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PubMed1993

Postsomatostatin hypersecretion of growth hormone from perifused rat anterior pituitary cells is dependent on calcium influx.

The role of ionic calcium (Ca2+) in the rebound secretion of growth hormone (GH) following termination of somatostatin (SRIF) administration was investigated in vitro by perifusion of acutely dispersed rat anterior pituitary cells. Treatment with 10 nM SRIF for 40 min significantly reduced the mean GH secretory rate by 3.3 +/- 0.2 ng min-1 representing a 58% decrease from baseline (p < 0.01). Following the withdrawal of SRIF treatment, GH levels surged 3- to 5-fold relative to baseline with the mean secretion rate increasing by 4.5 +/- 0.99 ng min-1 (p < 0.05). GH rebound secretion following SRIF removal from the perifusion medium was completely abolished (p < 0.01) when zero calcium medium (0 Ca2+) or medium containing 2 mM cobalt chloride (Co2+) were administered after SRIF termination. Perifusion with 0 Ca2+ caused the GH release rate to return to above baseline levels. In contrast, Co2+ perifusion caused the GH secretion rate to remain at the level observed during SRIF treatment (-4.52 +/- 0.38 ng min-1 relative to baseline; p < 0.01). Similarly, when cells were exposed to Co2+ alone, a reduction in the rate of GH secretion (-3.96 +/- 0.56 ng min-1; p < 0.01) was evident. After termination of Co2+ treatment, either by itself or following SRIF pretreatment, and upon changing from 0 Ca2+ to normal calcium-containing medium following SRIF pretreatment, a significant overshoot in GH release similar to SRIF withdrawal-induced GH release was observed (p < 0.05 and 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Mechanisms of altered prolactin secretion due to the administration of interleukin-1 beta into the brain ventricles of the rat.

The ability of the intracerebroventricular (icv) injection of interleukin-1 beta (IL-1 beta) to alter plasma prolactin (PRL) levels in rats remains controversial, with reports of increases, decreases, or no changes in secretory rate. These discordant results may reflect, at least in part, the use of different doses of cytokines, as well as a gender specificity in the response of the brain circuits that control PRL release. In a first series of experiments, we investigated the effect of one acute icv injection of IL-1 beta to alter PRL secretion in intact male and female rats. Using this paradigm, we also determined the potential modulating role of secretagogues reportedly released by IL-1 beta, such as dopamine, corticosterone and progesterone. A second series of experiments involved the long-term (3-5 days) i.c.v. infusion of IL-1 beta to identify the influence of gender on the pattern of PRL release. The acute icv injection of IL-1 beta (5-50 ng) to intact adult males or females caused comparable and significant (p < 0.01) decreases in plasma PRL levels 1-5.5 h after treatment. At the 8 h time point PRL secretion started to increase in females exposed to the cytokine, while PRL values of males were comparable in vehicle- and IL-1-injected rats. In intact males, blockade of pituitary dopamine receptors with domperidone (3.5 mg/kg) did not reverse the inhibitory effect of the immune protein. In either gender, blockade of IL-1-induced corticosterone and adrenal progesterone release with CRF antibodies was also without effect on PRL secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Changes in salt intake alter the release of multiple renin species in a nonuniform manner.

Six distinct forms of renin were found to be released from rat renal cortical slices incubated in vitro. The multiple renin forms were demonstrated using shallow gradient isoelectric focusing, and focused at pH 5.7, 5.55, 5.3, 5.15, 4.9 and 4.8. Before renal cortical slices were prepared, rats were given free access to both high- and low-salt diets containing, respectively, 0.2 or 0.005 mEq Na+/g food. Renal cortical slices prepared from rats maintained on the high-salt diet for 8 days (group I) released significantly different proportions of the six renin forms as well as less total renin when compared to rats first maintained on the high-salt diet for 8 days followed by the low-salt diet for 8 additional days (group II). In a second series of experiments, renal cortical slices prepared from rats maintained on the low-salt diet for 19 days (group III) secreted significantly different proportions of the six renin forms, as well as more total renin when compared to rats first maintained on the low-salt diet for 10 days, followed by the high-salt diet for 4 additional days (group IV). These studies demonstrate that the relative proportions of released multiple renin forms change when the kidney alters its renin secretory rate in response to changes in Na+ intake.

Animals↗
PubMedDate not supplied

Ca2+ antagonists and db-cAMP sustain a rise in renal blood flow induced by acetylcholine in indomethacin-treated dogs.

Renal arterial infusion of acetylcholine (ACh) in the dog normally produces a sustained rise in sodium excretion (UNaV) and in renal plasma flow (RPF). When prostaglandin (PG) synthesis is inhibited, ACh induces only a transient increase in UNaV and RPF followed by a progressive decline in UNaV and RPF, and a rise in renin secretory rate (RSR). Renal arterial infusion of PGE2 but not a vasodilator such as bradykinin restored the response to ACh to normal in indomethacin (Indo)-treated dogs. During renal arterial infusion of dibutyryl cyclic AMP (6 mg/min), ACh also produced a sustained increase in UNaV and RPF despite an inhibition of PG synthesis by Indo. Renal arterial infusion of verapamil (60 micrograms/min) or diltiazem (60 micrograms/min) also prevented the subsequent fall in RPF when ACh was infused; RSR, however, did not show a rise. The results suggest that synthesis of PGE2 with stimulation of cAMP is required for sustained ACh action. When PGE synthesis is inhibited, ACh may produce renal vasoconstriction by increasing intracellular Ca2+ concentration. The partial effect of calcium channel blockers suggests that release of calcium from intracellular stores as well as calcium entry may mediate the response.

Acetylcholine↗
PubMed1986

Characteristics of insulin and glucagon release from the perfused pancreas, intact isolated islets, and dispersed islet cells.

There are a variety of different tissue preparations which have been used to study secretion from the endocrine pancreas and there are considerable differences in the results obtained from these. The purpose of this study was to compare several preparations in one laboratory using the same rats, buffers, and radioimmunoassays. The preparations included the isolated perfused rat pancreas, fresh isolated intact islets and dispersed cells, and cultured islets and cells. Insulin release from the perfused rat pancreas at 2.8 mM glucose was so low that it could not be measured, such that over a 90-min time period the amount of insulin released was less than 0.004% of pancreatic insulin content. In contrast, islets in static incubation appear to release 2.0% of their stored content and dispersed cells appear to release 2.6% of their content. Samples were taken at early time points during incubations of fresh islets and dispersed cells, and it was found that almost all of the insulin found at the end of a 90-min incubation period was present during the first 5 min. It is therefore suspected that the true secretory rate of insulin at a low glucose concentration is far lower than had been generally appreciated. Glucagon release patterns showed similarities in that with isolated islets and dispersed cells a disproportionate amount of glucagon release was found during a 0- to 30-min incubation period when compared with the 30- to 90-min period. In summary, artifacts have been identified in some of the in vitro systems used for the study of endocrine pancreatic secretion and these deserve greater recognition.

Animals↗
PubMed1991

Growth progression and 24-hour hormone profile in an infant treated chronically with a long-acting somatostatin derivative.

The diagnosis of nesidioblastosis was established in a 9-month-old male child with a history of recurrent convulsive seizures and hypoglycemia. After unsuccessful subtotal pancreatectomy, treatment was started with the long-acting somatostatin derivative Sandostatin (Octreotide, Sandoz) at a dosage of 25 micrograms t.i.d. spaced between carbohydrate-enriched meals. With this regime, blood glucose was maintained at the low normal range and seizures ceased. During a 30-month observation period, growth velocity and weight progression were well within the predicted limits. A 24-hour hormone profile recorded at the end of the observation period revealed the following: (1) failure to improve blood glucose with carbohydrate-enriched food due to reactive hyperinsulinemia; (2) hyperglycemic reaction after administration of Sandostatin caused by a reduction of plasma insulin; this effect was particularly marked during sleep; (3) low mean GH, decreased spiking frequency and reduced area covered by the nocturnal peaks by recognized standards, and (4) normal somatomedin C levels for age. Interpretation of growth hormone (GH) data is hindered by the lack of pertinent information from the patient's age group. Recording of normal growth progression in the case illustrated here can only be explained by the capability of a reduced GH secretory rate to maintain full biological activity as shown by the normal plasma level of somatomedin C. Indeed, recent evidence has been provided elsewhere for normal growth progression in the presence of low GH secretion, although other factors unrelated to this hormone may also be operative at this early age. Further reports concerning the treatment of non-GH-dependent conditions with somatostatin derivatives will certainly contribute to the better understanding of the mechanisms governing growth in the postnatal period.

Blood Glucose↗
PubMed1976

Mineralocorticoid secretion in essential hypertension with normal and low plasma renin activity.

In 19 control subjects, 33 patients with essential hypertension and normal plasma renin activity (PRA) and 11 patients with low PRA, secretory rates of 18-hydroxy-11-deoxy-corticosterone (18-OH DOC), 11-deoxycorticosterone (DOC) and corticosterone were measured. Patients with low PRA were significantly older and had higher arterial pressure and slightly lower plasma potassium levels than patients with normal PRA. Mean 18-OH DOC secretion rate was higher in patients with normal PRA (603 +/- 112 SEM mug/24 hr) than in control subjects (219 +/- 19) and considerably higher (P less than 0.001) in patients with low PRA (1800 +/- 472). DOC and corticosterone secretion rates were within normal limits in most hypertensive patients. Plasma aldosterone was significantly higher in the hypertensive population than in control subjects whereas no significant difference was observed between the low- and normal-renin groups. A significant (P less than 0.01) mutual positive correlation was found between the secretion rates of 18-OH DOC, DOC and corticosterone in patients with low plasma renin activity. In contrast, there was no correlation between the secretion rates of the three mineralocorticoids in control subjects and patients with normal plasma renin activity. These data suggest a biosynthetic variation of the mineralocorticoid pathways in essential hypertension.

18-Hydroxycorticosterone↗
PubMed1994

Evidence of abnormalities in corticosteroid secretion leading to volume-dependent hypertension in Milan rats.

We examined corticosteroid secretory patterns and their relation to altered salt and water metabolism in Milan hypertensive and normotensive rats. Hypertensive rats had significantly higher blood pressures, exchangeable sodium (hypertensive, 41.2 +/- 0.3 mmol.kg-1; normotensive, 38.4 +/- 0.03 mmol.kg-1, P < .001), plasma volume (hypertensive, 5.39 +/- 0.12 mL.100 g-1; normotensive, 4.84 +/- 0.10 mL.100 g-1, P < .001), and plasma concentrations of atrial natriuretic peptide (hypertensive, 38.8 +/- 4.0 pg.mL-1, normotensive, 22.4 +/- 3.1 pg.mL-1, P < .02). These features coincide with those of mineralocorticoid-induced hypertension. Adrenal venous secretory rates (picomoles per minute) of corticosterone (hypertensive, 1696 +/- 202; normotensive, 873 +/- 139), 18-hydroxycorticosterone (hypertensive, 49.7 +/- 8.3; normotensive, 25.7 +/- 3.3), and aldosterone (hypertensive, 1.16 +/- 0.17; normotensive, 0.52 +/- 0.08) were higher in the hypertensive than the normotensive strain, but that of 11-deoxycorticosterone (DOC) (hypertensive, 94.4 +/- 14.9; normotensive, 114.3 +/- 33.9) was similar in the two strains. The corticosterone-DOC, 18-hydroxycorticosterone-DOC, and aldosterone-DOC ratios were higher in the hypertensive than the normotensive strain (P < .02), but the 18-hydroxycorticosterone-corticosterone and aldosterone-18-hydroxycorticosterone ratios were not. These results indicate increased activity of the "late" aldosterone biosynthetic pathway in the hypertensive compared with the normotensive strain caused by an increased conversion rate of DOC to corticosterone. The comparison of corticosterone secretion between the two strains indicates that 11 beta-hydroxylase rather than aldosterone synthase activity is more active in the hypertensive than the normotensive rats.

18-Hydroxycorticosterone↗
PubMed1976

The role of angiotensins in aldosterone production.

The hypothesis that the COOH-terminal heptapeptide mediates the aldosterone-stimulating activity of angiotensin II was evaluated by comparing the relative effects on aldosterone production of angiotensin II and the heptapeptide to angiotensin analogues that are poorly metabolized to the heptapeptide and to a nonapeptide, des-Asp-1-angiotensin I, that is directly converted to the heptapeptide. In in vivo studies utilizing the adrenocorticotropic hormone-suppressed bilaterally nephrectomized dog, angiotensin II and the heptapeptide produced statistically significant increases in both aldosterone and cortisol secretory rates (P less than 0.001 for both relations). Sar-1-angiotensin II stimulated the production of both steroids to the same extent, but had much longer duration of action. [Poly(oAc)Seryl]angiotensin II was a weak agonist, having only about 30% of the steroidogenic potency of either angiotensin II or the heptapeptide. In equimolar concentrations des-Asp-1-angiotensin I had about one-half of the aldosterone-stimulating activity of the hepatpeptide. In in vitro studies, employing the trypsin-dispersed cat adrenal zona glomerulosa cells, the steroidogenic potency of angiotensin II and the heptapeptide was identical to maximal aldosterone production of 10(-8) M peptide concentration. By contrast, the response to Sar-1-angiotensin II was approximately a 10-fold increase in relative potency, while the response to [poly(oAc)Seryl]angiotensin II demonstrated a 10-fold decrease. These findings suggest that, although the heptapeptide may play an important role in the regulation of aldosterone production, the possibility remains open that angiotensin II could stimulate aldosterone biosynthesis without prior conversion to the heptapeptide.

Adrenal Cortex↗
PubMed1992

Permeability of rat atrial endocardium, epicardium, and myocardium to large molecules. Stretch-dependent effects.

Atrial distension, which stimulates atrial natriuretic peptide secretion by atrial myocytes, also stretches nonmuscle cells. In a noncontracting in vitro preparation of combined right and left atria we demonstrated by electron microscopy that, at 37 degrees C, transition from zero pressure to a physiological distending pressure of 5.1 mm Hg rapidly rendered atrial endocardial endothelium permeable to the macromolecular probes horseradish peroxidase (HRP; M(r), approximately 40,000) and wheat germ agglutinin-HRP (M(r), approximately 70,000); each probe was introduced at the atrial cavitary endocardial surface. Stretch-dependent permeabilization was also demonstrable in spontaneously contracting atria, was reversed by removing the distending pressure, and was unaffected by varying external Ca2+ concentration from 0.2 to 1.4 mM or by experimental perturbations that markedly decrease ANP secretory rates. Although transendocardial HRP and wheat germ agglutinin-HRP passage required stretch, native ferritin (M(r), = 500,000) could traverse unstretched endocardium. Probes were detected in noncoated endocardial vesicles and intercellular junctions between endocardial cells, but the relative contributions of vesicular transcytosis and paracellular diffusion could not be determined. Although HRP entered plasmalemmal caveolae of myocytes in stretched atria, myocytes did not internalize HRP by fluid-phase endocytosis. Distending pressure also caused apparent flow reversal in thebesian blood vessels, with retrograde transfer of HRP across the endocardium into the myocardium. HRP and ferritin presented at the external surface of the epicardium (visceral pericardium) were endocytosed by mesothelial cells, entered junctions between mesothelial cells, and readily crossed the epicardium of both stretched and unstretched preparations.

Animals↗
PubMed1996

Hypothalamic-pituitary-adrenal axis in corticosteroid-resistant bronchial asthma.

We have examined whether the lack of clinical response to corticosteroids seen in corticosteroid resistant (CR) bronchial asthma is reflected in abnormalities of endogenous cortisol secretion and in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in CR subjects by using a modification of the standard dexamethasone suppression test (DST) in response to 0.25 and 1 mg oral dexamethasone. Five corticosteroid-sensitive (CS) and five CR asthmatic subjects were studied on two occasions 1 mo apart. In the first limb of the study subjects received 0.25 mg of oral dexamethasone, and in the second limb they received 1 mg. Urinary cortisol was measured by fluorimetry after extraction, and plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations were estimated by enzyme-linked immunosorbent assay (ELISA) and immunoradiometric assays, respectively. On Day 1, a 24-h urine sample was collected for estimation of urinary free cortisol. On Day 2, a fasting blood sample was taken at 9:00 A.M. for estimation of plasma cortisol and ACTH. At 11:00 P.M., 0.25 mg (1 mg) of dexamethasone was taken orally by each subject. On Day 3, blood was taken at 9:00 A.M. and 3:00 P.M. for similar estimations. The levels of urinary free cortisol (nmol/24 h) and predose plasma ACTH (ng/L) and cortisol (nmol/L) were 199 +/- 42, 27.4 +/- 5.7, and 300 +/- 48 (mean +/- SEM), respectively, in the CS group, and 210 +/- 74, 23.4 +/- 6.7, and 263 +/- 32 (mean +/- SEM), respectively, in the CR group (p > 0.05 for all comparisons). Plasma ACTH and cortisol concentrations were not significantly suppressed in either group after 0.25 mg dexamethasone, but were equally suppressed in both groups to undetectable levels by 1 mg dexamethasone. We conclude that CR asthma is not reflected in an altered secretory rate of endogenous cortisol or in an altered sensitivity of the HPA axis to dexamethasone suppression.

Adrenocorticotropic Hormone↗
PubMed1971

Abnormal membrane sodium transport in Liddle's syndrome.

We have documented the presence of abnormal sodium transport in Liddle's syndrome by measuring sodium concentration, sodium influx, and fractional sodium outflux in vitro in erythrocytes from normal subjects, two patients with Liddle's syndrome, and one patient with primary hyperaldosteronism. Sodium influx and fractional sodium outflux, but not sodium concentration, were significantly increased in patients with Liddle's syndrome. Sodium outflux in a patient with primary hyperaldosteronism did not differ significantly from normal. These alterations of sodium transport in erythrocytes from patients with Liddle's syndrome were not attributable to circulating levels of aldosterone, renin, angiotensin, or serum potassium. Furthermore, changes in aldosterone secretory rate and levels of circulating renin produced by varying dietary sodium intake, did not alter sodium influx or fractional sodium outflux in either patients with Liddle's syndrome or normal subjects. The response of fractional sodium outflux and sodium influx to ouabain, ethacrynic acid, and to changes in the cation composition of the incubation medium suggests that the increased sodium fluxes in Liddle's syndrome do not result solely from a quantitative increase in those components of sodium transport which occur in normal human erythrocytes. Instead, at least a portion of the increased erythrocyte sodium transport in Liddle's syndrome represents a component of sodium transport which does not occur in normal human erythrocytes.

Adolescent↗
PubMed1979

Mechanisms of renin secretion during hemorrhage in the dog.

The importance of renal perfusion pressure (RPP), the sympathetic beta adrenergic nervous system and renal prostaglandins (PG) on renin release during a uniform 15-17% reduction in blood pressure by hemorrhage (HH) was studied systematically in anesthetized dogs. All groups of animals had similar decrements in systemic and renal hemodynamics with HH. In control dogs (n = 7), both plasma renin activity (PRA, 4.1-9.0 ng angiotensin I/ml per h, P < 0.05) and renin secretory rate (RSR, 26-228 ng/ml per h.min, P < 0.005) increased significantly with HH. This increase in renin release during HH was not abolished by any single maneuver alone including beta adrenergic blockade with d,l-propranolol (n = 6), renal PG inhibition with indomethacin (n = 7), or control of RPP (n = 6). However, when beta adrenergic blockade was combined with control of RPP (n = 7) during HH, neither PRA (1.9-2.7 ng/ml per h, NS) nor RSR (16-53 ng/ml per h.min, NS) increased significantly. Similarly, a combination of beta adrenergic blockade and PG inhibition (n = 6) also abolished the increase in PRA (1.5-1.4 ng/ml per h, NS) and RSR (14-55 ng/ml per h.min, NS) during HH despite significant decreases in sodium excretion. Finally, a combination of PG inhibition and RPP control was associated with significant increases in PRA and RSR during HH. These results support a multifactorial mechanism in renin release during HH and implicate both the beta adrenergic receptors, renal baroreceptors, and possibly the macula densa as constituting the primary pathways of renin release during HH of this magnitude. Because either constant RPP or PG inhibition blunted renin release during HH in the setting of beta adrenergic blockade, the present results strongly suggest that the renal baroreceptor, and probably the macula densa mechanism are PG mediated.

Animals↗
PubMed1979

Functional profile of the isolated uremic nephron: potassium adaptation in the rabbit cortical collecting tubule.

As a renal function declines in patients and experimental animals with chronic renal disease, potassium homeostasis is maintained by a progressive increase in potassium secretion by the surviving nephrons, a phenomenon known as potassium adaptation. To determine the nephron site and the underlying mechanisms responsible for this phenomenon, studies were performed on normal and 75% nephrectomized rabbits maintained on normal or high-potassium diets. Cortical collecting tubules (CCT) were dissected from the normal and remnant kidneys and perfused in vitro in an artificial solution. In normal CCT mean (+/- SE) net K secretion, JK, (peq/cm per s) was 1.26 +/- 0.43 (normal diet) and 3.27 +/- 0.66 (high-K diet). In uremic CCT, JK was 3.55 +/- 0.60 (normal diet) and 6.83 +/- 0.58 (high-K diet). By reducing the dietary intake of potassium in proportion to the reduction of renal mass in these uremic animals, the adaptation in K secretion was prevented (JK: 1.22 +/- 0.40). Transepithelial potential difference was similar in CCT from normal and uremic animals on a normal diet despite the fact that JK was significantly greater in the latter group. However, in both normal and uremic CCT, the increase in JK caused by potassium loading was associated with an increase in luminal negativity. Uremic CCT underwent significant compensatory hypertrophy regardless of the dietary intake or potassium secretory rates. Plasma aldosterone levels were elevated only in the uremic-high potassium rabbits suggesting that a mineralocorticoid effect on the CCT may be exaggerated when potassium loading is superimposed upon decreased excretory capacity. The activity of Na-K ATPase was comparable in normal and uremic CCT from rabbits on either normal or high-K diets indicating that potassium adaptation may occur independently of changes in the activity of this enzyme. Intracellular potassium content measured chemically and by 42K exchange, was not significantly altered in either normal or uremic CCT when dietary potassium intake was increased, despite the fact the JK was increased under these circumstances. These data indicate that the CCT is an important site of potassium adaptation in the surviving nephrons of animals with reduced renal mass. This adaptation is an intrinsic property of the CCT and is expressed in the absence of a uremic milieu. Potassium adaptation by the uremic CCT is not fixed according to the degree of compensatory hypertrophy but varies according to the excretory requirements of the animal. Transepithelial potential difference and circulating aldosterone levels contribute to the adaptation but neither factor can entirely account for the phenomenon. Potassium adaptation by the CCT occurs in the absence of changes in Na-K ATPase activity and intracellular potassium content.

Animals↗
PubMed1983

Tolbutamide perifusion of rat islets. Sequential changes in calcium, phosphorus, sodium, potassium, and chlorine in single beta cells.

Fluctuations of calcium, phosphorus, sodium, potassium, and chlorine in beta cells were followed during rat islet perifusion with tolbutamide and related to insulin secretion. In 24 paired experiments two chambers containing 100 islets were perifused with buffered medium containing 4.2 mM glucose alone or with added tolbutamide (200 micrograms/ml). Effluent was collected frequently for insulin determinations. At eight different time intervals from 0 to 20 min islets were acutely fixed, prepared for scanning electron microscopy and beta cells in islet tissue were identified. Element content in 480 single cells was measured by energy dispersive x-ray analysis. Tolbutamide elicited typical monophasic insulin release that exceeded control islet secretory rates from 2 to 6 min with a peak value at 3 min. This pattern was preceded by monophasic calcium accumulation in beta cells that abruptly rose 150% above control cells at 1 min and declined to base line by 4 min. The rapid ascent of calcium was associated with significant depressions of sodium and potassium content without alterations of cell phosphorus. Chlorine fell at 2 min and then rose greater than 50% above control cells at 4 min. After 6 min insulin secretion and element content remained near control levels. We conclude that monophasic calcium accumulation in beta cells is the earliest, most predictive event of islet insulin secretion after a tolbutamide stimulus. Oscillations of beta cell sodium and potassium reciprocally relate to calcium, and an elevation of chlorine content is a relatively late phenomenon in the stimulus-secretion coupling process.

Animals↗
PubMed1984

Plasma growth hormone responses to constant infusions of human pancreatic growth hormone releasing factor. Intermittent secretion or response attenuation.

Administration of human pancreatic tumor growth hormone (GH) releasing factor (hpGRF[1-40]) as a single injection to normal human subjects stimulates the secretion of GH in a dose-responsive manner. In the present studies, hpGRF(1-40) was infused in a graded stepwise manner over a 6-h period in order to determine whether the GH secretory response would be sustained. Normal adult males received four consecutive 90-min infusions of hpGRF(1-40) at doses of 1, 3.3, 10, and 33 ng/kg per min, preceded and followed by a 90-min saline infusion; and the plasma GH responses were compared with those during a separate control infusion. Plasma GH levels were significantly elevated by each hpGRF(1-40) infusion; and dose responsiveness was evident for the lowest three doses. Mean integrated GH secretory rates for the four doses were 1.95, 3.29, 4.29, and 3.65 times those of the respective control study. Plasma GH responses exhibited considerable variability, frequently decreasing during the latter part of each infusion; and at the highest dose, they decreased continuously beginning shortly after the onset of infusion. Episodic GH secretion occurred in individual subjects during each of the infusion periods. The possible contribution of hypothalamic somatostatin secretion to the diminished GH responsiveness was evaluated by determining plasma thyroid stimulating hormone (TSH) levels during the infusions and the TSH responses to thyrotropin-releasing hormone (500 micrograms i.v.) during a separate hpGRF(1-40) infusion of 2 ng/kg per min. Neither basal nor stimulated TSH levels differed between GRF-infused and control groups. The results indicate that GH secretion is dose responsive to hpGRF(1-40) infusions, though the response to hpGRF(1-40) infusions, though the response is complex. The absence of impaired TSH secretion provides evidence against a mediating role of somatostatin. The explanation for the loss of GH responsiveness remains undetermined but could include GRF-induced receptor down-regulation, a postreceptor effect, or, in spite of our negative results, a somatostatin-mediated inhibition.

Adult↗
PubMed1995

Ethanol impairs post-prandial hepatic protein metabolism.

The effects of acute ethanol ingestion on whole body and hepatic protein metabolism in humans are not known. To simulate social drinking, we compared the effects of the association of a mixed meal (632 kcal, 17% amino acids, 50% glucose, 33% lipids) with a bottle of either table wine (ethanol content 71 g) or water on the estimates ([1-14C]-leucine infusion) of whole body protein breakdown, oxidation, and synthesis, and on the intravascular fractional secretory rates (FSR) of hepatically (albumin, fibrinogen) and extrahepatically (IgG) synthesized plasma proteins in two randomized groups (ethanol n = 7, water n = 7) of healthy nonalcoholic volunteers. Each study was carried out for 8 h. Protein kinetics were measured in the overnight post-absorptive state, over the first 4 h, and during a meal infusion (via a nasogastric feeding tube at constant rate) combined with the oral ingestion of wine or water, over the last 4 h. When compared with water, wine ingestion during the meal reduced (P < 0.03) by 24% the rate of leucine oxidation, did not modify the estimates of whole body protein breakdown and synthesis, reduced (P < 0.01) by approximately 30% the FSR of albumin and fibrinogen, but did not affect IgG FSR. In conclusion, 70 g of ethanol, an amount usual among social drinkers, impairs hepatic protein metabolism. The habitual consumption of such amounts by reducing the synthesis and/or secretion of hepatic proteins might lead to the progressive development of liver injury and to hypoalbuminemia also in the absence of protein malnutrition.

Blood Glucose↗
PubMed2001

5-hydroxytryptamine strongly inhibits fluid secretion in guinea pig pancreatic duct cells.

We studied the distribution of 5-hydroxytryptamine- (5-HT-) containing cells in the guinea pig pancreas and examined the effects of 5-HT on fluid secretion by interlobular pancreatic ducts. The 5-HT-immunoreactive cells with morphological characteristics of enterochromaffin (EC) cells were scattered throughout the duct system and were enriched in islets of Langerhans. The fluid secretory rate in the isolated interlobular ducts was measured by videomicroscopy. Basolateral applications of 5-HT strongly but reversibly reduced HCO(3)-dependent, as well as secretin- and acetylcholine- (ACh-) stimulated, fluid secretion, whereas 5-HT applied into the lumen had no such effects. Secretin-stimulated fluid secretion could be inhibited by a 5-HT(3) receptor agonist, but not by agonists of the 5-HT(1), 5-HT(2), or 5-HT(4) receptors. Under the stimulation with secretin, 5-HT decreased the intracellular pH (pH(i)) and reduced the rate of pH(i) recovery after acid loading with NH(4)(+), suggesting that 5-HT inhibits the intracellular accumulation of HCO3(-). The elevation of intraductal pressure in vivo reduced secretin-stimulated fluid secretion, an effect that could be attenuated by a 5-HT(3) receptor antagonist. Thus, 5-HT, acting through basolateral 5-HT(3) receptors, strongly inhibits spontaneous, secretin-, and ACh-stimulated fluid secretion by guinea pig pancreatic ducts. 5-HT released from pancreatic ductal EC cells on elevation of the intraductal pressure may regulate fluid secretion of neighboring duct cells in a paracrine fashion.

Acetylcholine↗