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PubMed1988

Disappearance of growth hormone from plasma of fetal and newborn sheep.

The disappearance of growth hormone (GH) from plasma was measured after a single intravenous injection in fetal and newborn sheep and fetal sheep after simulated birth in utero. The process was adequately described when separated into two exponential components, consistent with an inner (plasma) and outer (composite tissue) pool. Plasma clearance rate increased from 3.4 +/- 0.2 (SE, n = 6) in fetuses to 3.9 +/- 0.1 (n = 5) ml.min-1.kg-1 in newborns (P less than 0.05), but was not altered significantly after simulated delivery in utero. The volume of distribution decreased from 74 +/- 4 ml/kg before birth to 47 +/- 2 ml after natural birth (P less than 0.001). The basal secretory rate decreased from 2.4 +/- 0.2 before birth to 0.27 +/- 0.02 microgram/min after birth (P less than 0.001) and to a lesser extent after simulated delivery. The rate constant for irreversible loss, Kd, increased from 0.052 +/- 0.004 min-1 before birth to 0.093 +/- 0.002 min-1 after birth (P less than 0.001). Because plasma GH concentration in steady state equals secretory rate/(volume of distribution X Kd), one may calculate that 83% of the total decrease in GH, which occurs after birth, can be explained by diminished secretory rate, whereas 17% can be explained by more rapid loss from the plasma.

Animals↗
PubMed2001

Hypothalamo-pituitary-adrenal axis activity is related to the level of central arousal: effect of sleep deprivation on the association of high-frequency waking electroencephalogram with cortisol release.

The temporal and quantitative interrelationships between the hypothalamo-pituitary-adrenal (HPA) axis activity and the level of central arousal were studied in 10 healthy young men during daytime wakefulness. Two experimental sessions were conducted randomly between 09.00 and 18.00 h, once after nocturnal sleep and once after a night of total sleep deprivation. Spectral analysis of serial waking electroencephalography (EEG) from a short target fixation task repeated every 10 min was undertaken, along with an estimation of cortisol secretory profiles by deconvolution of plasma radioimmunoassay measures obtained from continuous blood withdrawal with regular sampling at a 10-min interval. Following nocturnal sleep, a temporal association between the HPA axis activity and the waking EEG activity was found, cortisol secretory rate following changes in frontal gamma (20-45 Hz) band power by 10 min (average R = 0.458, p < 0.001). Although it remained significant (average R = 0.276, p < 0.05), the association strength decreased significantly following total sleep deprivation (p < 0.05, Wilcoxon test). Cortisol plasma level, secretory rate and pulse amplitude were increased as well as waking EEG power in the delta (0.5-5.5 Hz), theta (5.5-8.5 Hz) and gamma frequency bands (all p values <0.05, Student t tests). The sleep deprivation-related increases in cortisol secretory rate and waking EEG gamma activity were quantitatively associated (R = 0.504, p < 0.05). These results support the existence of a common ultradian regulatory mechanism, co-ordinating HPA axis activity to the level of central arousal in man, which seems involved in the sleep deprivation-induced hyper-arousal.

Adrenal Glands↗
PubMed1995

Measurements of human minor salivary gland secretions from different oral sites.

Unstimulated secretions from labial (upper and lower), buccal, lingual and palatal minor glands were measured with a Periotron 6000 model 2 (Proflow) in 99 non-medicated, healthy individuals aged from 17 to 81 yr (49 males and 50 females). The palatal minor glands had the lowest flow rates, buccal and anterior lingual glands the highest, and labial glands (upper and lower) intermediate secretory rates. Lower labial glands (p < 0.01) in both sexes and upper labial glands in females (p < 0.05) demonstrated a significant decrease in unstimulated output with age, while buccal glands in both sexes (p < 0.05) showed a significant decrease in flow rates only after the age of 50 yr. Thus minor glands show regional variation in their secretory rates and labial and buccal glands appear to show a decreased unstimulated flow in older individuals.

Adolescent↗
PubMed1978

Role of aldosterone in the antihypertensive effect of spironolactone in essential hypertension.

In order to evaluate the relationship between aldosterone status and the blood pressure-lowering effect of spironolactone, 38 patients with essential hypertension were treated with spironolactone (400 mg/day) during one week in hospital on a rigidly sodium-restricted diet. The degree of hyperaldosteronism was assessed by the aldosterone secretory rate after 5 days of salt loading (315 mmol Na+/day). The mean arterial pressure decreased 5.6% (range, -21 to +8%). When the patients were divided into subgroups with low and normal renin activity, there was no difference in the change in mean arterial pressure (-5.0% and -6.1%). When the patients were divided into three groups with low, normal, and supranormal aldosterone secretory rates, the last group had a significantly greater fall in blood pressure after the spironolactone than the other groups (-1.0, -7.1, -11.1%). Thus there was a correlation between the aldosterone secretory rate after sodium loading and the blood pressure-lowering effect of spironolactone (r = -0.53, p less than 0.01). The blood pressure-lowering effect was not related to changes in body weight, kidney function, or plasma electrolytes. Our findings do not provide solid arguments for the view that the blood pressure-lowering effect of high dose spironolactone is due to its antimineralocorticoid activity, but the correlation between the degree of hyperaldosteronism and the blood pressure-lowering effect strongly suggests that aldosterone does play a role in the genesis or maintenance of the hypertension in these patients.

Adult↗
PubMed1990

A potential role for phospholipase-D in the angiotensin-II-induced stimulation of aldosterone secretion from bovine adrenal glomerulosa cells.

The mechanism by which angiotensin-II (Ang II) stimulates aldosterone secretion from adrenal glomerulosa cells involves a phospholipase-C-mediated increase in phosphoinositide turnover and diacylglycerol (DAG) production. Because agonist-induced activation of phospholipase-D (PLD) also contributes to elevations in DAG in other cell types, the ability of Ang II to stimulate PLD activity in cultured bovine adrenal glomerulosa cells was examined. Ang II elicited significant increases in the levels of phosphatidic acid and, in the presence of ethanol, of phosphatidylethanol, a more specific marker for PLD activation. The potential role of this increased PLD activity in the regulation of aldosterone secretion was examined by investigating the ability of exogenous PLD to alter secretory rates. PLD alone dose-dependently increased aldosterone secretion from 5.9 +/- 0.5 to 135 +/- 48 pg/min.mg protein. In the presence of the calcium channel agonist Bay K 8644, which by itself had only a modest effect on aldosterone production, the stimulatory action of PLD was enhanced, yielding a secretory rate (442 +/- 119 pg/min.mg protein) that was approximately 60% of that elicited by 10 nM Ang II (763 +/- 182 pg/min.mg protein). Exogenous PLD also induced a significant increase in DAG levels (from 0.76 +/- 0.03 to 1.10 +/- 0.1 nmol/mg protein), which was not altered by the addition of Bay K 8644. However, PLD did not stimulate inositol phosphate production. These data indicate that 1) Ang II activates PLD; 2) exogenous PLD can elevate aldosterone secretory rates and DAG levels without eliciting phosphoinositide hydrolysis; and 3) the stimulatory action of exogenous PLD on aldosterone secretion is enhanced in the presence of Bay K 8644. Thus, PLD-induced DAG production may play an important role in the Ang II-mediated stimulation of aldosterone secretion from the adrenal zona glomerulosa.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

The effects of fatty acids on apolipoprotein B secretion by human hepatoma cells (HEP G2).

We have investigated the effect of fatty acids on the rate of apolipoprotein B (apo B) secretion by human hepatoma cells (Hep G2). When Hep G2 cells were maintained in tissue culture flasks oleic acid up to 0.4 mM increased apo B secretion in a dose-dependent manner, whereas increases in triacylglycerol (TG) were smaller and dose dependency was less evident. In the absence of oleic acid, apo B accumulating in the tissue culture medium was predominantly in lipoproteins of higher density than very low density lipoproteins (VLDL). However, when the rate of secretion was stimulated with oleic acid the apo B-containing lipoproteins became lower in density. We postulated that there was a high rate of lipolysis of newly secreted VLDL by Hep G2 cells, which would account both for the relatively smaller effect of oleic acid on TG as opposed to apo B accumulating in the culture medium and the predominance of apo B in lipoproteins of a higher density than VLDL, which became less evident when VLDL secretory rates were stimulated by oleic acid. To test this hypothesis, cultured Hep G2 cells were transferred to columns containing Cytodex beads, permitting their continuous perfusion with culture medium so that newly secreted VLDL did not remain in contact with the cells. Apo B recovered from the perfusate was largely in VLDL range lipoproteins and the TG measured in the perfusate indicated that the true secretory rate of TG-rich lipoproteins was substantially higher than had been reflected by TG accumulating in culture medium left in contact with cells. Apo B measured in the culture medium of Hep G2 cells may thus be a better reflection of VLDL secretion, even though it is contained in higher density lipoproteins due to removal of TG by lipolysis. The effects of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) on apo B (apo B) secretion by Hep G2 cells maintained in tissue culture flasks were next investigated. SFA (0.4 mM), with the exception of stearic acid (C18:0), increased apo B secretion. Lauric acid (C12:0) increased apo B secretion by 32%, myristic acid (C14:0) by 41% (P<0.005), palmitic acid (C16:0) by 154% (P<0.025), and arachidic acid (C20:0) by 186% (P<0.005). The effect of MUFA (0.4 mM) was to increase apo B secretion, oleic acid (C18:1) by 239% ((P<0.0005) and palmitoleic acid (C16: 1) by 125% (P<0.005). Of the PUFA investigated, linolenic acid (C18:3) (0.4 mM) did not have any significant effect on apo B secretion, whereas linoleic acid (C18:2) (0.4mM) arachidonic acid (C20:4) (0.1 mM) and eicosapentaenoic acid (C20:5) (0.1 mM) caused significant increases of 164, 171 and 171%, respectively (P<0.005). The fatty acids studied increased intracellular TG and cholesteryl ester concentrations to varying extents. The increase in intracellular TG produced by the different fatty acids correlated with the rate of apo B secretion (r=0.6; P<0.05). In this human hepatoma cell line, with the exception of the saturated fatty acids, the rate of secretion of apo B-containing lipoproteins does not follow the same pattern as changes in circulating low density lipoprotein (LDL) concentrations reported with dietary manipulation in man. If our findings reflect the in vivo situation, we suggest that whilst the dietary effects of SFA on serum LDL may in part be determined by the hepatic apo B secretory rate, the effects of MUFA and PUFA must be largely mediated through a catabolic effect rather than an effect on hepatic secretion. The marked increase in apo B secretion with the more highly polyunsaturated fatty acids, such as eicosapentaenoic acid, may also explain why they do not lower circulating LDL, despite reports of their apparently favourable effect on LDL-receptor mediated clearance.

Apolipoproteins B↗
PubMed1994

Physiological regulation of the secretion of histatins and statherins in human parotid saliva.

The small salivary phosphoproteins, histatins and statherins, have important functions in the oral cavity in terms of antimicrobial actions and regulation of calcium phosphate homeostasis. Neither the effects of various physiological stimuli on their secretion nor the nature of the efferent receptor involved in the stimulus-secretion coupling has been determined previously. These aspects are important for improved understanding of the secretory control of salivary proteins and may have implications regarding the effects of specific medications on salivary constituents and oral health. The effects of graded mechanical (chewing on short and long silicone tubings) and gustatory stimulation (0.5, 1.5, and 5.0% citric acid) on the secretion of histatins and statherins were studied in the presence and absence of adrenolytic agents (n = 10). In this model, secretory rates of both proteins increased with increases in flow rate, with 5.0% citric acid representing a particularly potent stimulus. Histatin and statherin secretory rates were significantly reduced by the beta 1-adrenolytic agent (histatins to 58 to 72% and statherins to 11 to 29% of that in corresponding control experiments), but not by the alpha 1-adrenolytic agent. Since the beta 1-adrenergic receptors played an important role in the stimulus-secretion coupling of these proteins, protective salivary functions in the oral cavity may be compromised during beta 1-adrenolytic treatment.

Adult↗
PubMed1992

Differential effects of somatostatin and prostaglandins on gastric histamine release to pentagastrin.

The effects of gastric acid antisecretory agents prostaglandins E2, I2 (PGE2, PGI2) and somatostatin on pentagastrin-stimulated gastric histamine and N tau-methyl histamine secretory rates were examined in anesthetized mixed breed dogs. We infused two gastric acid antisecretory doses of PGE2 and PGI2 to test the effect of prostaglandins on pentagastrin-stimulated gastric histamine release. Neither dose of PGE2 and PGI2 had an effect on pentagastrin-stimulated histamine and N tau-methyl histamine release, even though the prostaglandins caused marked gastric vasodilation. In addition, the infusion of the higher dose of PGE2 and PGI2 alone had no effect on histamine secretory rates. In contrast, somatostatin inhibited both pentagastrin-stimulated gastric histamine release by approximately 95% as well as basal histamine release by approximately 60%. Somatostatin also inhibited the pentagastrin-stimulated N tau-methyl histamine secretory rates. The results indicate that neither PGE2 nor PGI2 at antisecretory doses affect pentagastrin-stimulated gastric histamine release, but somatostatin has a very potent inhibitory effect in that regard. Our data suggest that the mechanisms by which prostaglandins and somatostatin affect gastric acid secretion may be diverse.

Animals↗
PubMed1984

Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs.

Auriculin is a potent vasoactive and natriuretic peptide that was recently isolated and purified from rat atrial tissue. Since this peptide could be of great importance for renal, cardiovascular, and volume homeostasis, its functional properties have been characterized in dogs. The effects of synthetic auriculin on renal function, mean blood pressure, plasma renin activity, renin secretory rate, and plasma aldosterone levels were determined. Auriculin was administered intravenously as a prime (1.0 microgram/kg body weight) and constant infusion (0.1 microgram per minute/kg body weight for one hour) to five anesthetized dogs. In addition, two conscious dogs were used to verify some of the results obtained in anesthetized dogs. Auriculin decreased mean blood pressure from 134 +/- 5 to 122 +/- 4 mm Hg (p less than 0.05, paired t test) and increased glomerular filtration rate (25.5 +/- 2.7 to 32.4 +/- 4.1 ml per minute per kidney, p less than 0.05), diuresis (0.21 +/- 0.03 to 1.06 +/- 0.14 ml per minute per kidney, p less than 0.05), natriuresis (38 +/- 0.6 to 187 +/- 35 mueq per minute per kidney, p less than 0.05), and kaliuresis (14.8 +/- 1.6 to 35.7 +/- 6.3 mueq per minute per kidney, p less than 0.05). These effects were sustained throughout the infusion of auriculin and were entirely reversible. Renal plasma flow increased transiently for one to two minutes, and then returned to or below control levels. Urine osmolality decreased by 40 percent (p less than 0.05) whereas free water clearance remained unchanged (p less than 0.05). Auriculin reversibly decreased plasma renin activity (11.6 +/- 2.3 to 3.6 +/- 1.2 ng/ml per hour, p less than 0.05), renin secretory rate (895 +/- 313 to 255 +/- 28 ng per hour per minute, p less than 0.05), and plasma aldosterone levels (8.4 +/- 1.6 to 3.6 +/- 0.7 ng/dl, p less than 0.05), whereas plasma cortisol levels remained unchanged. These results demonstrate that auriculin has a unique combination of functional properties, increasing glomerular filtration rate, diuresis, and natriuresis, without a sustained increase in total renal blood flow, and lowering blood pressure, plasma renin levels, renin secretory rate, and plasma aldosterone levels. These properties suggest an important potential role for atrial natriuretic peptides in the regulation of renal function, extracellular volume, and blood pressure.

Aldosterone↗
PubMed1999

Neuroendocrine processes underlying ultradian sleep regulation in man.

Sleep is not a uniform state but is characterized by the cyclic alternation between rapid eye movement (REM) and non-REM sleep with a periodicity of 90-110 min. This cycle length corresponds to one of the oscillations in electroencephalographic (EEG) activity in the delta frequency band (0.5-3.5 Hz), which reflect the depth of sleep. To demonstrate the intimate link between EEG and neuroendocrine rhythmic activities in man, we adopted a procedure permitting simultaneous analysis of sleep EEG activity in the delta band and of two activating systems: the adrenocorticotropic system and the autonomic nervous system. Adrenocorticotropic activity was evaluated by calculating the cortisol secretory rate in blood samples taken at 10-min intervals. Autonomic activity was estimated by two measures of heart rate variability: 1) by the ratio of low-frequency (LF) to high-frequency (HF) power from spectral analysis of R-R intervals; and 2) by the interbeat autocorrelation coefficient of R-R intervals (rRR intervals between two successive cardiac beats). The results revealed that oscillations in delta wave activity, adrenocorticotropic activity, and autonomic activity are linked in a well-defined manner. Delta wave activity developed when cortisol secretory rates had returned to low levels and sympathetic tone was low or decreasing, as reflected by a low LF/HF ratio and by low levels in rRR. Conversely, the decrease in delta wave activity occurred together with an increase in the LF/HF ratio and in rRR. REM sleep was associated with a decrease in cortisol secretory rates preceding REM sleep onset, whereas the LF/HF ratio and rRR remained high. These results demonstrate a close coupling of adrenocorticotropic, autonomic, and EEG ultradian rhythms during sleep in man. They suggest that low neuroendocrine activity is a prerequisite for the increase in slow wave activity.

Adult↗
PubMed1997

Nicotinamide counteracts alcohol-induced impairment of hepatic protein metabolism in humans.

We have recently shown that a large amount of wine (750 mL, approximately 70 g of alcohol) markedly impairs postprandial hepatic protein metabolism in healthy subjects. This is probably due to the shift in the intracellular redox state (increased NADH/NAD+) induced by ethanol oxidation. If this hypothesis is true, the administration of nicotinamide (NAD+ precursor) should provide NAD+ in excess and thus correct the NADH/NAD+ abnormalities and prevent the ethanol hepatotoxicity. Whole-body protein metabolism and the fractional secretory rates of hepatic (albumin, fibrinogen) and extra-hepatic (immunoglobulin G, IgG) plasma proteins were measured in the basal postabsorptive and in the absorptive states in 15 healthy subjects, that had been assigned to three groups matched for age and body mass index. During the absorptive state (intragastric meal), the three groups received water (control), 750 mL of wine, or 750 mL of wine + 1.25 g of nicotinamide, respectively. The redox state was estimated by determining the plasma lactate/pyruvate ratio. Compared with the basal state, wine alone increased the lactate/pyruvate ratio twofold and depressed the fractional secretory rates of albumin and fibrinogen (P < 0.01 vs. control and nicotinamide); nicotinamide reduced the effects of wine on the lactate/pyruvate ratio (P < 0.02 vs. wine alone) and prevented the reduction of albumin and fibrinogen secretory rates (P > 0.05 vs. control). These results indicate that nicotinamide counteracts the acute hepatotoxic effects of ethanol by ameliorating the redox state.

Adult↗
PubMed1975

Secretion of electrolytes by the pancreas of the anaestetized rat.

1. HCO-3, Na+ and K+ concentrations were measured in bile-free pancreatic juice collected from fasted and fed anaesthetized rats. 2. Resting flow rates averaged 0.62 mul. g-1 .min-1 (fasted) and 2.8 mul. g-1. min-1 (fed) and the mean HCO-3 concentrations, respectively, were 25.8 and 33.3 mM. 3. In fasted rats, instillation of HCl into the duodenum caused flow rate to increase threefold and HCO-3 concentrations to double (66 mM). Intravenous infusion of pure natural (GIH) secretin caused a fivefold increase in flow rate; HCO-3 concentrations, again, doubled (67.5 mM). Infusion of synthetic secretin produced effects essentially the same as those produced by GIH secretin. 4. Infusion of Boots secretin caused a thirteenfold increase in flow rate (8.32 mul.g-1. min-1) but HCO-3 concentrations rose only slightly (43.3 mM). However, following cessation of infusion, when flow rate approximated the maximum obtained with pure secretin, the HCO-3 concentration was much higher (57.2 mM at 3.19 uml.g-1.min-1). In fed animals the responses were similar but maximum flow rates were greater (12 mul. g-1. min-1). 5. Infusion of caerulein produced a secretory rate slightly less than with Boots secretin (5.06 mul. g-1.min-1) and HCO-3 concentrations were plasmalike (30.2 mM); infusion of the synthetic octapeptide of cholecystokinin (OP-CCK) gave similar flow rates and HCO-3 concentrations. 6. Infusion of a mixture of caerulein and GIH secretin mimicked closely the effect of Boots secretin. At maximum flow rates (7.6 mul. g-1. min-1) the HCO-3 concentration was 43.7 mM and at lower flow rates (3.90 mul.g-1. min-1) it rose to 54.2mM. 7. It is concluded that the response of the rat pancreas to secretin is qualitatively similar to that of all other vertebrates so far studied, but, relative to other animals, the response is sluggish. In contrast, the rat pancreas responds well to cholecystokinin (CCK) stimulation, yielding a juice with plasma-like HCO-3 concentration. Boots secretin, which is heavily contaminated with CCK, causes a mixed response resembling that of CCK at high secretory rates and that of pure secretin at lower rates. 8. An unexplained feature of rat pancreatic juice was that K+ concentrations, although plasma-like in unstimulated samples, rose to about 8mM when flow rate increases as a result of secretin, but not CCK, stimulation. In all other animals so far studied, the K+ concentration has been found to be independent of flow rate.

Animals↗
PubMed1998

Pulsatile cortisol secretion and EEG delta waves are controlled by two independent but synchronized generators.

We have previously described a temporal relationship between plasma cortisol pulses and slow-wave sleep and, more recently, an inverse significant cross-correlation between cortisol secretory rates and delta wave activity of the sleep electroencephalogram (EEG). The aim of this study was to observe ACTH, cortisol, and sleep delta wave activity variations throughout 24 h to get a better insight into their initiating mechanisms. Two groups of 10 subjects participated in a 24-h study, one group with a night sleep (2300-0700) and the other with a day sleep (0700-1500). Cortisol secretory rates were calculated by a deconvolution procedure from plasma levels measured at 10-min intervals. Delta wave activity was computed during sleep by spectral analysis of the sleep EEG. When delta waves and cortisol were present at the same time at the end of the night sleep as well as during the daytime sleep, they were negatively correlated, cortisol changes preceding variations in delta wave activity by approximately 10 min. Increases in delta wave activity occurred in the absence of cortisol pulses, as observed at the beginning of the night. Cortisol pulses occurred without any concomitant variations of sleep delta wave activity, as observed during wakefulness and intrasleep awakenings. In no case did delta wave activity increase together with an increase in cortisol secretory rates. In conclusion, cortisol secretion and delta wave activity have independent generators. They can oscillate independently from each other, but when they are present at the same time, they are oscillating in phase opposition.

Activity Cycles↗
PubMed1984

Mesulergine, a new dopamine agonist: effects on anterior pituitary function and kinetics.

We investigated the effects of single doses of mesulergine on basal and thyrotropin-releasing hormone (TRH)-stimulated serum levels of several anterior pituitary hormones in healthy men and defined its kinetics. We also compared the effects on serum prolactin (PRL) levels of three doses (0.1, 0.35, and 0.5 mg) of mesulergine to those in response to 2.5 mg bromocriptine. Secretory rates of PRL before the first dose of TRH were not affected by any dose of mesulergine or bromocriptine. TRH-stimulated PRL secretion was not altered by 0.1 mg mesulergine but was blunted by both the 0.35- and 0.5-mg doses at 10 A.M. and 1 P.M. Bromocriptine inhibited TRH-stimulated PRL secretion at 10 A.M. and 8 P.M. When analyzed as the 8 A.M. to 8 P.M. and the 8 P.M. to 9 A.M. (day 2) intervals, PRL secretion was not changed by 0.1 or 0.35 mg mesulergine but was suppressed during both periods by the 0.5-mg dose. A dose-response relationship was evident, however, between mesulergine and PRL secretion during both the 8 A.M. to 8 P.M. (R2 = 0.27) and the 8 P.M. to 9 A.M. (day 2; R2 = 0.18) intervals. Bromocriptine lowered PRL secretion during both intervals. Secretory rates of growth hormone during these intervals were not affected by 0.1 mg or 0.35 mg mesulergine but were increased during both intervals by the 0.5-mg dose. Neither the secretory rates of thyrotropin in response to TRH nor those of cortisol, luteinizing hormone, or follicle-stimulating hormone were changed by 0.1 or 0.35 mg mesulergine.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1994

A new method for comparing portal and peripheral venous insulin delivery in humans: tolbutamide versus insulin infusion.

We describe a new noninvasive method for comparing insulin secreted acutely by the pancreas vs. a matched peripheral venous insulin infusion in humans. An intravenous tolbutamide infusion algorithm was developed that produced sustained steady rates of portal insulin secretion over 5 h in 11 healthy young men. Plasma glucose levels were maintained in the euglycemic range by adjusting the rate of an iv dextrose (20%) infusion. The pancreatic insulin secretory rate was calculated from peripheral C-peptide levels by deconvolution using standard parameters for a two-compartment mathematical model for C-peptide distribution and metabolism. On a subsequent occasion in the same subject, exogenous insulin was infused peripherally at a rate that matched the earlier tolbutamide-induced pancreatic insulin secretory rate, and euglycemia was maintained with a variable 20% dextrose infusion. The assumption that tolbutamide, when used in this fashion, has no independent insulin-like or insulin-potentiating effect at either low or high levels of peripheral insulinemia, does not affect insulin clearance, and does not suppress peripheral glucagon levels was validated in four patients with insulin-dependent diabetes mellitus. Mean peripheral immunoreactive insulin was significantly higher in the insulin infusion study than in the tolbutamide study (286 +/- 31 vs. 156 +/- 21 pmol/L; P = 0.0001). The dextrose infusion rates required to maintain euglycemia were also higher in the insulin infusion study (0.44 +/- 0.03 vs. 0.32 +/- 0.03 mmol/kg.min; P = 0.003). The MCR of insulin was greater in the tolbutamide infusion vs. the exogenous insulin infusion study (32.6 +/- 2.9 vs. 19.8 +/- 2.2 mL/kg.min; P = 0.0003), probably due to the hepatic first pass effect on insulin clearance when insulin is delivered by the portal route. This noninvasive method can be used in future studies to examine the relative importance of direct hepatic vs. peripheral effects of insulin in controlling hepatic glucose and lipid production.

Adult↗
PubMed1985

Variability in transport rates of secretory glycoproteins through the endoplasmic reticulum and Golgi in human hepatoma cells.

We have previously shown that newly synthesized liver secretory proteins are exported at three distinct characteristic rates, with intracellular retention half-times of 110-120 min (e.g. transferrin), 75-80 min (e.g. ceruloplasmin), and 30-40 min (e.g. alpha 1-protease inhibitor) (J. B. Parent, H. Bauer, and K. Olden (1985) Biochim. Biophys. Acta, in press). In the present study we have determined the average time required for specific glycoproteins to move through the various compartments of the intracellular transport pathway, consisting of endoplasmic reticulum and Golgi complex. Localization in particular compartments was monitored by the use of the following complementary approaches: (i) Percoll density gradient fractionation of the subcellular organelles, (ii) sensitivity of the glycan moiety of N-linked glycosylation to endo-beta-N-acetylglucosaminidase H, and (iii) by the lectin-binding characteristics. The cell fractionation studies revealed that alpha 1-protease inhibitor, ceruloplasmin, and transferrin were transported from the rough endoplasmic reticulum with a retention half-time of 10, 30, or 45 min, respectively. Measurements of the rate at which newly synthesized glycoprotein became endo H-resistant (an event localized near the medial region of Golgi) demonstrated that it took 60-70, 30, and 18 min for 50% of transferrin, ceruloplasmin, and alpha 1-protease inhibitor, respectively, to reach the medial Golgi. Consistent with this finding, maximal binding of transferrin to wheat germ agglutinin (also a medial Golgi event) and Ricinus communis agglutinin I (a trans Golgi event) required 75 and 90 min, respectively, and maximal binding of ceruloplasmin to both lectins occurred in approximately 30 min. Maximal binding of alpha 1-protease inhibitor to wheat germ agglutinin and Ricinus communis agglutinin I required 15 and 30 min, respectively. The results presented here clearly indicate that (i) the time required for protein secretion cannot be entirely accounted for by lag in transport from the rough endoplasmic reticulum to the Golgi since the glycoproteins examined are retained in the former organelle for no more than two-fifths of the total intracellular retention half-time, and (ii) the variability in rates of protein secretion is not due solely to differences in rates of transport from the rough endoplasmic reticulum to the Golgi as variability in retention within the Golgi is also demonstrated. The results are discussed in terms of their compatibility with receptor-mediated transport of glycoproteins in both the endoplasmic reticulum and Golgi.

Biological Transport↗
PubMed1991

Mirex inhibits bile acid secretory function in vivo and in the isolated perfused rat liver.

The insecticides mirex and chlordecone suppress the biliary excretion of a wide variety of non-bile acid organic anions in vivo in the rat, and mirex inhibits the uptake of taurocholate (TC), a common bile acid, in isolated rat hepatocytes. We have therefore investigated the effects of mirex and chlordecone on bile acid secretory function (bile flow, bile acid concentration, bile acid secretory rate) in vivo and in the single-pass isolated perfused liver. Male Sprague-Dawley rats were orally dosed with corn oil, mirex (50 mg/kg), or chlordecone (18.75 mg/kg; in vivo studies only) for 3 consecutive days and experiments performed on Day 6. Mirex significantly increased liver weight from 12.2 +/- 0.8 to 20.8 +/- 1.3 g with no change in body weight whereas chlordecone had no significant effect on liver weight (11.9 +/- 0.7 g) or body weight. Mirex significantly decreased while chlordecone increased bile flow per gram liver in vivo; both compounds, however, increased bile flow when expressed per kilogram of body weight. Mirex and chlordecone significantly decreased the bile acid concentration in bile and the bile acid secretory rate (nmol/min/g liver and mumol/min/kg body weight). Studies in the isolated perfused liver were designed to determine the effect of mirex on the ability of the liver to extract increasing concentrations of [3H]TC from the perfusate and excrete it in the bile. Mirex treatment significantly decreased the TC extraction ratio by 40-89% and the hepatic intrinsic clearance by 85-95%. Mirex also significantly decreased the TC-induced choleresis, the concentration of TC in the bile, and the TC secretory rate. The data indicate that mirex treatment markedly inhibits the ability of the liver to extract TC from the blood/perfusate and concentrate it in the bile.

Animals↗
PubMed1998

Fluid secretion in interlobular ducts isolated from guinea-pig pancreas.

1. Pancreatic HCO3- and fluid secretion were studied by monitoring luminal pH (pHL) and luminal volume simultaneously in interlobular duct segments isolated from guinea-pig pancreas. The secretory rate and HCO3- flux were estimated from fluorescence images obtained following microinjection of BCECF-dextran (70 kDa, 20 microM) into the duct lumen. 2. Ducts filled initially with a Cl--rich solution swelled steadily (2.0 nl min-1 mm-2) when HCO3-/CO2 was introduced, and the luminal pH increased to 8.08. When Cl- was replaced by glucuronate, spontaneous fluid secretion was reduced by 75 %, and pHL did not rise above 7.3. 3. Cl--dependent spontaneous secretion was largely blocked by luminal H2DIDS (500 microM). We conclude that, in unstimulated ducts, HCO3- transport across the luminal membrane is probably mediated by Cl--HCO3- exchange. 4. Secretin (10 nM) and forskolin (1 microM) both stimulated HCO3- and fluid secretion. The final value of pHL (8.4) and the increase in secretory rate (1.5 nl min-1 mm-2) after secretin stimulation were unaffected by substitution of Cl-. 5. The Cl--independent component of secretin-evoked secretion was not affected by luminal H2DIDS. This suggests that a Cl--independent mechanism provides the main pathway for luminal HCO3- transport in secretin-stimulated ducts. 6. Ducts filled initially with a HCO3--rich fluid (125 mM HCO3-, 23 mM Cl-) secreted a Cl--rich fluid while unstimulated. This became HCO3--rich when secretin was applied. 7. Addition of H2DIDS and MIA (10 microM) to the bath reduced the secretory rate by 56 and 18 %, respectively. Applied together they completely blocked fluid secretion. We conclude that basolateral HCO3- transport is mediated mainly by Na+-HCO3- cotransport rather than by Na+-H+ exchange.

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