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Nature of bile acid maximum secretory rate in the rat.

We studied the determinants of maximum bile acid secretory rate (SRm) in the rat. The choledochocaval fistula rat model manifested a bile acid secretory rate far in excess of the SRm previously reported for taurocholate in this species. We studied the ability of various bile acid solutions to maintain the high secretion rate in this model. Whole-rat bile, but not taurocholate in 2% albumin nor rat bile with bile acid content over 90% taurocholate, maintained secretion rate. We concluded that the mixture of bile acids in rat bile was the most important determinant of the high secretion rate and that the high rate was not due to a peculiarity of the model itself nor to the infusion of biliary lipids together with bile acids. Conventional determination of the SRm in the bile fistula rat confirmed this impression, with the least toxic bile acids manifesting the highest SRm. During infusion of taurocholate beyond the SRm, bile flow and bile acid secretion rate fell. This was accompanied only by scattered focal necrosis of single liver cells or of small aggregates of cells and not by any diffuse subcellular morphological change. We believe the maximum bile acid secretory rate is determined by toxicity of a specific bile acid for the secretory mechanism rather than by a limitation in transport receptor number as is usual with substances manifesting classical transport maxima. The high SRm of the 7 beta-hydroxy bile acid, ursodeoxycholic acid, is probably related to its very low toxicity. The high SRm in the choledochocaval fistula rat is probably related to the presence of 7 beta-hydroxy muricholic acids in the bile of this species.

Animals↗

Influence of common bile duct cannula size on maximal secretory rate of taurocholate in the rat.

The common bile duct of male Sprague-Dawley rats was cannulated with either PE 10 or PE 50 tubing. Maximal secretory rate of taurocholate averaged 389 +/- 67 (SD) and 657 +/- 115 nmoles X min-1 X g liver-1 in the PE 10 and PE 50 group, respectively (p less than 0.005). Maximal bile secretory pressure was significantly higher in the PE 10 group (240 +/- 28 vs 174 +/- 8 mm H20; p less than 0.005). When the maximal secretory rate was exceeded, bile flow decreased in both groups but this was accompanied with a decrease in maximal bile secretory pressure in the PE 10 group only. Maximal secretory rate of bile salts is markedly influenced by experimental technique. Use of small caliber common bile duct cannulae leads to partial obstruction and decreases the apparent maximal secretory rate for taurocholate.

Animals↗

Liver cell membrane solubilization may control maximum secretory rate of cholic acid in the rat.

The factors modulating the maximum secretory rate of cholic acid were investigated. Rats were infused intravenously with cholic acid in measured stepwise increasing doses (1, 2, 3, and 4 mumol X min-1 X 100 g body wt-1). Each dose was infused for 30 min and bile samples were collected every 10 min. Bile flow, bile acid, cholesterol, individual biliary phospholipids, and the fatty acid profiles of the biliary phospholipids were determined. Microsomal and bile canalicular membrane-enriched fractions were isolated from cholic acid-treated rats at the end of the experiment. Membranes were analyzed for cholesterol, phospholipid, and phospholipid fatty acid composition. During cholic acid infusion, the secretion rates of bile acid, cholesterol, phospholipid, and bile flow initially increased and then declined. No evidence of liver cell damage was observed by light or electron microscopy. Maximum phospholipid secretion rate (13.5 nmol X min-1 X g-1) occurred before peak bile flow and bile acid secretory rate maximum (4.72 microliter X min-1 X g-1 and 375 nmol X min-1 X g-1). When phospholipid output declined, the proportion of sphingomyelins and phosphatidylethanolamine relative to phosphatidylcholine increased. This was also reflected in the fatty acid composition. Cholic acid infusion caused a decline in microsomal and bile canalicular membrane phospholipid content without affecting their phospholipid composition. Depletion of membrane phospholipid resulted in an increase in the cholesterol:phospholipid ratio, which is suggested to be the underlying mechanism for modulating cholic acid secretion.

Animals↗

Influence of age on the secretory rates of the human minor salivary glands and whole saliva.

This investigation comprised two studies of healthy, unmedicated individuals. The first measured the effect of collection time on the volume of secretions of the minor salivary glands at four specified areas of the lower lip of 13 individuals before and after a mild gustatory stimulus. The second (n = 51) monitored the influence of age and gender on the secretory rates of unstimulated labial, buccal and palatal salivary glands. Also, unstimulated and stimulated flow rates of whole saliva were monitored to provide a point of reference. Volumes of minor gland secretions were measured with a Periotron unit. Results of the first study indicated a linear increase in volumes with collection time (15, 30, 45 and 60 s). Flow rates were similar among the four labial sites, approx. 1 microliter/cm2/min, and were not influenced by mild citric acid stimulation. Results of the second study indicated that flow rates differed significantly (p = 0.0001) among the anatomical sites, with similar rates on the right- and left-hand sides. Gender exerted no influence on flow from the minor salivary glands. Similarly, age exerted no influence on flow from the buccal or labial glands. However, the secretory rate for the palatal glands decreased significantly with age (r = -0.44; p < 0.005). As for unstimulated whole saliva, secretory rates were not influenced by age nor gender; rates for stimulated whole saliva increased with age (r = 0.31; p < 0.05). No association was detected between the flow rates of the whole saliva and that of the minor salivary glands.

Adult↗

Appraising the instantaneous secretory rates of luteinizing hormone and testosterone in response to selective mu opiate receptor blockade in late pubertal boys.

The pulsatile properties of gonadotropin and testosterone release were examined before and after chronic mu opiate receptor blockade with naltrexone, 50 mg every other day, in four normal boys in late puberty (ages 14 8/12 to 15 1/12 years). The nature of spontaneous secretory events was appraised for immunoactive LH and testosterone in blood withdrawn every 20 minutes for 24 hours, using a novel, discrete deconvolution algorithm to estimate apparent instantaneous secretory rates. The application of this methodology revealed that the frequency of discrete LH instantaneous secretory rates increased after mu opiate receptor blockade (P = 0.011). More strikingly, all parameters of testosterone secretory events responded significantly to mu opiate receptor blockade, including increases in mean estimated secretory rate (+47%, P = 0.02), testosterone pulse frequency (+ 64%, P less than 0.001) and amplitude (+ 20%, P = 0.027). Correspondingly, decreases in testosterone interpulse secretory intervals (-35%, P = 0.001), secretory pulse duration (-19%, P = 0.042) and interpulse valley duration (-35%, P = 0.006) also were noted. There was a prominent diurnal rhythm in testosterone secretion with maximal values in the morning and late evening, and marked reductions in the afternoon, sometimes to prepubertal levels. This variation in the testosterone secretory profile paralleled that of LH. In response to naltrexone, the FSH concentration series showed a significant increase in the mean FSH concentration (+ 18%) P = 0.003) and mean peak amplitude (+ 15%, P = 0.002). These data provide indirect evidence of functional coupling of the opiate system with the hypothalamic GnRH pulse generator.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Effect of KCl infusion on renin secretory rates and aldosterone excretion in dogs.

The effects of unilateral intrarenal arterial KCl infusion in dogs (12 mueq/kg per min) on bilateral renal function, renin secretory rates, and aldosterone excretion were studied. During KCl infusion, infused-side renal arterial plasma [K+] increased by 2.2 +/- 0.6 meq/liter. Systemic plasma [K+] simultaneously rose by 0.6 +/- 0.1 meq/liter. Plasma renin activity decreased 29 +/- 9%, and the decrease correlated with the increases in plasma [K+]. Renin secretory rate decreased bilaterally, the decrease being greater in each experiment on the infused side. Aldosterone excretion increased during KCl infusion by 72 +/- 17%, despite a decrease in plasma renin activity. With KCl infusion there was a bilateral increase in K+ excretion, and a positive correlation was observed between the net alterations in K+ and Na+ excretion. No significant alterations in systemic blood pressure, glomerular filtration rate, total renal blood flow, or intracortical renal blood flow distribution were observed. These studies suggest that K+ inhibits the release of renin by an intrarenal mechanism, which may be related to a K+-induced alteration in Na+ absorption.

Aldosterone↗

Maximal proton secretory rate of rat distal tubules is higher during chronic metabolic alkalosis.

In vivo microperfusion studies show augmented proton secretion in the distal tubule of rats with chronic metabolic alkalosis. The present studies used the same technique to determine whether this augmented proton secretion is due predominantly to an increase in substrate affinity or alternatively to a predominant increase in the maximal proton secretory rate. Surface distal tubules of alkalotic and control rats were microperfused in vivo with solutions containing increasing concentrations of HCO3. Proton secretion was determined as the difference between measured net HCO3 reabsorption and passive HCO3 transport calculated by use of the permeability derived from perfusing with a HCO3-free solution. Proton secretion was expressed as a function of the initial luminal HCO3 concentration and was assumed to follow saturable Michaelis-Menten kinetics. Alkalotic animals had a significantly higher Km (33.9 vs. 21.6 mM, P less than 0.03) and Vmax (223.8 vs. 99.1 pmol.mm-1.min-1, P less than 0.001) compared with control. These data are consistent with the augmented proton secretion in the distal tubule of alkalotic animals as predominantly due to an increased maximal proton secretory rate rather than to increased substrate affinity.

Alkalosis↗

Estimation of instantaneous secretory rate of luteinizing hormone in women during the menstrual cycle and in men.

In both men and women the pulsatile secretory pattern of LH has been extensively characterized. In the present study we used the algorithm for computation of instantaneous secretory rate (ISR) incorporated into the DETECT program to evaluate the secretory activity of gonadotrophs in vivo. We studied the pulsatile release of LH in four healthy women during four phases of the same menstrual cycle (early and late follicular and luteal phases) and in five healthy men. Computation of ISR permitted us to estimate the frequency and the duration of the secretory events from the gonadotrophs. Samples were collected every 10 min for 6 h. The apparent LH pulsatile frequency during the menstrual cycle varied from 5.0 +/- 0.8 (mean +/- SD) during the early follicular phase (EFP) to 5.3 +/- 1.2 peaks/6h during the late follicular phase (LFP), to 3.3 +/- 1.0 during early luteal phase (ELP) and to 5.3 +/- 0.4 peaks/6h during the late luteal phase (LLP). The mean pulse duration also changed throughout the phases of the cycle (EFP 47.4 +/- 13.2 min; LFP 55.4 +/- 21.6 min; ELP 100 +/- 50.4 min; LLP 48.1 +/- 11 min). In healthy men the LH pulse frequency was 3.8 +/- 1.6 peaks/6h and the duration was 71.5 +/- 35.7 min. When time series were analysed for ISR determination no significant changes were observed between the LH pulse frequency detected on ISR and that observed on plasma concentrations. Conversely, a significant reduction of the duration of the pulses was found when using ISR instead of plasma concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Hepatic clearance and biliary secretory rate maximum of taurocholate in the recirculating and single pass isolated perfused rat liver. Effects of the cholestatic agent, estradiol-17 beta-(beta-D-glucuronide).

The ability of the cholestatic steroid glucuronide, estradiol-17 beta-(beta-D-glucuronide) (E(2)17G), to inhibit the hepatic clearance (ClH) and biliary secretory rate maximum (SRm) of taurocholate was investigated in the recirculating and single pass isolated perfused male rat liver. In the recirculating perfused liver, E(2)17G (0, 2, 4, or 6 mumol) was added as a bolus dose to the reservoir at zero time while taurocholate was infused into the portal vein in increasing amounts (15, 30, 45, or 60 mumol/mL; 1 mL/hr for 15 min each). E(2)17G (4 mumol) caused a significant (P less than 0.05) inhibition of bile flow and bile acid secretion at 10-15 min during infusion of 15 mumol/hr taurocholate but did not inhibit the SRm which occurred at 42 min, indicating that E(2)17G had not caused an irreversible inhibition of taurocholate transport. E(2)17G (6 mumol) caused a profound and irreversible inhibition of bile flow attributable to retention of E(2)17G in the liver. The noncholestatic estradiol-3-(beta-D-glucuronide) (E(2)3G; 6 mumol) had no significant effect on bile flow or the SRm. In the single pass perfused liver (10 mL/min flow rate), E(2)17G (0, 1, 2, 5, or 10 nmol/mL) or E(2)3G (2 nmol/mL) was added to the perfusate resulting in a stable infusion to the liver. [3H]Taurocholate was infused into the portal vein in increasing amounts to give inflow concentrations (Cin) of 25, 50, 75 or 100 nmol/mL. In the absence of E(2)17G, taurocholate ClH decreased from 0.92 to 0.70 mL/min/g liver with increasing taurocholate concentrations. Neither E(2)17G nor E(2)3G altered the ClH of 25 nmol/mL taurocholate. E(2)17G (10 nmol/mL) inhibited bile flow and bile acid secretion first at 20-25 min, followed by inhibition of ClH of 75 and 100 nmol/mL taurocholate (35-60 min). In contrast, E(2)3G stimulated bile acid secretion and increased the SRm by 80%. Thus, at doses that did not block its own elimination, E(2)17G did not cause an irreversible inhibition of taurocholate transport into bile. E(2)17G did not directly inhibit the uptake of taurocholate into the liver but first inhibited the biliary excretion of taurocholate, resulting in its intrahepatic accumulation and decreased clearance from the perfusate.

Animals↗

Decreased salivary glucose secretory rate: usefulness for detection of diabetic patients with autonomic neuropathy.

In this study we investigated whether the presence of diabetic autonomic neuropathy (DAN) leads to an altered composition of saliva. DAN was evaluated in 33 normal subjects and 31 diabetic patients by means of the Valsalva manoeuvre, R-R variation during deep breathing, heart rate response to standing and lying down and blood pressure response to standing. Salivary flow (ml/h), salivary glucose levels (mumol/l) and salivary glucose secretory rate (mumol/h) were measured in each subject. Twelve diabetic patients were positive for DAN. Salivary flow (13 +/- 2 ml/h) and glucose concentration (330 +/- 50 mumol/l) were not significantly lower in patients with DAN than in normal subjects (18 +/- 2 ml/h, 500 +/- 50 mumol/l) and diabetic patients without DAN (16 +/- 1.9 ml/h, 500 +/- 40 mumol/l). The salivary glucose secretion rate was significantly lower (P less than 0.02) in diabetic patients with DAN (4.2 +/- 1.0 mumol/h) than in normal subjects and diabetic patients without DAN (9.0 +/- 1.0 mumol/h and 8.0 +/- 0.9 mumol/h respectively). The test had a good sensitivity and specificity, and appeared to be particularly indicated in discriminating patients without DAN. It is suggested that the measurement of salivary glucose may represent a simple, quick and inexpensive method for the screening of diabetic autonomic neuropathy.

Adult↗

Elevated growth hormone secretory rate in premature infants: deconvolution analysis of pulsatile growth hormone secretion in the neonate.

Premature infants have higher circulating concentrations of growth hormone (GH) than term infants. Previous investigations of these differences have used sampling frequencies of every 30 min with subsequent application of pulse detection algorithms, such as the CLUSTER program, to assess serum GH pulse parameters. To determine differences in GH secretory rates or GH t1/2 values between premature and term infants, we have sampled 11 neonates at 15-min intervals. We performed deconvolution analysis of the resultant plasma GH values to estimate GH secretory and clearance parameters. Five premature infants (gestational age range 24-34 wk) and six term infants (gestational age range 38-42 wk) were sampled every 15 min for 6 h. All subjects had indwelling arterial catheters. GH was measured (in duplicate) by RIA using 10 microL of plasma. Premature infants had higher secretory burst amplitudes (2.2 +/- 0.13 micrograms/L/min versus 1.4 +/- 0.27 micrograms/L/min, p = 0.02), higher production rates (product of the total number of bursts and the mean mass of GH secreted per burst, 811 +/- 173 micrograms/L/6 h versus 283 +/- 77 micrograms/L/6 h, p = 0.03), and a higher mass of GH per secretory burst (106 +/- 25 micrograms/L versus 38 +/- 11 micrograms/L, p = 0.049) than term infants. The integrated plasma GH concentration exhibited a strong trend toward a higher value in the premature infants (18,100 +/- 800 micrograms/L versus 10,200 +/- 2,700 micrograms/L, p = 0.067).(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗

The influence of taurine on the bile acid maximum secretory rate in the guinea pig.

In view of the effect of taurine feeding on the cholestasis induced by sulfated lithocholate in the guinea pig, it was of interest to explore the influence of taurine on the bile acid secretory maximum (SRm) of chenodeoxycholic acid and of its glycine and taurine conjugates. Bile acid secretory rate measured in response to stepwise increasing rates showed for chenodeoxcholic acid an SRm of 147 +/- 6 nmol/min/g liver and any SRm that was higher (p less than 0.01) for taurine than for glycine (426 +/- 21 versus 327 +/- 24 nmol/min/g liver). Pretreatment for 3 days with taurine 0.5% in drinking water led to a 70% increase of the SRm for chenodeoxycholic acid. Analysis of the biliary bile acids after supplemental taurine demonstrated a large increment of tauroconjugates and no change in the percent of free bile acids or of sulfated forms. Experiments with labeled chenodeoxycholic acid showed no difference in the distribution of radioactivity between total liver, blood, bile, and urine on and off taurine thereby suggesting that neither sinusoidal uptake nor translocation across the cell were factors responsible for the difference in SRm. Inasmuch as taurine feeding increased the SRm for glycine by 30% and for taurine by 25%, it is suggested that taurine augments the canalicular excretion of bile acids that represents the rate-limiting step in the transfer of bile acids from blood into bile through a mechanism that cannot be explained only by a modification of the conjugation pattern.

Animals↗

Tricyclic antidepressant imipramine reduces the insulin secretory rate in islet cells of Wistar albino rats through a calcium antagonistic action.

AIMS/HYPOTHESIS: Treatments with antidepressants have been associated with modifications in glucose homeostasis. The aim of this study was to assess the effect of imipramine, a tricyclic antidepressant, on insulin-secreting cells. METHODS: Insulin radioimmunoassay, radioisotopic, fluorimetric and patch-clamp methods were used to characterise the effects of imipramine on ionic and secretory events in pancreatic islet cells from Wistar albino rats. RESULTS: Imipramine induced a dose-dependent decrease in glucose-stimulated insulin output (IC(50)=5.2 micromol/l). It also provoked a concentration-dependent reduction in (45)Ca outflow from islets perifused in the presence of 16.7 mmol/l glucose. Moreover, imipramine inhibited the increase in (45)Ca outflow mediated by K(+) depolarisation. Patch-clamp recordings further revealed that imipramine provoked a marked and reversible decrease of the inward Ca(2+) current. In single islet cells, imipramine counteracted the rise in [Ca(2+)](i) evoked by glucose or high K(+) concentrations. CONCLUSIONS/INTERPRETATION: These data indicate that imipramine dose-dependently reduces the insulin secretory rate from rat pancreatic beta cells. Such an effect appears to be mediated by the inhibition of voltage-sensitive Ca(2+) channels with subsequent reduction in Ca(2+) entry. Thus, it is possible that some adverse effects of imipramine are related, at least in part, to its capacity to behave as a Ca(2+) entry blocker.

Animals↗

Growth hormone secretory rates in children as estimated by deconvolution analysis of 24-h plasma concentration profiles.

The kinetics of growth-hormone (GH) distribution and elimination was estimated in five GH-deficient children who received 11 intravenous single injections of GH. The plasma disappearance data were analyzed in terms of a two-compartment model. The kinetic parameters obtained were then used in calculating the GH-secretory rate by a numerical deconvolution technique. A simple formula was derived for calculation of the cumulated secretion from the area under the concentration curve of 145 healthy children of various ages, heights, and stages of puberty. The estimated 24-h GH secretion increased with age, corresponding to a two- to fourfold increase during the adolescence period. The highest secretions were found in pubertal stages 3-4. In prepubertal children the heights correlated markedly with the secretion of GH (r = 0.83). Thus an indication of the range of the GH secretion in normal growing children is found, which is important to estimate substitution doses for treatment of GH-deficient children.

Activity Cycles↗

Maximal PTH secretory rate and set point for calcium in normal subjects and patients with primary hyperparathyroidism. In vivo studies.

The characteristics of PTH secretion, which have been extensively studied in vitro with dispersed cells of normal and abnormal parathyroid glands, remain poorly studied in vivo. We performed ethylenediamine tetraacetate (EDTA) intravenous infusions in 12 normal subjects and 5 patients with hypercalcemia (serum ionized calcium between 2.72 and 2.89 mEq/l) and surgically proven primary hyperparathyroidism (PHPT) to establish the relationship between nephrogenous cyclic AMP (NcAMP) used as an index of PTH secretion and serum ionized calcium. We determined the maximal NcAMP taken as an index of maximal secretory rate for PTH, the set point and sensitivity of parathyroid cells for calcium. In normal subjects, mean values (+/- SD) were 4.04 +/- 0.47 nmol/dl glomerular filtrate (GF) for maximal NcAMP, 2.23 +/- 0.04 mEq/l for set point, and -250 +/- 58 for sensitivity when NcAMP was expressed in percent of maximal value and serum calcium in mEq/l. In patients with PHPT, the differences between maximal and basal values of NcAMP represented 50% or more of maximal NcAMP, indicating that PTH secretion was suppressible. Sensitivity values were within normal limits in all patients. Calculated set point values were abnormally elevated (between 2.64 and 2.83 mEq/l) in all patients. Maximal NcAMP values ranged from low to normal (2.77 nmol/dl GF) to abnormally high (6.64 nmol/dl GF), and a positive linear correlation was observed with parathyroid cell mass. Basal serum calcium concentrations were not correlated with either parathyroid cell mass or maximal NcAMP values, and were close to calculated set point values for each patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Increases in salivary lysozyme and IgA concentrations and secretory rates independent of salivary flow rates following viewing of humorous videotape.

Several studies have shown increases in salivary, secretory IgA (sIgA) levels following exposure to humor and various relaxation strategies. However, the use of sIgA as a marker of immunocompetence has been questioned. In this study we investigated the potential of an alternative marker, salivary lysozyme (sLys) in addition to sIgA. sIgA and sLys concentrations and secretion rates were measured from saliva samples collected immediately prior to and alter viewing a humorous (situation comedy) and a control videotape (documentary). sLys concentrations and secretion rates were significantly increased after viewing of the humorous videotape (p = .0007 and p = .009, respectively) but not following viewing of the control video. Similarly, increases were obtained for sIgA (p = .01 and p = .05) following viewing of the humorous tape. sIgA concentration decreased following viewing of the control tape (p = .05). Salivary flow rates did not significantly change following the viewing of either the humorous or the control tapes. Changes following the humorous video were significantly different from changes following the control video for both sLys and sIgA levels (concentration, p = .007 and p = .005; secretory rate p = .02 and p = .03), but not for salivary flow rates. The results suggest an enhancement of the innate and specific mucosal immune parameters following exposure to humor, independent of salivary flow. Use of sLys may serve as a useful additional or alternative marker of the effects of humor on mucosal immunity.

Journal Article↗