amplitude of these events. ANG was also without significant effect on the mean frequency or amplitude of mini synaptic currents analyzed in voltage-clamp experiments. This increase in inhibitory input after ANG can be abolished by the nitric oxide synthase inhibitor Nomega-nitro-l-arginine methylester, demonstrating a requisite role for nitric oxide in the activation of this pathway. The depolarization of magnocellular neurons that show increased inhibitory postsynaptic potential (IPSP) frequency in response to ANG is significantly smaller than that observed in neurons in which IPSPs frequency was unaffected (3.2 +/- 1.1 vs. 8.0 +/- 0.5 mV, P < 0.05). Correspondingly, after nitric oxide synthase inhibition, the depolarizing effects of ANG on magnocellular neurons are augmented (2.0 +/- 0.7 vs. 6.7 +/- 0.7 mV, P < 0.05). The depolarization was also enhanced in the presence of the GABAergic antagonist bicuculline (1.9 +/- 1.2 vs. 11.9 +/- 2.3, P < 0.001). These data demonstrate that there exists within the PVN an intrinsic negative feedback loop that modulates neuronal excitability in response to peptidergic excitation.

Angiotensin II↗

PubMed1999

Alterations in platelet Ca2+ signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production.

Increased aggregation of platelets might contribute to the development of vascular complication in diabetes mellitus. In this study release of superoxide anions, intracellular Ca2+ signalling and nitric oxide formation stimulated by the receptor-dependent agonist adenosine 5 '-diphosphate (ADP) and the receptor-independent stimulus thapsigargin, were compared in platelets isolated from patients with Type II (non-insulin-dependent) diabetes mellitus and healthy control subjects. Diabetes augmented intracellular Ca2+ release and Ca2+ entry to ADP by 40 and 44% (control subjects: n = 11; diabetic: n = 6), while the median effective concentration (EC50) of ADP to initiate Ca2+ signalling was similar in both groups. The effect of thapsigargin on Ca2+ concentration was increased by 69% in diabetic patients (control subjects: n = 22; diabetic patients: n = 9). In addition, release of superoxide anions was 70% greater in diabetic patients (control subjects: n = 9; diabetic patients: n = 6). Treatment of platelets from control subjects with the superoxide anion-generating mixture xanthine oxidase and hypoxanthine or buthioninesulphoximine (BSO) mimicked the effect of diabetes on platelet Ca2+ signalling. The antioxidant glutathione normalized enhanced Ca2+ response in the diabetic group (control subjects: n = 5: diabetic patients: n = 6). Basal and thapsigargin-evoked nitric oxide synthase activity was reduced in the diabetic group by 85 and 64%, respectively (control subjects: n = 13; diabetic subjects: n = 13). The nitric oxide-donor 2-(N,N-diethylamino)-diazenolate-2-oxide sodium (DEA/NO) normalized enhanced Ca2+ signalling in platelets preincubated with xanthine oxidase and hypoxanthine (n = 12) and in those from diabetics (control subjects: n = 6; diabetic patients: n = 6). Inhibition of nitric oxide synthase by N-nitro-L-arginine (L-NA) augmented thapsigargin-induced Ca2+ signalling by 51% (n = 8). These data indicate that in diabetes platelet Ca2+ signalling might be enhanced by excessive superoxide production and an attenuated negative direct or indirect feedback control by nitric oxide, due to its reduced production.

Adenosine Diphosphate↗

PubMed1994

Ionic currents and endothelin signaling in smooth muscle cells from rat renal resistance arteries.

The repertoire of ionic channels expressed in myocytes freshly isolated from microdissected interlobar and arcuate arteries of rat kidney and their integrative behavior in response to endothelin-1 (ET-1) were studied by identification and characterization of major whole cell current components using patch-clamp technique. In renal microvascular smooth muscle cells (RMSMC) dialyzed with K(+)-containing solution, rapidly inactivating (Ito) and sustained outward K+ currents were identified. Voltage-dependent Ito was categorized as "A" current based on its kinetics, sensitivity to 4-aminopyridine (4-AP), and refractoriness to tetraethylammonium (TEA+). Ca(2+)-activated component of K+ current was completely blocked by 10 mM TEA+, whereas 5 mM 4-AP did not affect this current. Maximal Ca2+ current (ICa) recorded in Cs(+)-loaded RMSMC reached 250 pA when cells were bathed in a solution with 2.5 mM Ca2+. Two patterns of ICa differing in kinetics, voltage range of activation and inactivation, and sensitivity to nifedipine were identified as T and L currents. Ca(2+)-dependent current component showing reversal potential near Cl- current (ECl) and sensitivity to blocking action of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid was identified as Ca(2+)-activated ECl. Activation of RMSMC with ET-1 (1-10 nM) induced elevation of [Ca2+]i and subsequent activation of Ca(2+)-activated ICl, which led to membrane depolarization sufficient to activate voltage-gated Ca2+ channels. ET-1-evoked transient reduction of ICa carried through voltage-gated Ca2+ channels was followed by augmentation of L-type ICa. ET-1-induced mobilization of intracellular Ca2+, accompanied by membrane depolarization, resulted in activation of Ca(2+)-dependent K+ channels, which can play the role of a feedback element terminating ET-1-induced membrane depolarization.

4-Aminopyridine↗

PubMedDate not supplied

Effect of bradykinin on the cytosolic free calcium activity and phosphoinositol turnover in human glomerular epithelial cells.

The effect of bradykinin (BK) on the intracellular free calcium activity [Ca2+]i and phosphoinositide (PI) turnover was investigated in human glomerular epithelial cells (GEC) in culture. Human GEC exhibited a baseline [Ca2+]i of 114 +/- 3 nmol (n = 81). BK (ED50 10(-9) mol/l) caused a rapid and transient increase in [Ca2+]i, which could also be observed in the absence of extracellular calcium. The effect of BK (10(-8) mol/l) on the [Ca2+]i was inhibited by the BK2 antagonist Hoe 140 (IC50 10(-8) mol/l). BK also induced PI turnover in a time- and dose-dependent manner. A transient increase in (1,4,5)-inositol-triphosphate (InsP3) formation from 1,445 +/- 119 to 4,629 +/- 323 cpm occurred after 5 s. Stimulation of protein kinase C (PKC) by short-term preincubation (15 min) of human GEC with phorbol-12-myristate-13-acetate (PMA) induced a dose-dependent inhibition of the BK-stimulated (10(-7) mol/l) inositol-phosphate formation. Downregulation of PKC by preincubation of human GEC with PMA (24 h, 10(-6) mol/l) or inhibition of PKC by pretreatment with staurosporin (1 h, 10(-6) mol/l) resulted in a slight but significant augmentation of the BK-induced InsP3 stimulation. The data indicate that BK induces stimulation of [Ca2+]i and PI turnover via a BK2 receptor in human GEC. PKC might exert a negative feedback function for the BK-induced PI turnover.

Bradykinin↗

PubMed1998

Growth hormone inhibits its own secretion by acting on the hypothalamus through its receptors on neuropeptide Y neurons in the arcuate nucleus and somatostatin neurons in the periventricular nucleus.

GH secretion is regulated by hypothalamic somatostatin and GH-releasing factor. It has been postulated that GH feeds back on the hypothalamus and regulates its own secretion. We focused our attention on the action of GH in the hypothalamus in relation to GH secretion. Adult male rats were used throughout the studies, and the observation was made in conscious rats. Systemic administration of human GH induced c-fos gene expression, a marker of neuronal activity, in the hypothalamic arcuate nucleus (ARC) and the periventricular nucleus (PeV) in hypophysectomized male rats. The major cells in which c-fos gene expression was induced were neuropeptide Y (NPY) neurons in the ARC and somatostatin neurons in the PeV. GH receptor mRNA was demonstrated to be present in these neurons by in situ hybridization. The injection of a small dose of rat GH into the ARC or PeV inhibited GH secretion, whereas microinjection of IGF-I into these nuclei did not. Intracerebroventricular injection of NPY suppressed GH secretion, and this effect was abolished by anterolateral deafferentation of the medial basal hypothalamus (MBH), a procedure which disrupts the somatostatinergic input to the MBH. Taken together, these findings suggest that GH acts on NPY neurons in the ARC and somatostatin neurons in the PeV through GH receptor, and the activation of these neurons augments somatostatin release and inhibits GH secretion.

Animals↗

PubMed1975

Role of prostaglandins in the pathogenesis of acute renal failure.

It is suggested that impaired glomerular infiltration in acute renal failure may be due, if only in part, to the derangement of a normal local feedback mechanism involving prostaglandins. According to this hypothesis, prostaglandins made in the medulla normally enter the loop of Henle and thus are present in distal tubule fluid reaching the macula densa. In the absence of direct vascular channels connecting the renal medulla with the outer cortex, this may be the only route by which medullary prostaglandins can reach the cortex without being destroyed by dehydrogenases. Under most circumstances in which renal perfusion and glomerular filtration fall, flow through Henle's loop continues, albeit at a reduced rate. This slowed flow through the loop and augmented prostaglandin release combine to produce a high concentration of prostaglandin in fluid leaving the medulla which, acting on the macula densa, counteracts the vasoconstrictor stimulus. If, however, filtration stops completely because of overwhelming vasoconstriction, flow along the loop also stops ans prostaglandins no longer reach the macula densa. Thus, the prostaglandin feedback loop would be opened, constrictor mechanism remain unchecked, and filtration failure perpetuated. It is proposed that such a self-perpetuating mechanism might operate in acute renal failure.

Acute Kidney Injury↗

PubMed1991

Cholecystokinin receptor antagonist loxiglumide modulates plasma levels of gastro-entero-pancreatic hormones in man. Feedback control of cholecystokinin and gastrin secretion.

The effect of the potent specific cholecystokinin (CCK) receptor antagonist loxiglumide on meal-stimulated plasma concentrations of CCK, gastrin, pancreatic polypeptide (PP), neurotensin, glucose-dependent insulinotropic polypeptide (GIP), insulin and C peptide was investigated in a placebo-controlled study in 10 healthy male volunteers. Intravenous infusion of loxiglumide (10 mg kg-1 h-1) significantly augmented integrated incremental IR-CCK levels 7.3-fold after stimulation by a standard breakfast (504 +/- 54 vs 3.665 +/- 365 pmol-1 135 min-1, P less than 0.001), as measured by a specific CCK radioimmunoassay. Basal IR-CCK concentrations were not affected by administration of loxiglumide. Oral treatment with bile acids (2 g ursodeoxycholic acid plus 2 g chenodeoxycholic acid) together with the meal abolished this augmentation, whereas high-dose substitution with pancreatic enzymes (4.2 g pancreatin) reduced elevated IR-CCK levels by only 38%. CCK-like bioactivity, determined by a bioassay using rat pancreatic acini, was not detectable in all samples that contained loxiglumide at plasma concentrations of 100-250 micrograms ml-1. Plasma gastrin concentrations in response to the breakfast were elevated 3.2-fold during loxiglumide infusion and not influenced by substitution with bile acids or pancreatic enzymes. Meal-stimulated integrated incremental plasma PP concentrations were significantly suppressed (55-65% inhibition, P less than 0.01) by loxiglumide. Infusion of the CCK receptor antagonist only slightly increased postprandial peak plasma glucose, insulin and C-peptide levels, whereas GIP and neurotensin levels were not significantly influenced. These findings suggest: (i) CCK secretion is under feedback control by intraduodenal bile acids and to a lesser extent by pancreatic enzymes; (ii) simultaneous extraction of CCK and loxiglumide results in circulating plasma CCK-like bioactivity of zero; (iii) gastrin secretion is feedback controlled via an indirect mechanism probably involving CCK-induced somatostatin secretion; (iv) release of PP is under inhibitory control of CCK; (v) CCK does not play a major role as insulinotropic hormone in the entero-insular axis in humans.

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