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The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different.

We have measured the urinary cortisol production rate (uCPR) simultaneously with the serum cortisol production rate (sCPR) in four healthy men within a period of 3 days. uCPR, determined by isotope dilution of 11-oxoetiocholanolone was compared with sCPR, which was measured in three different ways (a, b, c). Blood was sampled at 10-min intervals for 24 h, and deconvolution analysis was applied to the cortisol concentrations. The daily serum cortisol production per liter, multiplied by the distribution volume yielded sCPR. The measurement methods are characterized as follows: a) the secretion and elimination terms were free; b) like method a, but with the input of the rate constants alpha and beta into the elimination function; c) the average 24-h cortisol concentration was multiplied by the metabolic clearance rate. uCPR was 25.4 +/- 4.7 [range: 21.3-31.4] micromol/(m2 x day), sCPR (method a) was 28.8 +/- 4.5 [range: 23.5-34.3] micromol/(m2 x day), sCPR (method b) was 27.9 +/- 8.1 [range: 18.5-37.7] micromol/(m2 x day), and sCPR (method c) was 29.3 +/- 4.8 [range: 22.7-33.2] micromol/(m2 x day). uCPR did not significantly differ from each of the 3 sCPR values (P > 0.30; > 0.46; and > 0.06, respectively). The patterns of the cortisol secretory rates in the present and previous studies do not necessarily represent the physiological process of the secretory bursts. We conclude that the estimated CPR, being 25-30 micromol/(m2 x day) [9-11 mg/(m2 x day)], can serve as a guideline for glucocorticoid replacement dose and that the urinary route to measure CPR is preferred because of its relative ease.

Humans↗

Influence of phenylbutazone on bile flow in the rat.

Phenylbutazone, a well-known enzyme inducer, at a dose of 80 mg . kg-1 once daily for 8 days increases liver weight and bile flow expressed per g of liver (p less than 0.01). The bile salt secretory rate is not increased.

Animals↗

Effects of cyclic adenosine 3':5'-monophosphate and related agents on acid secretion by isolated rabbit gastric mucosa.

The effects of various adenosine phosphate compounds, theophylline, histamine,a nd metiamide, on steady rates of acid secretion by isolated fundic mucosa of the rabbit were measured by the pH stat method. Cyclic adenosine 3':5'-monophosphate (cyclic AMP), N(6), O(2')-dibutyryl adenosine 3':5'-monophosphate and theophylline increased the rate of acid secretion. Addition of theophylline in a concentration which has no stimulatory effect, reduces the effective concentrations cyclic AMP or histamine required for stimulation of acid secretion. Measurements of lactate, pyruvate, and CO2 appearances indicated that the increases in acid secretory rates were predominantly due to H+ and not organic acid accumulation in the luminal bath-secretion. Metiamide prevented the stimulatory effects of histamine and ATP. However, metiamide did not prevent the stimulatory effects of N(6),9(2')-dibutyryl adenosine 3':5'-monophosphate, theophylline, or 5'-AMP. The results provide further evidence for a role of cyclic AMP in governing the rate of acid secretion by rabbit stomach. The data also are consistent with histamine and ATP (at least in the concentration used) requiring adenylate cyclase activity for stimulation of acid secretion and 5'-AMP inhibiting phosphodiesterase activity.

Adenosine Monophosphate↗

Saliva composition and caries development in asthmatic patients treated with beta 2-adrenoceptor agonists: a 4-year follow-up study.

In an earlier study, we found that chronic treatment with beta 2-adrenoceptor agonists in asthmatic subjects gave an impaired saliva secretion and a higher caries prevalence than in healthy controls. Twenty-one of the asthmatics and their matched controls were examined 4 yr later in a follow-up study. Samples of whole saliva stimulated by chewing and parotid saliva stimulated by citric acid were collected and dental caries was scored. In the asthmatic group the secretory rates of stimulated whole and parotid saliva decreased by 20% and 35%, respectively, compared to the control group. The number of lactobacilli increased. The asthmatic subjects had a decreased output per minute of total protein, amylase, hexosamine, salivary peroxidase, lysozyme, secretory IgA, a bacteria-aggregating glycoprotein, potassium, and calcium in stimulated parotid saliva. Initial and manifest caries lesions as well as the number of DFS were significantly increased in the asthma group. We conclude that asthmatic patients treated with beta 2-adrenoceptor agonists have an increased caries susceptibility due to an impaired saliva secretion caused by the use of beta-adrenergic agonists.

Adolescent↗

Defects in beta-cell function in functional ovarian hyperandrogenism.

Previous studies have shown that hyperinsulinism is associated with hyperandrogenism in patients with the polycystic ovary syndrome, a form of functional ovarian hyperandrogenism (FOH). Although many studies have documented insulin resistance and hyperinsulinemia in polycystic ovary syndrome, the relative roles of insulin secretion and clearance in the pathogenesis of the hyperinsulinism remain uncertain. In this study, using individually derived C-peptide kinetic parameters, insulin secretion rates were calculated directly from plasma C-peptide concentrations in 10 patients with FOH and 7 weight-matched control subjects. All subjects were studied during a 24-h period when they ate a standardized diet consisting of 3 mixed meals. On a separate occasion, insulin sensitivity was calculated during a hyperinsulinemic euglycemic clamp. Although glucose concentrations in both groups were within the normal range, the FOH group had higher basal (P < 0.01) and 24-h insulin (P < 0.04) concentrations. The increased insulin concentrations reflected both a reduced clearance (P < 0.02) and an increased secretion of insulin. Basal insulin secretion rates were significantly increased (P < 0.04) in the FOH patients. By contrast, their incremental insulin secretory response to meals was markedly reduced. This reduction in the postprandial responses resulted from a reduction in the relative amplitude of meal-related (P < 0.007) secretory pulses, rather than from a reduction in the number of pulses present. Insulin sensitivity was also lower in those with FOH. Thus, women with FOH have significantly higher basal insulin secretory rates and attenuated secretory responses to meals. These secretory patterns resemble those of noninsulin-dependent diabetes mellitus more than they do those of simple obesity.

Adult↗

Stimulation by endocytosis of the secretion of collagenase and neutral proteinase from rabbit synovial fibroblasts.

Rabbit synovial fibroblasts in monolayer culture secrete a specific collagenase and a neutral endopeptidase into their serum-free culture medium. The rate of secretion of these two enzymes is increased after the ingestion and storage of latex particles within the vacuolar system of the cells. The increased rates of secretion of the neutral enzymes are stable for over 2 wk in the absence of a further phagocytic bout. In constrast there is little change in the extracellular levels of two lysosomal hydrolases, cathepsin D and beta-glucuronidase. The increase in the secretory rates for the two neutral enzymes is related to the number of latex particles ingested by the cells, and increases of up to 12-fold over the nonphagocytosing cultures were observed. A variety of other materials including mycostatin particles and dextran sulfate also induced increases in the secretion of collagenase. These results are discussed in relation to the turnover of connective tissue matrix macromolecules.

Animals↗

Gastric acid responses to graded vagal stimulation in the anaesthetized cat.

Graded acid secretory responses were obtained in anesthetized cats with intact pyloric region when the frequency of electrical stimulation of the neck vagi was increased from 0.5 to 8 Hz; 4-8 Hz induced maximal acid secretion. Antrectomy reduced the response to vagal stimulation but the reduction reached statistical significance only after additional resection of the duodenum. Administration of per se subthereshold or threshold doses of exogenous gastrin restored the acid response to vagal stimulation in antrectomized cats. Combination of a high dose of histamine and vagal stimulation in antrectomized output in anaesthetized cats which roughly amounted to two thirds of the reported maximal acid secretory rate during histamine stimulation in non-anaesthetized cats. The present results suggest that the physiological vagal discharge rate to the acid secreting glands does not reach higher frequencies than aroung 8 Hz. It is also suggested that an intact antroduodenal region is essential for acid responses to physiological vagal stimulation in the cat. Finally, the reduced sensitivity to gastric secretory stimulants under anaesthesia appears to be due in part to a reduced vagal tonus.

Animals↗

Renal handling of uric acid in normal and gouty subject: evidence for a 4-component system.

Bidirectional renal urate tranport was studied in both control and gouty subjects. 99.3% of filtered urate undergoes reabsorption as assessed by pyrazinamide suppression of urate secretion. The maximum uricosuric response to benzbromarone, equated with the minimum secretory rate, amounted to 50% of the filtered load in normal persons and was lower in gouty normoproducers. Since benzbromarone selectively inhibits reabsorption of secreted urate, the difference between secreted and excreted uric acid becomes a valid measure of urate reabsorption distal to the secretory site and amounts to 80% of the secreted load in both groups. These data conform to a 4-component model of renal urate handling in man.

Absorption↗

Salivary gland function in persons with ectodermal dysplasias.

Ectodermal dysplasias (EDs) constitute a group of conditions comprising developmental defects in two or more of the following tissues: hair, teeth, nails, and sweat glands. The aim of the present study was to contribute to a better understanding of salivary gland involvement in EDs. An ED group (n = 39, median age 12 yr; 24 males, 15 females) and a healthy age- and sex-matched control group were studied. Citric acid stimulated submandibular and parotid salivary flow rates and salivary concentrations, and output of total protein, acidic proline-rich proteins and histatins were analysed. The associations between quantitative and qualitative salivary parameters were also studied. In the ED group, 13 persons (33%) demonstrated a significantly reduced secretion of submandibular and/or parotid saliva, in addition to a low unstimulated and/or chewing-stimulated whole salivary flow. In the ED group as a whole, a reduced median secretory rate of submandibular saliva was found, whereas the median concentrations of some protein parameters were increased. However, the overall output of proteins was normal or reduced. Submandibular glands seemed to be more affected than parotid glands in EDs. In conclusion, salivary secretory tests are recommended in persons with known or suspected EDs.

Adolescent↗

The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations.

To investigate patterns of endogenous hormone release, we have proposed a biophysical model in which measured hormone concentrations at any given instant reflect the operation of a suitable cumulation function (secretory input) convolved with an appropriate elimination mechanism (metabolic clearance). The cumulation function underlying a macroscopic hormone secretory burst can be represented by a random (Gaussian) distribution of instantaneous molecular secretory rates, which are centered with some finite and determinable standard deviation about a particular moment in time. The hormone elimination mechanism is described by a mono- or biexponential clearance function. The resultant convolution integral is solved by iterative nonlinear least-squares parameter estimation, in which all plasma hormone concentrations and their variances are considered simultaneously. Experiments with human endocrine time series revealed that the spontaneous secretory patterns of any of multiple distinct anterior pituitary hormones (luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, thyrotropin, and adrenocorticotropic hormone) can be described effectively by this parsimonious model. In addition, endogenous hormone disappearance rates determined by deconvolution agreed well with those reported earlier that were determined after exogenous hormone injections. Moreover, this model predicted that durations of underlying secretory impulses are extremely brief; i.e., the standard deviations of the Gaussian distributions of instantaneous secretory rates range from 4.5 min (luteinizing hormone) to 16 min (growth hormone) compared to plasma hormone concentration peaks of 90-140 min in duration. Accordingly, we conclude that observed physiological patterns of fluctuating plasma hormone concentrations can be accounted for by distinct, highly delimited, random bursts of hormone release separated by intervals of secretory quiescence.

Adrenocorticotropic Hormone↗

Stimulation of insulin release by isosmolar addition of permeant molecules.

Pancreatic beta-cells are known to respond to hyposmolar stress by releasing insulin. It was evident from perifusion studies using islet cells from ob/ob-mice mixed with polyacrylamide beads that a similar type of secretory response can be obtained by isosmolar addition of 10-25 mM of the rapidly penetrating urea molecule. There was no effect with hyperosmolar addition of urea. The urea-induced insulin release differed from the ordinary stimulation of secretion in not disappearing but being more pronounced after previous heating to 45 degrees C or removal of extracellular Ca2+. Isosmolar urea was exceptional as an insulin secretagogue in being effective also in the presence of the alpha 2-adrenergic agonist clonidine or when lowering the temperature to 24 degrees C. Further support for the idea that isosmolar addition of rapidly penetrating molecules induces insulin release was obtained by testing non-metabolizable glucose analogues. Whereas 25 mM 3-O-methyl-D-glucose doubled the secretory rate within 4 min, the non-permeant L-glucose had only a slight initial action. When not compensating for the alterations of the medium osmolarity 3-O-methyl-D-glucose was without effect. Although expansion of beta-cells cannot explain the existence of a pronounced initial secretory response to D-glucose it may under certain conditions contribute to the stimulatory effects of the sugar.

3-O-Methylglucose↗

Electrical events during activation and inhibition of gastric HCl secretion.

A brief review of some of the relationships between the secretory rate and the electrophysiological characteristics of the canine and frog gastric mucosa is presented. There is no simple relationship between the potential difference (PD) and H+ rate in the in vitro frog gastric mucosa with standard Cl- bathing solutions. In contrast, with Cl- -free solutions (PD is inverted) there is a precise linear relationship between the PD and the H+ rate. This linear relationship is strong support for the concept that the H+ mechanism under these conditions is electrogenic. In the past it has been difficult rigorously to exclude the possibility that the inverted PD is due to a liquid junction potential between acid fluid in the lumina and the secretory bathing solution. Use of aminopyrine or imidazole essentially eliminates the possibility that the inverted PD is due to a liquid junction potential. Hence the linear relationship is solid evidence for the electrogenicity of the H+ mechanism. Recently we have shown that aminopyrine or imidazole can reverse thiocyanate inhibition of H+ secretion.

Aminopyrine↗

Bay K 8644, a voltage-sensitive calcium channel agonist, facilitates secretion of atrial natriuretic polypeptide from isolated perfused rat hearts.

Effects of Bay K 8644, a voltage-sensitive calcium channel agonist, on atrial natriuretic polypeptide (ANP) secretion from isolated rat hearts perfused with Krebs-Henseleit solution were investigated. After a ninety-min period for stabilization, coronary sinus effluents were collected every two min and ANP levels were measured by radioimmunoassay. The basal secretory rate of ANP was 1.65 +/- 0.15 ng/min (mean +/- standard error). Bay K 8644 stimulated ANP secretion dose-dependently. This stimulatory action was blocked by simultaneous administration of nifedipine, its competitive antagonist. Heart rate was also increased by Bay K 8644 administration. In the gel filtration study, the major secretory form of ANP corresponded to alpha-rat ANP, a 28-amino acid peptide. These results suggest that voltage-sensitive calcium channels are involved in two principal biological properties, contraction and ANP secretion, of atrial cardiocytes.

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

Interactions of intracellular mediators of amylase secretion in permeabilized pancreatic acini.

Mouse pancreatic acini were permeabilized with streptolysin O to investigate amylase secretion stimulated by various intracellular mediators and the kinetics of secretion as a function of temperature. Amylase secretion was temperature dependent in that the initial rate of Ca2(+)-stimulated secretion increased with increasing temperature. In addition, there was no enhancement of Ca2(+)-stimulated secretion by GTP[gamma S] at 14 degrees C, while enhancement was maximal at 30 degrees C. GTP[gamma S]-mediated enhancement of secretion at a given temperature was mostly due to sustained secretion with a small increase in secretory rate. At 30 degrees C Ca2(+)-stimulated secretion was also enhanced by cAMP and phorbol ester (TPA) to similar extents as by GTP[gamma S]. The maximally effective concentration of cAMP was 1-10 microM in the presence of 0.1 mM isobutylmethylxanthine. The enhancements of Ca2(+)-stimulated amylase secretion by all combinations of cAMP (100 microM plus 0.1 mM isobutylmethylxanthine), TPA (1 microM), and GTP[gamma S] (30 microM) were fully additive. In Ca2(+)-free buffer, cAMP, TPA or GTP[gamma S] individually had no effect on amylase secretion. Together, TPA and GTP[gamma S] stimulated Ca2(+)-independent secretion, which was 187 +/- 38% of basal. Cyclic AMP together with TPA and GTP[gamma S] in the absence of Ca2+ stimulated 329 +/- 30% of basal secretion. Ca2(+)-stimulated amylase secretion was decreased about 50% by metabolic inhibition, while the enhancement by cAMP, TPA or GTP[gamma S] was totally blocked by metabolic inhibitors. These data demonstrate that amylase secretion in the acinar cell is mediated by multiple intracellular pathways which act in parallel and probably converge at a distal step in the exocytotic process.

Adenosine Triphosphate↗

Pharmacokinetics in children.

The first year of life is associated with major changes in the processes affecting the absorption, distribution, metabolism and excretion of drugs. Drug absorption by the oral route is affected by reduced gastric emptying so that this route is unreliable in the neonate. The intramuscular route is also unreliable but transdermal absorption is often greater, with risks of toxicity. The volume of distribution of many drugs is often markedly increased in the neonate, partly because of reduced plasma protein binding (both to albumin and to alpha-1-acid glycoprotein) but also because of an increased volume of extracellular fluid relative to total body water. These factors both result in increased half-life of elimination of drugs. Metabolic processes are often immature at birth and this results in reduced clearance rates and prolonged half-life of elimination of those drugs for which metabolism is a significant mechanism for elimination. Renal excretion in the newborn is reduced although glomerular filtration rate (a passive process) and active tubular secretory rate increase relatively rapidly during infancy. Since these processes tend to be the most important drug elimination mechanism for antibiotics, dose adjustment is particularly important; methods using calculated glomerular filtration rate and the role of therapeutic drug monitoring are described. Finally, the pharmacokinetic processes develop at different rates during the first year of life and an understanding of these factors can help in the safe and effective prescribing of antibiotics.

Absorption↗

Effects of peptide histidine isoleucine on pancreatic exocrine secretion in anaesthetized dogs.

1. The effects of peptide histidine isoleucine (PHI) on pancreatic exocrine secretion were investigated in preparations of the isolated and blood-perfused dog pancreas as compared with those of vasoactive intestinal peptide (VIP), secretin and glucagon. 2. Each peptide tested was injected intra-arterially (i.a.) as a single bolus. Graded doses of PHI (3-300 nmol/kg), VIP (1-100 nmol/kg) and secretin (0.01-0.3 nmol/kg) caused dose-dependent increases in the secretion of pancreatic juice and bicarbonate outputs, but had little effect on the protein outputs. Glucagon (0.1-10 mumol/kg) produced a bell-shaped dose-response curve for the secretory rate, bicarbonate and protein outputs. 3. The secretory activity of 30 nmol/kg of PHI corresponded roughly to that of 80 pmol/kg of secretin, 9 nmol/kg of VIP and 0.6 mumol/kg of glucagon, respectively. Thus, based on administered dose, PHI was about 375 x less potent than secretin, 3 x less potent than VIP and 20 x more potent than glucagon. 4. The PHI- and VIP-stimulated secretions were inhibited by a VIP antagonist, but not by a glucagon antagonist, SCH23390 (a dopamine D-1 antagonist), L-364718 (a cholecystokinin antagonist) or atropine. 5. Each peptide increased cyclic AMP concentration, but not cyclic GMP concentration, concomitant with the increase in pancreatic secretion. 6. From these results, it is concluded that PHI produces an increase in pancreatic secretion by acting on VIP-preferring receptors on the exocrine pancreatic gland of the dogs. This may be mediated at least in part through the increase of intracellular cyclic AMP concentrations.

Animals↗

Tripartite neuroendocrine activation of the human growth hormone (GH) axis in women by continuous 24-hour GH-releasing peptide infusion: pulsatile, entropic, and nyctohemeral mechanisms.

Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h i.v. infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 microg/kg x h) in estrogen-unreplaced (mean serum estradiol, 12 +/- 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (+/-SEM) GH concentrations, viz. from 0.32 +/- 0.042 (saline) to 2.4 +/- 0.34 microg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 +/- 0.18 (control) vs. 6.3 +/- 1.3 microg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion; i.e. from 0.592 +/- 0.073 (saline) to 0.824 +/- 0.074 (GHRP-2; P = 0.0011), signifying more irregular or disorderly GH release patterns during secretagogue stimulation. Cosinor analysis of 24-h GH rhythms disclosed a significantly earlier (daytime) acrophase at 2138 h (+/- 140 min) during GHRP-2 stimulation vs. 0457 h (+/-42 min) during saline infusion (P = 0.013). Concomitantly, the cosinor amplitude rose 6-fold (P = 0.018), and the mesor (cosine mean) rose 5-fold (P = 0.003). Fasting (0800 h) plasma insulin-like growth factor (IGF-I) concentrations rose by -11 +/- 12 microg/L during saline infusion and by 102 +/- 18 microg/L during GHRP-2 infusion (P = 0.0036). GHRP-2 infusion did not modify (24-h pooled) serum LH, FSH, or TSH concentrations and minimally increased serum (pooled) daily PRL (6.8 +/- 0.83 vs. 12 +/- 1.2 microg/L; P < 0.05) and cortisol (5.3 +/- 0.59 to 7.0 +/- 0.74; P < 0.05) concentrations. In summary, 24-h constant iv GHRP-2 infusion in the gonadoprival female neurophysiologically activates the GH-IGF-I axis by potentiating GH secretory burst mass and amplitude by 7- to 10-fold and augmenting the basal (nonpulsatile) GH secretion by 4.5-fold. GHRP-2 action is highly selective, as it does not alter GH secretory burst frequency, interpulse interval, event duration, or GH half-life. GHRP-2 effectively elevates IGF-I concentrations, unleashes greater disorderliness of GH release patterns, and heightens the 24-h rhythmicity of GH secretion. These tripartite features of GHRP-2's action in estrogen-withdrawn (postmenopausal) women also characterize normal human puberty and/or sex steroid regulation of the GH-IGF-I axis. However, how or whether GHRP-2 interacts further with sex hormone modulation of GH neurosecretory control in older women and men is not yet known.

Aged↗

Depression of exocrine pancreatic secretion by collection through duodenoscopic catheters.

Two dogs were equipped with gastric and duodenal cannulas permitting quantitative collection of pure pancreatic juice. Two series of experiments were performed: 1) collection through a short catheter, length 35 cm, volume 0.3 ml, and internal diameter 1.0 mm, and 2) collection through a long catheter used for duodenoscopic cannulation in man, length 110 cm, volume 1.7 ml, and internal diameter 1.0 mm at the tip and 1.4 mm in the other part of the catheter. After a basal period of 30 min the secretion was stimulated with secretin in the doses 0.1, 0.5, and 2.0 clinical units/kg/h, each dose being infused over a period of 30 min. With the long catheter the dose-response curve for fluid and bicarbonate was shifted to the right. The basal secretion of fluid was depressed 40%; with increasing secretory rates the depression was less pronounced. No significant depression of the bicarbonate concentration was seen. The protein secretion was insignificantly reduced.

Animals↗