Arginine HCl Research Articles

Formulation of tablets containing lyophilized powder to improve the stability of alpha-chymotrypsin

This study aimed to develop a stable lyophilized formulation and the tableting process of lyophilized powder to improve the stability of the enzyme alpha-chymotrypsin (ACT). The impacts of the bulking agent and stabilizer on the freeze-drying process and the stability of ACT were determined. The effects of the filler excipients and the compression force on the activity of ACT tablets containing lyophilized powder were also evaluated. The findings revealed that arginine HCl, which had a multipoint interaction with the surface of ACT, and the crystalline excipient mannitol stabilized the structure of the enzyme and the lyophilized cake. The dehydration process through freeze-drying effectively protected the active substance against denaturing factors such as heat, moisture, and mechanical force. The study also demonstrated that the use of elastic fillers such as compressuc and a minor compression force contributed to the enhancement of ACT tablet stability. In summary, the study successfully developed a formulation for tablets containing ACT lyophilized powder, initially overcoming the poor stability of this enzyme to environmental factors, showing the applicability of lyophilization and stabilizing excipients in enhancing the stability of biomolecules.

Toward Biotherapeutics Formulation Composition Engineering using Site-Identification by Ligand Competitive Saturation (SILCS).

Formulation of protein-based therapeutics employ advanced formulation and analytical technologies for screening various parameters such as buffer, pH, and excipients. At a molecular level, physico-chemical properties of a protein formulation depend on self-interaction between protein molecules, protein-solvent and protein-excipient interactions. This work describes a novel in silico approach, SILCS-Biologics, for structure-based modeling of protein formulations. SILCS Biologics is based on the Site-Identification by Ligand Competitive Saturation (SILCS) technology and enables modeling of interactions among different components of a formulation at an atomistic level while accounting for protein flexibility. It predicts potential hotspot regions on the protein surface for protein-protein and protein-excipient interactions. Here we apply SILCS-Biologics on a Fab domain of a monoclonal antibody (mAbN) to model Fab-Fab interactions and interactions with three amino acid excipients, namely, arginine HCl, proline and lysine HCl. Experiments on 100mg/ml formulations of mAbN showed that arginine increased, lysine reduced, and proline did not impact viscosity. We use SILCS-Biologics modeling to explore a structure-based hypothesis for the viscosity modulating effect of these excipients. Current efforts are aimed at further validation of this novel computational framework and expanding the scope to model full mAb and other protein therapeutics.

Effect of Bonded Arginine Silicate on Inflammatory Markers and Arthritis

BackgroundThe purpose of this preclinical study was to examine the effects of inositol‐stabilized arginine silicate supplementation (ASI; Nitrosigine®) on inflammatory markers and joint health in an arthritis‐joint health model. ASI is a sports nutrition ingredient that has been clinically shown to provide efficacious levels of arginine and silicon, reduce markers of muscle damage, and increase nitric oxide levels among other sports nutrition endpoints. This preclinical study was designed to evaluate the potential of ASI to reduce inflammatory markers and promote joint health, important endpoints to athletes, fitness enthusiasts and people with joint pain due to inflammation. The study recorded arthritis score, inflammation score, inflammatory markers, and serum and joint arginine and silicon levels upon administration of ASI in rats with collagen‐induced arthritis.MethodsFemale Wistar rats were reared at 22 ± 2°C in a 12/12 hour light/dark cycle and randomized into four groups (n=7 in each group; 8 weeks‐old): Control group Arthritic control group Arthritic group supplemented with a simple mixture of arginine HCl + silicon + inositol (A+S+I) at doses equivalent to those in ASI Arthritic group supplemented with ASI at a dose of 1.81 g/kg/day (corresponding to a human dose of 1500mg/day) Rats were dosed for 30 days. On day 14 and day 29, rats were analyzed for arthritis score, inflammation score, and 10 inflammatory markers in the blood and tissue: TNF‐α, IL‐17, IL‐6, ghrelin, obestatin, sclerostin, DKK‐1, Cox‐2, NF‐κB, and B‐catenin.ResultsDay 29 arthritis scores and inflammation scores were both significantly lower in the ASI group (IV) compared to the arthritic control group (II) and the A+S+I group (III). Seven inflammatory markers tested in the blood — TNF‐α, IL‐17, IL‐6, ghrelin, obestatin, sclerostin, and DKK‐1 — were significantly lower in the ASI group (IV) compared to the arthritic control group (II). Four of five inflammatory markers tested in the tissue — Cox‐2, TNF‐α, IL‐6, NF‐κB, and B‐catenin — were significantly lower in the ASI group (IV) compared to the arthritic control group (II).ConclusionsASI supplementation significantly improved markers of inflammation and overall arthritis and inflammation score over the arthritic control group and the A+S+I group. These results demonstrate that ASI may be effective in reducing inflammation and that the ASI complex is more effective than a combination of the individual ingredients. ASI may also be of physiological benefit to athletes and fitness enthusiasts concerned with joint health and inflammation and to those experiencing joint pain due to inflammation.Support or Funding InformationFunding for this study was provided by Nutrition 21, LLC (Purchase, NY, USA) through a restricted grant.

High resolution triple resonance micro magic angle spinning NMR spectroscopy of nanoliter sample volumes.

To be able to study mass-limited samples and small single crystals, a triple resonance micro-magic angle spinning (μMAS) probehead for the application of high-resolution solid-state NMR of nanoliter samples was developed. Due to its excellent rf performance this allows us to explore the limits of proton NMR resolution in strongly coupled solids. Using homonuclear decoupling we obtain unprecedented (1)H linewidths for a single crystal of glycine (Δν(CH2) = 0.14 ppm) at high field (20 T) in a directly detected spectrum. The triple channel design allowed the recording of high-resolution μMAS (13)C-(15)N correlations of [U-(13)C-(15)N] arginine HCl and shows that the superior (1)H resolution opens the way for high-sensitivity inverse detection of heteronuclei even at moderate spinning speeds and rf-fields. Efficient decoupling leads to long coherence times which can be exploited in many correlation experiments.

Controlling protein stability: Mechanisms revealed using formulations of arginine, glycine and guanidinium HCl with three globular proteins

Three distinct interactions between the amino acid arginine and a protein explain arginine’s ability to modulate the thermal stability of proteins. Arginine’s effect on the protein unfolding behaves like the sum of its constituent parts, glycine and the guanidinium ion. The authors propose that glycine can affect the thermal stability of a protein in two ways: (1) direct interaction with the charged side chains and/or the peptide backbone of the protein which is observed at low concentrations and (2) competition for water between the unfolding protein and the cosolute increasing the energy required to hydrate the unfolding protein. The guanidinium ion acts by (3) direct interaction with apolar regions exposed during unfolding reducing the energy required to hydrate the unfolding protein.

Arginine HCL for treatment of CSF leakage in rat

Arginine HCL for treatment of CSF leakage in rat

Investigation of cosolute-protein preferential interaction coefficients: new insight into the mechanism by which arginine inhibits aggregation.

The relatively new technique of vapor pressure osmometry was utilized to determine the preferential interaction of five common solution additives (arginine HCl, guanidine HCl, glycerol, glucose, and urea) using three different model proteins (BSA, lysozyme, and alpha-chymotrypsinogen). Results for guanidine, glycerol, glucose, and urea are comparable to literature values, which utilized the dialysis/densimetry technique. However, values for arginine differ greatly from literature values, making it unclear what is the nature of arginine-protein interactions. A repeat of the dialysis/densimetry measurements reported in the literature supports the vapor pressure osmometry measurements and reveals a never before seen trend in the interaction of arginine with proteins as a function of concentration. This trend is dependent on the protein size and shows arginine to be unique among solution additives. For concentrations below 0.5 M, arginine has a preferential interaction coefficient near zero (slightly greater than zero for small proteins but decreases as the size of the protein increases), which indicates that arginine is neither strongly bound nor excluded from the protein surface. This trend differs greatly from cosolutes that influence the protein folding equilibrium. However, as the concentration of arginine increases beyond 0.5 M, arginine becomes increasingly excluded. Such behavior might be indicative of the protein surface becoming saturated with arginine, thus causing any additional arginine added to the solution to be excluded from interacting with the surface. All of this behavior is most likely the result of a balance between the affinity arginine has for the peptide backbone and certain amino acids and the repulsion generated by surface tension increment and volume exclusion effects [Arakawa et al. Biophysical Chemistry 2007, 127, 1]. In addition, such behavior may explain why arginine has little effect on protein folding equilibrium but is an effective aggregation suppressor.

Interferon Gamma: Activity and ELISA Detection Comparisons

Interferon-gamma (IFN-γ) is a pleiotropic cytokine secreted by Natural Killer (NK) cells and many T cells. It is the sole representative of Type II IFN. IFN-γ has pleiotropic activities including: inducing an antiviral state in cells, upregulating cell surface markers such as Class I and II MHC, and regulating the activity of macrophages, NK cells, neutrophils, B-cells, and T-cells. As such, IFN-γ is one of the most widely studied proteins [Scroder et al (2004) J. Leuk. Biol. 75:163; Young and Bream (2007) Curr. Top. Microbiol. Immunol. 316:97].

Metabolic effects of a novel silicate inositol complex of the nitric oxide precursor arginine in the obese insulin-resistant JCR:LA- cp rat

Insulin resistance is a major contributor to macro- and microvascular complications, particularly in the presence of the metabolic syndrome, and is also associated with polycystic ovary syndrome. Impaired nitric oxide metabolism and endothelial function are important components of the vascular disease. Increasing the bioavailability of arginine, the precursor of nitric oxide, thus potentially offers protection against end-stage disease. We have recently demonstrated that dietary supplementation with a novel silicate inositol arginine complex reduces vasculopathy and glomerular sclerosis in the insulin-resistant JCR:LA- cp rat. The objective of this study was to address the absorption of, and the underlying metabolic alterations caused by, the arginine silicate inositol complex and arginine HCl (as a reference agent) in obese insulin-resistant male and female JCR:LA- cp rats. Male and female rats were treated with the preparations at 1.0 mg/(kg d) (expressed as arginine HCl) from 8 to 12 and 12 to 18 weeks of age, respectively. Obese female, but not male, rats treated with the arginine silicate inositol complex showed a reduced rate of weight gain without concomitant reduction in food intake. Plasma silicon levels were raised very significantly in arginine silicate–treated rats, consistent with significant absorption of the complex. In male rats, arginine levels were elevated by treatment with arginine silicate only; and female rats responded to both preparations. Plasma concentrations of oxides of nitrogen in rats treated with the silicate complex showed a dimorphism, decreasing in male and increasing in female rats. Fasting insulin levels were elevated in male rats treated with the arginine silicate complex, whereas fasting and postprandial insulin levels were decreased in female rats. Furthermore, female, but not male, rats treated with either of the arginine preparations showed significant reductions in cholesterol, triglyceride, and phospholipid concentrations. We conclude that the arginine silicate inositol complex is absorbed efficiently, raising plasma arginine levels, and is more biologically effective than the free amino acid hydrochloride. This has different beneficial metabolic effects in both sexes of an animal model of insulin resistance and cardiovascular disease, consistent with reduction in end-stage disease.

A Report of the Vancouver Forum on the Care of the Live Organ Donor: Lung, Liver, Pancreas, and Intestine Data and Medical Guidelines

An international conference of transplant physicians, surgeons, and allied health professionals was held in Vancouver, Canada, on September 15 and 16, 2005 to address the care of the live lung, liver, pancreas, and intestine organ donor. The Vancouver Forum was convened under the auspices of the Ethics Committee of The Transplantation Society. Forum participants included over 100 leaders in organ transplantation, representing many countries from around the world, including participants from the following continents: Africa, Asia, Australia, Europe, North and South America. The objective of the Vancouver Forum was to develop an international standard of care for the live lung, liver, pancreas and intestinal organ donor. This Vancouver Forum followed a conference convened in Amsterdam on the care of the live kidney donor (1, 2). There were four organ specific work groups at the Vancouver Forum: lung, liver, pancreas and intestine. Each organ work group addressed the following topics in concert and reported their findings in a plenary presentation to all participants:

Heat denaturation and aggregation of β-lactoglobulin enriched WPI in the presence of arginine HCl, NaCl and guanidinium HCl at pH 4.0 and 7.0

The heat denaturation and aggregation behaviour of β-lactoglobulin ( β-LG) enriched WPI was investigated at pH 4.0 and 7.0 in the presence of arginine HCl, NaCl and GdnHCl using differential scanning calorimetry (DSC) and dynamic light scattering (DLS). Beside the classical endothermic signal attributed to protein heat denaturation, DSC thermograms displayed appearance of an additional exothermic peak in the presence of cosolute. Using in situ DLS, it was shown that the appearance of the exothermic peaks is linked to protein aggregation, in particular to a strong increase in aggregate size. Upon increased cosolute concentration at pH 4.0 the exothermic peak occurred at temperatures lower than the actual denaturation peak (∼85 °C). At this pH, negatively charged chloride anions interact with β-LG leading to charge screening and physical aggregation. At pH 7.0, exothermic peaks appeared at higher temperatures than the denaturation peak (∼75 °C). Upon increased cosolute concentration the exothermic peak was shifted to lower temperatures, indicating protein destabilisation in the presence of cosolutes. Charge screening of β-LG by the positively charged cations (arginine, Na and guanidinium) reduced repulsion forces and promoted aggregation.

Effects of Carbon Dioxide on Bacterial Growth Parameters in Milk as Measured by Conductivity

Inhibition of bacterial growth by dissolved carbon dioxide (CO2) has been well established in many foods including dairy foods. However, the effects of dissolved CO2 on specific growth parameters such as length of lag phase, time to maximum growth rate, and numbers of organisms at the stationary phase have not been quantified for organisms of concern in milk. The effect of dissolved CO2 concentrations of 0.6 to 61.4mM on specific bacterial growth parameters in raw or single organism inoculated sterile milk was determined at 15°C by conductance. Commingled raw or sterile milks were amended to a final concentration of 0.5mg/ml each of urea and arginine HCl. Sterile milks were inoculated singly with one of six different microorganisms to a final concentration of approximately 102 to 103cfu/ml; raw milk was adjusted to a final indigenous bacterial population of approximately 103cfu/ml. Conductivity of the milk was recorded every 60s over 4 to 5 d in a circulating apparatus at 15°C. Conductivity values were fit to Gompertz equations and growth parameters calculated. Conductance correlated with plate counts and was satisfactory for monitoring microbial growth. Data fit the Gompertz equation with high correlation (R2 = 0.96 to 1.00). In all cases, dissolved CO2 significantly inhibited growth of raw milk bacteria, influencing lag, exponential, and stationary growth phases as well as all tested monocultures.

Growth and endocrine responses of lambs fed rumen-protected ornithine and arginine

Twenty Hampshire × Western wether lambs (initial body weight (BW) 29.9 ± 1.5 kg) were used in a 42-day study to evaluate growth and endocrine responses to rumen-protected ornithine or arginine. Treatments consisted of no supplemental amino acid (CON), or supplements that provided 0.42 g day −1 ornithine HCl per kg BW (ORN), 0.5 g day −1 arginine HCl per kg BW (L-ARG) or 0.75 g day −1 arginine HCl per kg BW (H-ARG). Amino acids were incorporated into a protective matrix containing ground corn, coconut oil and zein. Serum ornithine and urea N concentrations were increased ( P < 0.05) in ORN, L-ARG and H-ARG lambs, while serum arginine concentrations were increased ( P < 0.05) in H-ARG lambs only. Serum concentrations of total essential amino acids were lower ( P < 0.05) in H-ARG lambs compared with L-ARG lambs. Consumption of ORN, L-ARG and H-ARG increased ( P < 0.05) mean somatotropin (STH) concentrations compared with CON, while basal STH concentrations were higher ( P < 0.05) in ORN and L-ARG lambs only. Mean and basal STH concentrations were higher ( P < 0.05) in ORN lambs compared with L-ARG and H-ARG lambs. Amplitude and frequency of STH pulses were not affected ( P > 0.05) by treatment. Serum insulin-like growth factor-I (IGF-I) concentrations were higher ( P < 0.05) in ORN, L-ARG and H-ARG lambs compared with CON lambs. Further increases ( P < 0.05) in IGF-I concentrations were noted in H-ARG lambs compared with ORN and L-ARG lambs. Performance of lambs was not improved ( P > 0.05) by the consumption of rumen-protected ornithine or arginine compared with CON lambs despite increased STH and IGF-I concentrations. Average daily gain of L-ARG lambs was increased ( P < 0.05) compared with H-ARG lambs, resulting in heavier ( P < 0.05) BW on Day 42 and improved ( P < 0.05) feed efficiency. These data provide further evidence that increasing post-ruminal supplies of arginine and ornithine may increase circulating STH and IGF-I concentrations in growing lambs. However, performance may not be improved by these amino acid-induced responses.

Circulating Growth Hormone, Insulin-like Growth Factor I, Cortisol and Free Thyroxine in Children with Schistosomiasis With and Without Hepatic Fibrosis

Serum insulin, growth hormone (GH), cortisol, free thyroxine (T4) and plasma insulin-like growth factor I(IGF-I) concentrations were measured in 20 children suffering from schistosomiasis as well as 10 healthy age-matched controls. Circulating GH and insulin levels were determined after an intravenous infusion of arginine HCl (10 per cent solution, 0.5 g/kg). Children with schistosomal hepatic fibrosis (n = 10) had heights more than 2 SD below the mean for their age and sex. Their circulating IGF-I, free T4, and cortisol levels were significantly reduced. They had markedly elevated serum insulin concentrations with normal response to arginine infusion. Their basal GH levels were normal with significantly reduced GH response to arginine provocation. Compared to controls, they had significantly lower serum albumin concentrations, prolonged prothrombin time and elevated alanine transferase (ALT) levels. Free T4 and IGF-I concentrations, and GH increments after provocation correlated significantly with the percentile heights of these patients (r = 0.90, 0.70, and 0.83, P less than or equal to 0.001, less than or equal to 0.05 and less than or equal to 0.01 respectively). Their IGF-I levels correlated closely with the prothrombin time and ALT concentrations (r = 0.87 and 0.77, P less than or equal to 0.002 and less than or equal to 0.01, respectively). It is suggested that the depressed circulating IGF-I and free T4 levels in addition to deficient GH reserve may be responsible for stunted stature in patients with schistosomal hepatic fibrosis.

Carbon Monoxide (CO)-lnduced Hypoxia in Mice: Evaluation as an Experimental Model of Cerebral Ischemia for Drug Screening

An injection of 12.5 ml of carbon monoxide (CO) gas into an air-filled chamber (780 ml in volume) caused the death of the ICR or ddY mouse (6-8 weeks old) inside. The average survival time was 2.5 min for either sex of animals treated with nothing or saline and never exceeded 8 min. Pretreatment with pentobarbital Na (30 mg/kg, i.p.), hopantenate Ca (100 mg/kg, i.p.), vinpocetine (5 mg/kg, i.p. or 50 mg/kg, p.o.), flunarizine HCl (5 mg/kg, i.p.), glucose (6 g/kg, i.p.), phenobarbital (30 mg/kg, i.p.), Phenytoin (20 mg/kg, i.p.), arginine HCl (100 mg/kg, i.p. or 1 g/kg, p.o.) and alanine (100 mg/kg, i.p. or 1 g/kg, p.o.) prolonged the survival time of male mice. Insofar as tested, female mice responded rather poorly to these pretreatments. Survival for longer than 8 min occurred in some of the drug-pretreated animals of either sex. To be noted is the finding that most of the animals which survived 8 min once were able to survive the second 8 min on the following day without any drug-treatment. Monitoring of the time course of carboxyhemoglobin formation revealed that the carboxyhemoglobin level reached a plateau of 70% saturation within 2 min and then gradually increased. The lethal level was about 72%. Pentobarbital decreased the formation rate but did not elevate the lethal level. The results indicate that the CO-induced hypoxia model of mice is usable for screening of drug candidates which may be effective for treatment of human ischemic diseases.

Carbon monoxide (CO)-induced hypoxia in mice: evaluation as an experimental model of cerebral ischemia for drug screening.

An injection of 12.5 ml of carbon monoxide (CO) gas into an air-filled chamber (780 ml in volume) caused the death of the ICR or ddY mouse (6-8 weeks old) inside. The average survival time was 2.5 min for either sex of animals treated with nothing or saline and never exceeded 8 min. Pretreatment with pentobarbital Na (30 mg/kg, i.p.), hopantenate Ca (100 mg/kg, i.p.), vinpocetine (5 mg/kg, i.p. or 50 mg/kg, p.o.), flunarizine HCl (5 mg/kg, i.p.), glucose (6 g/kg, i.p.), phenobarbital (30 mg/kg, i.p.), phenytoin (20 mg/kg, i.p.), arginine HCl (100 mg/kg, i.p. or 1 g/kg, p.o.) and alanine (100 mg/kg, i.p. or 1 g/kg, p.o.) prolonged the survival time of male mice. Insofar as tested, female mice responded rather poorly to these pretreatments. Survival for longer than 8 min occurred in some of the drug-pretreated animals of either sex. To be noted is the finding that most of the animals which survived 8 min once were able to survive the second 8 min on the following day without any drug-treatment. Monitoring of the time course of carboxyhemoglobin formation revealed that the carboxyhemoglobin level reached a plateau of 70% saturation within 2 min and then gradually increased. The lethal level was about 72%. Pentobarbital decreased the formation rate but did not elevate the lethal level. The results indicate that the CO-induced hypoxia model of mice is usable for screening of drug candidates which may be effective for treatment of human ischemic diseases.

Stimulation of T cell immunity by arginine enhances survival in peritonitis

T cell-mediated immunity may play a role in host responses to infection. Arginine is a known thymic and T cell stimulator which enhances host allogenic, mitogenic, and anti-tumor responses. We, therefore, examined the effect of arginine on the survival of rats with severe and lethal peritonitis induced by cecal ligation and double-needle puncture (CLP). In Experiment 1, arginine HCl (100 mg) was given bid by gavage starting immediately after CLP. In Experiment 2, the same dose of arginine was given by gavage bid for 3 days pre-CLP and continued thereafter. In Experiment 3, arginine was administered iv post-CLP (100 mg tid). Arginine had no effect on overall survival in Experiment 1. In Experiments 2 and 3, arginine therapy significantly increased survival at all times. A separate experiment was carried out to determine the reason for the differential response to arginine administered via gavage or iv post-CLP (Experiments 1 and 3). Nonseptic rats showed a 400% increase in plasma arginine 30 min after gavage with 100 mg arginine ( P < 0.001). No rise in plasma arginine was noted when arginine was administered by gavage post-CLP. The impaired intestinal absorption or markedly increased utilization of arginine in this septic model may explain why no improved survival was seen in Experiment 1. The mechanism for the improved survival with arginine therapy seen in Experiments 2 and 3 may be related to its known thymic and T cell immunostimulatory effects.

Glucagon and prostaglandins are mediators of amino acid-induced rise in renal hemodynamics

An oral protein load or infusion of amino acids induces a rise in renal hemodynamics in normal subjects, but the mechanisms mediating this phenomenon are unknown. We investigated whether glucagon may mediate the increase in RPF and GFR induced by an arginine infusion and whether prostaglandins are required for this effect. In four different studies, normal subjects underwent 13 inulin and PAH clearances of 30 minutes each. During the fourth and tenth clearance periods arginine HCl, 250 mg/kg, was infused over 30 minutes. At the beginning of the fifth clearance period several subjects ingested indomethacin, 150 mg, (N = 8) or ibuprofen, 800 mg (N = 6). Control subjects (N = 4) did not receive cyclooxygenase inhibitors. Six subjects underwent a similar protocol except that they were infused with glucagon, 6 ng/kg/min, instead of arginine, for 30 minutes during the fourth and tenth periods. They also ingested indomethacin, 150 mg, in the fifth period. In all four studies, a transient and significant rise in RPF and GRF and fall in RVR occurred during the first arginine or glucagon infusion. These changes in renal hemodynamics were blocked when the arginine or glucagon infusion was repeated after administration of indomethacin or ibuprofen. Urinary excretion of 6-keto-PGF1 alpha did not rise with either arginine infusion in the control subjects or in the individuals who received indomethacin. As predicted, urinary 6-keto-PGF1 alpha fell significantly after ingestion of indomethacin before the second infusion of arginine. Plasma norepinephrine and epinephrine concentrations were unaffected by the arginine infusions or by indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of growth hormone in the amino acid-induced acute rise in renal function in man

To examine whether plasma growth hormone is necessary for the amino acid-induced rise in effective renal plasma flow (ERPF, PAH clearance) and GFR (inulin clearance), arginine HCl, 500 mg/kg, was infused for 30 minutes into eight normal and six growth hormone-deficient individuals. During infusion, ERPF increased in the normal and growth hormone-deficient subjects by 28.9 +/- 11.4 SD-% (P less than 0.01) and 46.5 +/- 14.4% (P less than 0.001). GFR rose by 23.7 +/- 5.9% (P less than 0.05) and 42.7 +/- 29.1% (P less than 0.001) in the two groups. Plasma growth hormone rose only in the normal subjects, while glucagon increased in both groups. Infusion of arginine HCl, 200 mg/kg, into normals increased ERPF and GFR without increasing plasma osmolality. Lower arginine doses essentially did not affect ERPF, GFR, growth hormone, or glucagon. Infusion of D-glucose into normals raised plasma osmolality as high as with arginine HCl, 500 mg/kg, but increased ERPF only slightly and not GFR; D-glucose infusion caused a delayed rise in growth hormone that was unassociated with an increase in ERPF or GFR. An infusion of ammonium chloride with sodium chloride, which provided an amount of chloride similar to the 500 mg/kg arginine HCl dose, did not change ERPF and GFR; this suggests that the chloride load did not cause the altered renal hemodynamics stimulated by arginine HCl. These findings indicate that neither normal plasma growth hormone levels nor a rise in growth hormone mediates the arginine-induced acute increase in ERPF or GFR. This effect is also not due to the osmolar load but could be caused by the rise in plasma glucagon.

Endogenous opioid modulation of pancreatic hormone secretion: Studies in dogs

The role of endogenous opioid peptides in the modulation of secretion of hormones from the endocrine pancreas was studied in dogs. In response to insulin-induced hypoglycemia, plasma glucagon secretion significantly increased, followed by an increase in plasma somatostatin immunoreactivity. Pretreatment with the opiate antagonist, naloxone, prevented the somatostatin response but had no effect on the augmented glucagon secretion. Neither the degree of hypoglycemia nor recovery from the induced glucose nadir were affected by naloxone. Arginine Hcl administration resulted in prompt increases in immunoreactive glucagon and insulin secretion, as well as a rise in serum glucose. Pretreatment with naloxone failed to affect any of these responses. Our results suggest that endogenous opioid peptides mediate the somatostatin response following hypoglycemia-induced glucagon secretion.