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PubMed2003

Islet amyloid polypeptide inhibits glucagon release and exerts a dual action on insulin release from isolated islets.

We have studied the influence of a wide concentration range of islet amyloid polypeptide (IAPP) on both glucagon and insulin release stimulated by various types of secretagogues. In an islet incubation medium devoid of glucose, the rate of glucagon release being high, we observed a marked suppressive action by low concentrations of IAPP, 10(-10) and 10(-8) M, on glucagon release. Similarly, glucagon release stimulated by L-arginine, the cholinergic agonist carbachol, or the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX), an activator of the cyclic AMP system, was inhibited by IAPP in the 10(-10) and 10(-8) M concentration range. Moreover, basal glucagon release at 7 and 10 mM glucose was suppressed by IAPP. In contrast, IAPP exerted a dual action on insulin release. Hence, low concentrations of IAPP brought about a modest increase of basal insulin secretion at 7 mM glucose and also of insulin release stimulated by carbachol. High concentrations of IAPP, however, inhibited insulin release stimulated by glucose (10 and 16.7 mM), IBMX, carbachol and L-arginine. In conclusion, our data suggest that IAPP has complex effects on islet hormone secretion serving as an inhibitor of glucagon release and having a dual action on insulin secretion exerting mainly a negative feedback on stimulated and a positive feedback on basal insulin release.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Tumor necrosis factor-alpha exerts interleukin-6-dependent and -independent effects on cultured skeletal muscle cells.

In vivo studies have shown that cancer-associated skeletal muscle wasting (cachexia) is mediated by two cytokines, tumor necrosis factor-alpha (TNF) and interleukin-6 (IL-6). It has been unclear from these studies whether TNF exerts direct effects on skeletal muscle and/or whether these effects are mediated via IL-6. Previous studies from our laboratory have shown that TNF induces IL-6 mRNA expression in cultured skeletal muscle cells. To further investigate the relationship between TNF and IL-6, the effects of TNF and IL-6 on protein and DNA dynamics in murine C2C12 skeletal myotube cultures were determined. At 1000 U/ml, TNF induced 30% increases in protein and DNA content. The effects of TNF on protein accumulation were inhibited by aphidicolin, an inhibitor of DNA synthesis. IL-6 mimicked the effects of TNF on C2C12 cultures, inducing a 32% increase in protein accumulation and a 71% increase in the rate of protein synthesis. IL-6 also decreased expression of mRNA for several proteolytic system components, including ubiquitin 2.4 kb (51%) and 1.2 kb (63%), cathepsin B (39%) and m-calpain (47%), indicating that IL-6 acts on both protein synthesis and degradation. Incubation of murine C2C12 myotube cultures with TNF (1000 U/ml) in the presence of a polyclonal mouse anti-IL-6 antibody resulted in an abolishment of the effects of TNF on protein synthesis, but did not inhibit TNF-induced stimulation of DNA synthesis. These findings indicate that the effects of TNF on muscle protein synthesis are mediated by IL-6, but that TNF exerts IL-6-independent effects on proliferation of murine skeletal myoblasts.

Animals↗
PubMed2004

Cough, exertional, and sex headaches.

Cough, exertional, and sex headaches are three relatively rare and distinct but related syndromes, all of which are triggered in the context of rapid rises in intra-abdominal pressure. Cough headache occurs after single or brief series of such rises, whereas exertional and sexual headache typically arise after more prolonged provocations. All three syndromes may occur as the manifestation of an underlying, potentially serious cause and appropriate management involves the elimination of intracranial structural or vascular abnormalities. The pathophysiology of the three syndromes is poorly understood. They share several clinical features including relatively brief duration and a response to indomethacin.

Coitus↗
PubMedDate not supplied

P815 mastocytoma cells, classical targets for cytotoxic T lymphocytes, exert natural cytotoxicity.

While investigating the tissue distribution of cytotoxic-T-lymphocyte-associated (CTLA) gene transcripts, we found that some of these could be detected in mast cells. This led us to test the cytolysis exerted by a number of mast cell populations. We briefly report here that P815 cells, classically known as excellent target cells for cytotoxic T cells, exert natural cytotoxicity toward WEHI-164 target cells.

Animals↗
PubMed2000

Homocysteine exerts cell type-specific inhibition of AP-1 transcription factor.

Homocysteine (Hcy) exerts either promoting or suppressive effects on mitogenesis in a cell type-specific manner. Hcy elicits proliferation of vascular smooth muscle cells, but is rather inhibitory to growth of endothelial cells and NIH/3T3 cells. In NIH/3T3 cells, we found that physiologically relevant concentrations (20-100 microM) of Hcy inhibit the activity of activating protein-1 (AP-1) transcription factor, although it is capable of eliciting immediate-early signaling events. Hcy induced p44/42 mitogen-activated protein kinase (MAPK) phosphorylation in control cells, but not in dominant negative p21ras transfected cells, indicating induction of the Ras-MAPK pathway. Hcy also induced the activity of serum response factor and expression of c-fos and c-jun genes. Despite the activation of these upstream events, Hcy potently inhibited AP-1 activity. Oxidized forms of Hcy (Hcy thiolactone, homocystine) were less effective in affecting AP-1. Hcy-mediated inhibition of AP-1 activity was not observed in A7r5 vascular smooth muscle cells. These results demonstrate that Hcy exerts cell type- and redox-specific inhibition of AP-1 dependent biological events.

3T3 Cells↗
PubMed2003

Overexpression of tuberous sclerosis complex 2 exerts antitumor effect on oral cancer cell lines.

Tuberous sclerosis is caused by mutations in tuberous sclerosis complex (TSC) 2 on chromosome 16p13.3, encoding tuberin which is thought to be essential for p27(Kip1) to regulate the cell cycle. In this study, we conducted to examine whether overexpression of TSC2 can affect the growth of oral cancer cells which have different expression level of p27(Kip1) protein. We constructed an expression vector containing sense-oriented rat TSC2 cDNA with pcDNA3.1. We transfected oral cancer cells, B88t (high expression of p27(Kip1) protein) and HI (low expression of p27(Kip1) protein) with the sense expression vector to up-regulate the expression of TSC2 gene. Overexpression of TSC2 exerted the growth inhibitory effect of B88t and HI in vitro and in vivo. These findings suggest that overexpression of TSC2 may exert the antitumor effect on oral cancer cells whether they have high expression of p27(Kip1) protein or not.

Animals↗
PubMed2003

Reliability of electromyographic and torque measures during isometric axial rotation exertions of the trunk.

OBJECTIVE: The aim of the present study was to investigate the between-days reliability of electromyographic (EMG) measurement of 6 bilateral trunk muscles and also the torque output in 3 planes during isometric right and left axial rotation at different exertion levels. METHODS: Ten healthy subjects performed isometric right and left axial rotation at 100, 70, 50 and 30% maximum voluntary contractions in two testing sessions at least 7 days apart. EMG amplitude and frequency analyses of the recorded surface EMG signals were performed for rectus abdominis, external oblique, internal oblique, latissimus dorsi, iliocostalis lumborum and multifidus bilaterally. The primary torque in the transverse plane and the coupling torques in sagittal and coronal planes were measured. RESULTS: For both EMG amplitude and frequency values, good (intraclass correlation coefficient, ICC=0.75-0.89) to excellent (ICC>/=0.90) reliability was found in the 6 trunk muscles at different exertion levels during axial rotation. The reliability of both maximal isometric axial rotation torque and coupling torques in sagittal and coronal planes were found to be excellent (ICC>/=0.93). CONCLUSIONS: Good to excellent reliability of EMG measures of trunk muscles and torque measurements during isometric axial rotation was demonstrated. This provides further confidence of using EMG and triaxial torque assessment as outcome measures in rehabilitation and in the evaluation of the human performance in the work place.

Abdominal Muscles↗
PubMedDate not supplied

Power spectra of sternocleidomastoids, splenius capitis, and upper trapezius in oblique exertions.

BACKGROUND CONTEXT: There is relatively little known concerning the spectral profile of the cervical muscles, despite the fact that neck injury and pain are quite prevalent. PURPOSE: The objective of the study was to calculate and study the power spectral characteristics of the sternocleidomastoids, splenii capitis and upper trapezii in anterolateral flexion and posterolateral extension in a ramp contraction. STUDY DESIGN/SETTING: In a laboratory setting experiments were conducted to record surface electromyographic (EMG) data from six cervical muscles and power spectral variables obtained. PATIENT SAMPLE: Forty normal and healthy young adults (21 men, 19 women). OUTCOME MEASURES: Power spectral of EMG signals. METHODS: EMG data for the left and right isometric anterolateral flexion and posterolateral extension were acquired from the sternocleidomastoids, splenii capitis and upper trapezius bilaterally. The subjects were seated in an upright posture and exerted left and right anterolateral flexor and posterolateral extensor efforts from rest to their maximal voluntary contraction in a gradual linear ramp fashion using visual feedback as a guide. The force exerted and the surface EMG data were sampled at 1 kHz at every 10th percentile grade of contraction and the EMG data were subjected to the Fast-Fourier transform analysis. The median frequency (MF), mean power frequency (MPF), peak power and total power of all six cervical muscles were analyzed. RESULTS: In the anterolateral flexion the ipsilateral sternocleidomastoid and splenius capitis had a wider band of frequency, which further widened with increasing grade of contraction. The trapezius did not engage in the same manner or to the same magnitude. The MF of the sternocleidomastoid in the anterolateral flexion in both genders progressively increased, the splenius capitis remained relatively unchanged, and the upper trapezius declined with the increasing grades of contraction. CONCLUSIONS: There is no significant difference between the genders in spectral profile. There is a bilateral symmetry in spectral profile with reference to activity; however, they are significantly different in different activities for the same muscles. With increasing magnitude of contraction power, spectral density distribution increases and the median frequency decreases. These results can serve as a useful reference for painful necks. Restoration of power spectral characteristics may indicate normalcy, which cannot be gleaned by other EMG or force variables.

Adult↗
PubMed2001

His-His-Leu, an angiotensin I converting enzyme inhibitory peptide derived from Korean soybean paste, exerts antihypertensive activity in vivo.

It has been reported that soybean peptide fractions isolated from Korean fermented soybean paste exert angiotensin I converting enzyme (ACE) inhibitory activity in vitro. In this study, further purification and identification of the most active fraction inhibiting ACE activity were performed, and its antihypertensive activity in vivo was confirmed. Subsequently, a novel ACE inhibitory peptide was isolated by preparative HPLC. The amino acid sequence of the isolated peptide was identified as His-His-Leu (HHL) by Edman degradation. The IC(50) value of the HHL for ACE activity was 2.2 microg/mL in vitro. Moreover, the synthetic tripeptide HHL (spHHL) resulted in a significant decrease of ACE activity in the aorta and led to lowered systolic blood pressure (SBP) in spontaneously hypertensive (SH) rats compared to control. Triple injections of spHHL, 5 mg/kg of body weight/injection resulted in a significant decrease of SBP by 61 mmHg (p < 0.01) after the third injection. These results demonstrated that the ACE inhibitory peptide HHL derived from Korean fermented soybean paste exerted antihypertensive activity in vivo.

Amino Acid Sequence↗
PubMed2002

Melanoidins exert a weak antiradical activity in watery fluids.

The Maillard reaction has a dramatic impact on the overall acceptance and nutritional quality of most of the foods consumed daily in European countries. Melanoidins are polymeric structures formed in the last stage of the Maillard reaction with nearly unknown effect on the human health. The antiradical activity of several melanoidins isolated from model systems and coffee has been studied. A novel antiradical efficiency concept has been applied to describe the antiradical activity in an aqueous medium by bleaching the radical cation N,N-dimethyl-p-phenylenediamine (DMPD(*)(+)). Melanoidins exerted a significantly lower antiradical activity than classical antioxidant compounds (tannic acid, ferrulic acid, caffeic acid, gallic acid, and Trolox) in an aqueous medium. Significant differences have been observed according to the type of amino acid used as reactant during the formation of the melanoidin structure and the antiradical efficiency exerted.

Antioxidants↗
PubMed2003

Quantification of contact surface pressure exerted during external cephalic version.

BACKGROUND: The amount of force exerted on the uterus and fetus during external cephalic version (ECV) may be associated with fetal effects or complications. We have designed an instrument to quantify the contact pressure exerted during the performance of ECV, as an indirect measurement of the applied force. METHODS: We have designed a pair of custom-made gloves. Each glove contains 16 piezo-resistive sensors positioned on the palmer surface of the fingers, thenar and hypothenar areas. Pressure readings were recorded simultaneously from all sensors every 0.22 s during each version procedure. Each recording was analyzed with a computer program written according to specified algorithms to ascertain the number of attempts in a version operation, and the duration and pressure changes of each attempt during the operation. RESULTS: Ten subjects having a singleton breech presentation at term underwent an operation of ECV. The number of attempts of version in each operation ranged from one to four. The median pressure-time integral and the duration of an attempt were 19,227 mmHg s (range 5089-42,597 mmHg s) and 42.5 s (range 11.9-80.3 s), respectively. The median pressure-time integral of a whole version operation was 38,110 mmHg s (range 5089-107,511 mmHg s). Subjects with a failed version operation received a higher pressure-time integral (p < 0.05). The number of attempts of each operation was accurately identified by the program. CONCLUSIONS: Measurement of force applied during ECV can be quantified indirectly in terms of contact surface pressure. The indirect measurement of the applied force may further improve the safety of this procedure by preventing excessive use of force by the operator.

Adult↗
PubMed2003

Melatonin exerts a therapeutic effect on cholestatic liver injury in rats with bile duct ligation.

We examined whether melatonin exerts a therapeutic effect on cholestatic liver injury in rats treated with bile duct ligation (BDL). Cholestatic liver injury was induced in male Wistar rats aged 4 wk by ligating the bile duct. Cholestatic liver injury developed 5 days after BDL and continued to 13 days, judging from the levels of serum hepatobiliary injury markers. The serum concentration of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation, and the hepatic level of TBARS and the activity of hepatic myeloperoxidase, an index of tissue neutrophil infiltration, increased 5 days after BDL, and these increases were enhanced at 13 days. A similar increase in the serum total cholesterol concentration occurred 5 and 13 days after BDL, while the hepatic cholesterol concentration tended to increase at 13 days. When melatonin [10 or 100 mg/kg body weight (BW)] was orally administered to BDL-treated rats everyday for 8 days, starting 5 days after BDL, the indoleamine attenuated cholestatic liver injury observed at 13 days after BDL was more effective at the higher dose than at the lower dose. The administered melatonin (10 or 100 mg/kg BW) reduced the increases in serum and hepatic TBARS concentrations and hepatic myeloperoxidase activity observed at 13 days after BDL and the higher dose of indoleamine was more effective than the lower dose. Neither dose of melatonin affected the increased serum total cholesterol concentration or the hepatic cholesterol concentration observed at 13 days after BDL. These results indicate that orally administered melatonin at pharmacological doses exerts a therapeutic effect on cholestatic liver injury in rats with BDL possibly through its antioxidant and anti-inflammatory actions.

Animals↗
PubMed2007

The synthetic TRH analogue taltirelin exerts modality-specific antinociceptive effects via distinct descending monoaminergic systems.

BACKGROUND AND PURPOSE: Exogenously administered thyrotropin-releasing hormone (TRH) is known to exert potent but short-acting centrally-mediated antinociceptive effects. We sought to investigate the mechanisms underlying these effects using the synthetic TRH analogue taltirelin, focusing on the descending monoaminergic systems in mice. EXPERIMENTAL APPROACH: The mice received systemic or local injections of taltirelin combined with either central noradrenaline (NA) or 5-hydroxytryptamine (5-HT) depletion by 6-hydroxydopamine (6-OHDA) or DL-p-chlorophenylalanine (PCPA), respectively, or blockade of their receptors. The degree of antinociception was determined using the tail flick and tail pressure tests. KEY RESULTS: Subcutaneously (s.c.) administered taltirelin exhibited dose-dependent antinociceptive effects in the tail flick and tail pressure tests. These effects appeared to be primarily supraspinally mediated, since intracerebroventricularly (i.c.v.) but not intrathecally (i.t.) injected taltirelin generated similar effects. Depletion of central NA abolished only the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, depletion of central 5-HT abolished only its analgesic effect on thermal nociception. Intraperitoneal (i.p.) and i.t. injection of the alpha2-adrenoceptor antagonist yohimbine respectively reduced the analgesic effect of taltirelin (s.c. and i.c.v.) on mechanical nociception. By contrast, the 5-HT1A receptor antagonist WAY-100635 (i.p. and i.t.) reduced the effect of taltirelin (s.c. and i.c.v.) on thermal nociception. Neither the 5-HT2 receptor antagonist ketanserin nor the opioid receptor antagonist naloxone altered the antinociceptive effect of taltirelin. CONCLUSIONS AND IMPLICATIONS: These findings suggest that taltirelin activates the descending noradrenergic and serotonergic pain inhibitory systems, respectively, to exert its analgesic effects on mechanical and thermal nociception.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Adenovirus lacking the 19-kDa and 55-kDa E1B genes exerts a marked cytotoxic effect in human malignant cells.

UNLABELLED: The adenovirus (Ad) E1A gene exerts an antitumor effect and can induce sensitivity to treatment with DNA-damaging agents. In contrast, the Ad 19-kDa E1B protein inhibits E1A-mediated apoptosis and the 55-kDa E1B inactivates the p53 protein. In this paper, we study the in vitro and in vivo effects of a 19-kDa and 55-kDa E1B-defective Ad in several malignant human tumor cell lines. MATERIALS AND METHODS: Nontumorigenic human fibroblasts (CCD-45SK and Hs67), peripheral blood lymphocytes, and several human tumor cell lines derived from cervix, colon, and breast carcinomas, epidermoid carcinoma, and osteosarcoma (HeLa, HT29, MCF7, Saos-2, and A431 cell lines) were studied. Wild-type (wt) Ad type 5 and H5 dL118 Ad, a mutant with the deleted E1B region, were employed. The cells were infected at 20 plaque-forming units, and cell viability was evaluated by the crystal violet method. In the in vivo experiments, 2 x 10(6) cells from the carcinoma cell lines HeLa, A431 and HT29 were injected into nude mice. The tumorigenicity of previously infected cells and after an intratumoral injection of Ad was analyzed. The mice received whole-body gamma-irradiation. RESULTS: The H5 dL118 mutant produced a marked cytopathic effect in all of the malignant cells, surpassing that of the wt Ad; viability at 72 hours ranged from 11% to 20% for H5 dL118 Ad and from 70% to 93% for the wt Ad with respect to uninfected controls. In the in vivo experiments, a total inhibition of tumorigenicity was detected when cells were infected prior to injection and a partial and transitory decrease in tumorigenicity was detected when the mutant H5 dL118 was injected intratumorally. gamma-irradiation enhanced the in vivo antitumor effects. CONCLUSIONS: These results indicate that infection with completely E1B-deficient Ads induced a marked cytopathic effect on malignant cells that was higher than that seen for wt Ads; in addition, infection with such Ads exerts a tumor suppressor effect in vivo.

Adenoviridae↗
PubMed1997

The bystander effect exerted by tumor cells expressing the herpes simplex virus thymidine kinase (HSVtk) gene is dependent on connexin expression and cell communication via gap junctions.

To elucidate the role gap junctions play in the bystander effect, we examined the cytotoxic effect of herpes simplex virus thymidine kinase (HSVtk) modified tumor cells on gap junction communication-deficient tumor cells and their connexin transfectants. Communication competent Walker 256 tumor cells engineered to express the HSVtk gene (Walker-tk+) when cocultured with N2A mouse neuroblastoma and PC12 rat pheochromocytoma cells with absent endogenous junctional conductance showed no bystander cytotoxicity. Transfection of N2A cells with the rat connexin37 gene (5Q) and PC12 cells with the human connexin43 gene rendered them susceptible to bystander cell death. Additionally, communication-deficient N2A cells transfected with the HSVtk gene failed to exert a bystander effect, whereas N2A transfectants coexpressing the connexin37 and HSVtk genes (5Qtk+ cells) exerted bystander cytotoxicity on gap junction communication-competent 5Q but not on communication-deficient N2A cells in vitro. In vivo experiments also showed tumor growth inhibition of communication-competent 5Q but not communication-incompetent N2A cells by 5Qtk+ cells. In conclusion, these results indicate that in several cellular environments the bystander effect is dependent on connexin expression and gap junctional communication between HSVtk-positive and HSVtk-negative cells.

Animals↗
PubMed2004

Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes.

Mutation of the p53 tumor suppressor gene is the most common genetic alteration in human cancer. A majority of these mutations are missense mutations in the DNA-binding domain. As a result, the mutated p53 gene encodes a full-length protein incapable of transactivating its target genes. In addition to this loss of function, mutant p53 can have a dominant negative effect over wild-type p53 and/or gain of function activity independently of the wild-type protein. To better understand the nature of the tumorigenic activity of mutant p53, we have investigated the mechanism by which mutant p53 can exert a dominant negative effect. We have established several stable cell lines capable of inducibly expressing a p53 mutant alone, wild-type p53 alone, or both proteins concurrently. In this context, we have used chromatin immunoprecipitation to determine the ability of wild-type p53 to bind to its endogenous target genes in the presence of various p53 mutants. We have found that p53 missense mutants markedly reduce the binding of wild-type p53 to the p53 responsive element in the target genes of p21, MDM2, and PIG3. These findings correlate with the reduced ability of wild-type p53 in inducing these and other endogenous target genes and growth suppression in the presence of mutant p53. We also showed that mutant p53 suppresses the ability of wild-type p53 in inducing cell cycle arrest. This highlights the sensitivity and utility of the dual inducible expression system because in previous studies, p53-mediated cell cycle arrest is not affected by transiently overexpressed p53 mutants. Together, our data showed that mutant p53 exerts its dominant negative activity by abrogating the DNA binding, and subsequently the growth suppression, functions of wild-type p53.

Cell Cycle↗
PubMed2004

ERbeta exerts multiple stimulative effects on human breast carcinoma cells.

Recent studies of ERs in breast cancer have demonstrated the existence of ERbeta in addition to ERalpha. Some clinical data indicated that ERbeta had prognostic value for patient's survival, which suggested that ERbeta plays a key role in breast cancer development and metastasis. To test this hypothesis, we generated an ERbeta high-expression cell line by reintroduced human ERbeta cDNA into MDA-MB-435 cells. We demonstrated that ERbeta exerted multiple tumor-stimulative effects on human breast carcinoma cells both in vivo and in vitro. In in vitro studies, ERbeta was able to increase the proliferation and invasion of MDA-MB-435 cells significantly, while these effects were totally estradiol independent. Also, this stimulation was characterized by downregulation of p21 and upregulation of MMP-9, as well as transcriptional factor Est-1. In in vivo studies, we also demonstrated that ERbeta-transfected MDA-MB-435 cells grew much faster and had more pulmonary metastasis than mock or wild-type cells in nude mice. In ERbeta-transfected MDA-MB-435 xenografts, ERbeta caused significant reduction in p21 protein levels. Similar effects of ERbeta on MMP-9 and Ets-1 expression noted in vitro studies were also observed in the in vivo studies. These in vitro and in vivo studies indicated that ERbeta exerted multiple stimulative effects on breast cancer development and metastasis.

Animals↗
PubMed1993

Phenylalaninylargininylarginine: a novel tripeptide exerting Zn(2+)-dependent, insulin-mimetic inhibitory action on myocardial proteolysis.

A novel tripeptide, Phe-Arg-Arg, was found to exert a potent, insulin-mimetic inhibitory action on lysosomal proteolysis in the Langendorff-perfused rat heart. This tripeptide was synthesized based upon its partial structural analogy to the biguanide anti-hyperglycaemic agent, phenformin (phenylethylbiguanide), which has previously been found to exert a Zn(2+)-dependent inhibitory action on lysosomal proteolysis. Hearts were biosynthetically labelled with [3H]leucine in vitro. The percentage change in subsequent release of [3H]leucine (2 mM non-radioactive leucine) was determined in non-recirculating perfusate. The background Zn2+ content of the perfusate was determined to be 20 nM. Major endogenous Zn2+ buffers were present in molar excess of Zn2+: 0.1 mM citrate, 0.2% BSA, and complete physiological amino acids. Infusion of maximally effective levels of chloroquine (30 microM) or insulin (5 nM) caused a 38% inhibition of total proteolysis, which corresponds to the lysosomal subcomponent. In the presence of background levels of perfusate Zn2+ the infusion of Phe-Arg-Arg (10 microM), insulin (5 nM), or phenformin (2 microM) maximally caused a 39% inhibition of [3H]leucine release. Combined infusion of maximally effective levels of insulin and Phe-Arg-Arg, or maximal levels of chloroquine and Phe-Arg-Arg did not cause additive inhibition of [3H]leucine release greater than the 39% inhibition caused by either agent alone, regardless of the order of infusion. Addition of physiological concentrations of Zn2+ (1 microM) to the background perfusate Zn2+ accelerated the insulin-mimetic action of submaximally effective levels of Phe-Arg-Arg, and increased its potency. Prior chelation of background Zn2+ by a 3 h perfusion with CaNa2 EDTA (2 microM) reversibly delayed the time course of Phe-Arg-Arg action and decreased its potency at submaximal concentrations.

Amino Acid Sequence↗