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PubMed1980

Micropipette measurement of airway submucosal gland secretion: laryngeal reflex.

We used our microcollection technique to study the effect of mechanical stimulationof the larynx on tracheobrochial gland secretion. The basal secretory rate of 8 glands in 5 cats rose from 18.6 +/- 2.0 nl/min (mean +/- SE) to a maximum of 47.8 +/- 4.0 nl/min within 1 min of mechanical stimulationof the laryngeal mucosa(p < 0.005) and returned to prestimulation levels within 4 to 5 min after cessation of the stimulus. The effect of laryngeal stimulation on gland secretion was prevented by cooling both cerevical vagi to - 3 degrees C before and during stimulation, and was restored by warming both vagito 37 degrees C before stimulaltion. Atropine sulfate (0.5 mg/kg given intravaenously) also prevented the secretory response to laryngeal stimulation. Transsection of the sensory nerves to the larynx blocked this response as well. Electrical stimulation (7 V, 20 Hz, 15 s) of the central end of the cut superior layyngeal nerve increased the rate of secretion of 6 glands in 5 cats from 10.0 +/- 2.0 nl/min to 26.0 +/- 3.0 nl/min (p < 0.01); atropine also prevented this effect.

Animals↗
PubMed1996

Initial transient phase of salivary secretion by the submandibular glands of rats under anoxic conditions.

Salivary secretion of the rat submandibular gland exhibits two phases upon administration of acetylcholine (ACh, 10(-6) M): an immediate initial transient phase of rapid secretion lasting 5 min followed by a longer steady phase of slower secretion. Application of an anoxic perfusate bubbled with 100% N2 for 10-20 min had no effect on the initial phase of secretion, but caused a marked decrease in secretion in the steady phase following stimulation with 10(-6) M ACh. After secretion under the anoxic condition, a recovery period without stimulation was performed for 30 min by perfusion with HEPES Ringer's solution bubbled with 100% O2 and containing various potassium concentrations. The initial secretion rate measured with application of an anoxic perfusate was markedly increased by the high-K+ recovery perfusate (25 mM) and decreased by the K(+)-free recovery perfusate. Administration of 10(-3) M ouabain in the normal perfusate resulted in inhibition of secretion during the steady phase similar to that seen under the anoxic condition, while the secretory rate during the initial phase remained unchanged. We concluded that the initial phase of secretion is relatively resistant to anoxia, and that oxygen supply and Na(+)-K+ pump activity were essential for maintaining the steady phase of secretion.

Acetylcholine↗
PubMed1982

Regulation of intestinal goblet cell secretion. II. A survey of potential secretagogues.

The factors that regulate the rate of mucus secretion in intestinal goblet cells are only partially defined. Autoradiographic and ultrastructural studies demonstrated that muscarinic cholinergic agents accelerate the exocytosis of mucus from goblet cells in the crypts throughout the small and large intestine, both in vivo and in mucosal organ culture. The present study seeks to identify other factors that may alter mucous secretory rates. Mucosal explants were exposed to potential secretagogues and inhibitors in the organ-culture system and analyzed by light and electron microscopy, alpha- and beta-Adrenergic agents, gastrointestinal regulatory peptides, serotonin, histamine, and dibutyryl cyclic nucleotides were tested over wide concentration ranges. With the exception of histamine, none of these agents accelerated or inhibited the exocytosis of mucous granules. Histamine was effective at the concentration of 10(-4) M and induced rapid, compound exocytosis by crypt goblet cells in mucosal explants from the colon but not from small intestine. The response to histamine was unaffected by atropine. Goblet cells on the mucosal surface released mucus by compound exocytosis when exposed to mustard oil, a nonspecific chemical irritant, but not when exposed to histamine or cholinergic agents.

Acetylcholine↗
PubMed1981

Correlation of urinary excretion of C-peptide with the integrated concentration and secretion rate of insulin.

The secretion rate of insulin (SR-I) of 50 normal subjects was calculated from the 24-h integrated concentration of insulin (IC-I), the peripheral metabolic clearance of insulin (pMCR-I), and the mean fractional hepatic insulin extraction (fhMCR-I) that was derived from our data. fhMCR-I was determined as the difference in the molar secretory rate of C-peptide (SR-C) and the molar peripheral clearance of insulin (pMCR-I x IC-I) divided by SR-C. The IC-I in our 50 subjects was 1.19 +/- 0.38 ng/ml and the IC-C was 2.93 +/- 0.58 ng/ml. Based on these data, the fhMCR-I was 0.40 and the Sr-I was estimated to be 54.8 +/- 18.0 U/24 h. The 24-h urinary C-peptide excretion (U-C), 44.9 +/- 20.4 micrograms/24 h, had a statistically significant correlation with SR-I (r = 0.838, P less than 0.0001), while the IC-I correlated significantly with the 24-h urinary C-peptide/g of creatinine (r = 0.838, P less than 0.0001). The U-C may thus serve as a practical method for estimating the SR-I.

Adolescent↗
PubMed1983

Abnormal regulation of parathyroid cell secretion and proliferation in primary cultures of bovine parathyroid cells.

We developed a method for establishing primary monolayer cultures of bovine parathyroid cells, characterized the cells morphologically, and studied the effects of calcium on PTH secretion and cellular proliferation. Fresh bovine parathyroid glands were enzymatically and mechanically dispersed, as previously described, using sterile solutions and apparatus. The cells were then plated at a density of 2.5 X 10(5) cells/cm2 into cluster wells and incubated at 37 C in a medium containing Dulbecco's Modified Eagle's and Ham's F-12 medium, 15% newborn calf serum, Hepes, antibiotics, and insulin. In 3-4 days, a near-confluent monolayer of polygonal-shaped cells with less than 10% fibroblasts was achieved. Electron microscopy revealed a homogeneous cell population containing electron-dense secretory granules as well as abundant rough endoplasmic reticulum and mitochondria, with no evidence of organelle swelling. Two parameters of cellular proliferation increased significantly in culture; viable cell number increased from 289,000 +/- 63,000 to 530,000 +/- 60,000 per well (P less than 0.02), and cellular protein increased from 40.00 +/- 1.40 to 177.60 +/- 57.10 micrograms/well (P less than 0.035). On an hourly basis, cultured cells showed a greater secretory rate than that of acutely dispersed cells (9.3 vs. 5.0 ng/10(5) cells X h, respectively). Unlike normal bovine parathyroid cells, however, high calcium concentrations inhibited PTH secretion only slightly (21.2 +/- 4.7%) and had no effect on cellular proliferation. Addition of the divalent cation ionophore A23187, on the other hand, inhibited PTH release by 50% or more, suggesting that the secretory apparatus is responsive to increases in the cytosolic calcium concentration. The present study reveals that bovine parathyroid cells in primary culture proliferate and secrete PTH in vitro. These cells display, however, a generalized decrease in sensitivity to the suppressive effects of extracellular calcium on hormonal secretion and cellular proliferation comparable to that of pathological parathyroid tissue. Thus, this cell culture system may provide a useful model for investigating the relationship between secretion and proliferation in normal and abnormal tissue.

Animals↗
PubMed1982

Potassium stimulates parathyroid hormone release from perifused parathyroid cells.

A method for perifusing dispersed bovine parathyroid cells is described. Using this approach, we have studied the effects of raised extracellular potassium and ouabain on calcium-regulated parathyroid hormone (PTH) secretion in vitro. Decreasing calcium from 1.5 to 0.5 mM stimulated PTH release within 5-10 min, and the increased secretory rate was maintained for the duration of the low calcium administration. High potassium (60 mM) promptly stimulated PTH secretion at 1.5 mM calcium. The effect of high potassium was more transient than that of low calcium. Raised potassium significantly enhanced the response to 0.5 mM calcium. Ouabain (10(-3) M) had no significant effect at 1.5 mM calcium, but depressed the secretory response to 0.5 mM calcium. In conclusion, the effect of raised potassium on parathyroid cells is qualitatively similar to its effect on other endocrine and exocrine systems.

Animals↗
PubMed1990

Functional and morphological changes in the eccrine sweat gland with heat acclimation.

Three adult male patas monkeys (11-15 kg) were heat acclimated by continuous exposure to an ambient temperature of 33 +/- 1 degree C at 13% relative humidity for 9 mo. During the last month, they were also exposed to 45 degrees C at 10% relative humidity for 4 h/day and 5 days/wk. Before and after 3 wk of acclimation, the animals were given a heat-tolerance test in which rectal (Tre) and mean skin (Tsk) temperatures, heart rate, and sweat rate (msw) were monitored during a 90-min exposure to 45 degrees C heat with 24% relative humidity under lenperone (1.0-1.4 mg/kg im) tranquilization. Maximal in vivo msw was also determined in response to subcutaneous injections (1 and 10% solutions) of methacholine (MCh). Before and after 9 wk and 9 mo of acclimation, sweat glands were dissected from biopsy specimens of the lateral calf, cannulated, and stimulated in vitro with MCh. Morphological measurements of isolated tubules were compared with maximal secretory rates produced by MCh stimulation. Three weeks of acclimation 1) reduced Tre and Tsk and increased msw during the heat tolerance test and 2) significantly increased maximal msw in response to MCh stimulation. Acclimation also increased (P less than 0.05) sweat gland size, as measured by tubular length and tubular volume. Maximal in vitro msw produced by MCh stimulation and msw per unit length of secretory coil also increased significantly. We conclude that heat acclimation increases the size of eccrine sweat glands and that these larger glands produce more sweat. They are also more efficient because they produce more sweat per unit length of secretory coil.

Acclimatization↗
PubMed1985

Investigation of drug absorption from the gastrointestinal tract of man. V. Effect of the beta-adrenoceptor antagonist, metoprolol, on postprandial gastric function.

The role of the adrenergic system in normal gastric function was assessed in five healthy volunteers by measuring gastric secretion and emptying after a mixed meal containing a non-absorbable marker, [14C]-PEG 4000, with and without 100 mg of metoprolol, a beta 1-adrenoceptor antagonist. Intraduodenal perfusion of PEG 4000, and gastric and jejunal sampling was achieved by means of a gastrointestinal intubation technique. Gastric function was assessed from the degree of dilution of the duodenal marker. Analysis of acid content by titration allowed the gastric acid secretory rate to be determined. Gastric emptying of a meal over 4 h was similar with and without metoprolol, the time to 50% emptying being 100 min. In the presence of metoprolol, gastric acid content was significantly increased during the late postprandial period producing a corresponding increase in acid load delivered to the duodenum. beta 1-adrenoceptor blockade appears to prolong the gastric secretory response to food without altering gastric emptying.

Food↗
PubMed1983

The systemic beta-adrenergic pathway to renin secretion: relationships with the renal prostaglandin system.

The relationship between renin release evoked by circulating beta-agonists and the renal prostaglandin (PG) system is incompletely defined. Thus, we evaluated systemic and renal hemodynamic responses to iv (0.5 micrograms/kg X min) and intrarenal arterial (0.6 micrograms/kg X min) infusions of the beta1-agonist prenalterol (PNL) in four separate groups of anesthetized dogs. Consecutive iv PNL infusions (n = 6) resulted in a reversible decrease in mean arterial pressure (130 to 117 mm Hg; P less than 0.05) and increases in cardiac output (3.93 to 4.90 liters/min; P less than 0.001), PRA (1.96 to 5.12 ng/ml X h; P less than 0.01), and 6-keto-PGF 1 alpha levels (190 to 482 pg/ml; P less than 0.01). The glomerular filtration rate and renal blood flow were modestly, but not significantly, decreased by the PNL infusions. In a second group of dogs, the infusion of the PG synthesis inhibitor indomethacin (IN; 10 mg/kg, iv; n = 7) before the second PNL infusion blunted PG increases but did not significantly modify the systemic or renal hemodynamic responses to PNL. The magnitude of the PRA and renin secretory rate (RSR) increases post-IN administration was similar to control values, but the absolute levels achieved were not as great as before IN infusion. To assess the role of the renal baroreceptor pathway to renin release after PNL, a suprarenal clamp was used to maintain a constant renal perfusion pressure during PNL infusion in a third group of dogs. In this group (n = 5), both PRA and RSR (from innervated and denervated kidneys) increased after PNL infusion, although IN again diminished the maximum PRA and RSR responses observed. Finally, the unilateral intrarenal arterial infusion of PNL in the last group of dogs did not alter PRA, RSR, or renal hemodynamics. These results demonstrate that renin release elicited by a circulating beta-agonist functions independently of PG synthesis, and that the pathway operates via an extrarenal mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Stimulation of rat parotid secretion by cAMP analogues that synergistically activate the type II isoenzyme of the cAMP-dependent protein kinase.

Beta-adrenergic-stimulated parotid secretion is believed to be mediated by activation of the cAMP-dependent protein kinase (PK-A). However, the relative roles of the type I and II PK-A isoenzymes are still unclear. Combinations of site-selective, lipophilic cAMP analogues that synergistically activate each PK-A were used to investigate this problem. The selectivity of synergistic activation with these combinations was verified with the partially purified parotid PK-A isoenzymes, using kemptide as a substrate. Synergism in activation of PK-AII was only seen with 8-thiomethyl cAMP (8-TM) and N-6-benzoyl cyclic AMP (N6B), while PK-AI was only synergistically activated by 8-(6-aminohexyl) amino cyclic AMP (AHA) and N6B. Additive activation of each isoenzyme was observed for the combination of 8-TM and AHA. Rates of amylase secretion from dispersed parotid acini in response to secretagogues were determined with a coupled enzyme assay for amylase activity, which was adapted for use in a microplate reader. Cells were stimulated to secrete during 30 min with different doses (0.1-1.0 mM) and combinations of the cyclic nucleotide analogues. Alone, N6B was most effective in stimulating amylase secretion. The basal amylase secretory rate was stimulated by these secretagogues (0.44 mM) to the following extent: 53-fold (N6B), 8-fold (8-AHA), 2-fold (8-TM). In combination at a series of concentrations, only 8-TM + N6B produced synergistic stimulation of secretion, while AHA + N6B and 8-TM + AHA did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗
PubMed1981

Direct stimulatory effect of histamine on aldosterone secretion of the perfused dog adrenal gland.

The left adrenal gland of the hypophysectomized-nephrectomized dog was perfused in situ with the blood from the femoral artery of the hypophysectomized-nephrectomized donor dog. After infusion of histamine (0.1 mg/min for 5 min) into the arterial inflow circuit, the rates of secretion of aldosterone, corticosterone and cortisol (ng/100 mg adrenal wt. each min) increased from the basal level of 0.66+/-0.21 (mean+/-S.E.M.) to 2.24+/-0.45 at 10 min, from 4+/-1 to 20+/-4 at 5 min and from 19+/-5 to 64+/-15 at 5 min, respectively. The maximal increments above the basal value after the infusion of histamine in the secretory rates of aldosterone, corticosterone and cortisol were 51, 16, and 13% that of the respective steroid after the infusion of ACTH (20mIU/min for 5 min). The results indicate that histamine has a direct stimulatory effect on the secretion of aldosterone by the adrenal gland as well as on that of corticosterone and cortisol.

Adrenal Glands↗
PubMed1985

Endogenous E-type prostaglandins in regulation of basal alkaline secretion by amphibian duodenum in vitro.

Segments of proximal duodenum from Rana catesbeiana, stripped of external muscle and mounted as a tube in a glass chamber, alkalinized the luminal-side bathing solution at a rate of 1.70 +/- 0.16 microEq/cm . h (n = 18, gross surface area approximately 1.5 cm2/cm). A single change of the serosal-side bathing solution for fresh solution reduced the rate of titratable alkaline secretion, which achieved a new steady state after 45 min amounting to 66% +/- 2% of the initial rate; transmucosal potential difference (lumen negative) fell from 10.6 +/- 1.2 to 8.8 +/- 1.1 mV. Concentrations of E-type prostaglandins in the serosal-side solution measured by radioimmunoassay were 8.5 nM (3 ng/ml) before, 0.17 nM 5 min after, and 1.7 nM 90 min after the solution change (n = 8). Reapplication of the original bathing solution 90 min after the initial change reestablished original secretory rate and potential difference. The increases in alkaline secretion and potential difference were comparable in magnitude and profile to those induced by serosal administration of 10 nM prostaglandin E2. Addition of the metabolic inhibitor 2,4-dinitrophenol (100 microM, serosal side) reduced basal alkaline secretion to 30% +/- 7% of the initial rate and abolished the potential difference (n = 8). These data demonstrate that endogenous prostaglandin E production by an isolated preparation of amphibian duodenum accounts for a proportion of alkaline secretion that is equivalent to 50% of metabolism-dependent basal secretion.

2,4-Dinitrophenol↗
PubMed1996

Effects of sodium butyrate on glucose transporter and glucose-phosphorylating enzyme gene expression in RINm5F insulinoma cells.

RINm5F insulinoma cells show a defective physiological insulin secretory response to glucose stimulation. The short chain carbonic acid sodium butyrate induced a growth arrest during a 72-h tissue culture period. In contrast to control RINm5F cells, 2 mM glucose increased insulin secretion by more than 70% in these sodium butyrate-treated cells (1 mM) without any further increase of the secretory rate between 2 and 20 mM glucose. This effect of sodium butyrate on insulin secretion was assessed in comparison with its effect on gene expression of the GLUT1 and GLUT2 glucose transporter, hexokinase type I and type II, glucokinase and insulin. Sodium butyrate at a 1 mM concentration decreased GLUT1 gene expression by nearly 50%, but did not induce gene expression of the low-affinity GLUT2 glucose transporter above the detection limit. Furthermore, sodium butyrate increased glucokinase gene expression by more than 50% and hexokinase type II gene expression by more than 100%, while insulin gene expression was increased only by 24%. Hexokinase type II enzyme activity was increased by more than 100% without a concomitant significant change of the glucokinase enzyme activity. Sodium butyrate (2 mM) caused effects comparable with those of 1 mM sodium butyrate. Thus the improved insulin secretory responsiveness of RINm5F insulinoma cells after sodium butyrate treatment at low non-physiological millimolar glucose concentrations can be interpreted as a result of an increased hexokinase-mediated metabolic flux rate through the glycolytic chain.

Blotting, Northern↗
PubMed1982

Adrenal medullary responses to repeated hemorrhage in the anesthetized dog.

Adrenal secretory rates of catecholamines in response to a repeated stimulus have not been described. We have used repeated small hemorrhages spaced 24 h apart in pentobarbital anesthetized dogs prepared with a chronic adrenal venous catheter to study this question. Our results confirm earlier reports that an initial 7.5 ml/kg hemorrhage is a mild stimulus to the adrenal medullar secretion of epinephrine and norepinephrine, However, when this stimulus is repeated 24 h later, a greatly potentiated secretory response of both hormones is seen. Cardiovascular changes after hemorrhage did not differ on the 2 days. Repeated 3.75 ml/kg hemorrhages did not lead to augmented adrenal medullary secretion of catecholamines on day 2. These data indicate that there is a factor associated with hemorrhage that potentiates the adrenal medullary response to second small hemorrhage. This factor appears to be subject to a threshold that lies between a 3.75 and 7.5 ml/kg hemorrhage. A significant catecholamine response on day 1 was not essential for the potentiated response on day 2. Thus, this phenomenon does not appear to be the result of adrenal enzyme induction as a consequence of prior adrenal medullary stimulation.

Adrenal Gland Diseases↗
PubMed2006

Nocturnal growth hormone secretory dynamics are altered after resistance exercise: deconvolution analysis of 12-hour immunofunctional and immunoreactive isoforms.

To characterize the effects of daytime exercise on subsequent overnight growth hormone (GH) secretion and elimination dynamics, serum was sampled, and GH was measured every 10 min for 12 h (1800 to 0600) in a control (CON) condition and after a 50-set resistance exercise protocol (EX) from 1500 to 1700. GH was measured with a conventional immunoreactive (IR) and an immunofunctional (IF) assay, and values were analyzed via a multi-parameter deconvolution analysis. EX resulted in a higher overnight secretory burst frequency [CON: 7.6 (SD 2.4) < EX: 9.4 (2.2) bursts per 12 h, P = 0.005] but lower mean burst mass [CON: 9.2 (4.7) > EX: 6.0 (2.9) microg/l, P = 0.019] and secretory rate [CON: 0.68 (0.29) > EX: 0.48 (0.23) microg/l/min; P = 0.015; ANOVA main effect means presented]. Approximate entropy (ApEn) was greater after EX, indicating a less orderly GH release process than CON. The estimated half-life of IF GH was significantly lower than IR GH [IF: 15.3 (1.1) < IR 19.8 (1.6) min, P < 0.001] but similar between the CON and EX conditions (approximately 17 min). Despite the changes in secretory dynamics, 12-h mean and integrated GH concentrations were similar between conditions. The results suggest that although quantitatively similar total amounts of GH are secreted overnight in CON and EX conditions, resistance exercise alters the dynamics of secretion by attenuating burst mass and amplitude yet increasing burst frequency.

Adaptation, Physiological↗
PubMed1997

Severe uremia depresses the ability of perifused rat pituitary cells to secrete growth hormone in response to growth hormone releasing hormone.

To examine whether growth hormone (GH) secretion is impaired by chronic renal failure (CRF) and to gain some insight into the influence of uremia itself and associated malnutrition, the GH secretory response of dispersed anterior pituitary cells perifused with GH-releasing hormone (GHRH) was investigated in 5/6 nephrectomized (UREM, N = 15) and three groups (N = 15 each) of normal renal function, sham-operated rats under three different nutritional conditions: fed "ad libitum" (SAL), pair-fed with a diet similar to the UREM group (SPF), and pair-fed with a diet similar to the UREM group in terms of protein ingestion but calorically supplemented up to intake of SAL group (SPF+). Ten days after nephrectomy, UREM rats had severe CRF, as shown by much higher (P < 0.0001) serum urea nitrogen concentrations (X +/- mean +/- SE) than sham groups (59 +/- 6 versus 8 +/- 0, 9 +/- 0, and 5 +/- 0 mmol/L, respectively), and they were growth retarded, as shown by lower gains (P < 0.0001) in weight (13.5 +/- 2.5 versus 62 +/- 2.1, 20.5 +/- 1.9, and 50.4 +/- 1.0 g) and length (2.9 +/- 0.2 versus 5.8 +/- 0.1, 3.6 +/- 0.1, and 5.6 +/- 0.1 cm). Perifusion studies showed similar basal GH secretory rate (ng/min/10(7) cells) in the four groups. A fixed sequence of progressively increasing GHRH doses resulted in a lower overall mean GH secretion in UREM rats (15.8 +/- 1.6 ng/min/10(7) cells), as compared with SAL (50.8 +/- 9.0 ng/min/10(7) cells, P < 0.01), SPF (33.0 +/- 3.3 ng/min/10(7) cells, P < 0.05), and SPF+ (49.4 +/- 5.1 ng/min/10(7) cells, P < 0.01) groups. Analysis of dose-response curves showed that the maximal secretory response was produced by the same concentration of GHRH (10 nM) in the four groups and was lower (P < 0.01) in UREM than SAL and SPF+ rats (34.9 +/- 5.0 versus 115.7 +/- 28.4 and 98.9 +/- 9.8 ng/min/10(7) cells). The concentration of GHRH that caused the half of maximal effect was identical, close to 1 nM, in the four groups of animals. This study provides direct evidence that the ability of pituitary cells to secrete GH in response to GHRH is depressed in severe CRF. The lower secretory capacity of pituitary gland is only partly dependent on caloric malnutrition associated with CRF. Data of dose-response curves suggest that decreased GH secretion may be related to a lesser number of pituitary receptors for GHRH.

Animals↗
PubMed1993

Early hepatobiliary dysfunction during total parenteral nutrition: an experimental study.

The etiology and pathophysiology of the liver disease associated with total parenteral nutrition (TPN) are unknown. In this study, we have attempted to define the early changes in hepatobiliary function during TPN in young rabbits nourished totally by the intravenous route for 3, 5, and 15 days, with age-matched rabbits on lab chow serving as controls. A decrease in basal bile flow along with elevations of serum bile acids and cholesterol was seen. The capacity for biliary secretion of sulfobromophthalein and of ursodeoxycholic acid was measured at the end of each diet regimen. Early impairment of biliary sulfobromophthalein (BSP) secretion was seen after 5 days of TPN, with no further deterioration after 15 days. Maximal bile acid secretory rate and bile flow, in response to the ursodeoxycholic acid load, were decreased after 15 days of TPN. Furthermore, after 15 days of TPN, both the volume of gallbladder bile and its bile acid content increased. The combined effects of the enteral fast and the intravenous administration of all nutrients were bile acid sequestration in an adynamic gallbladder with interruption of the enterohepatic circulation. In the parenterally fed rabbit, we have demonstrated bile secretory failure and gallbladder sludge, the two common complications of clinical TPN. These may be the early events that subsequently lead to cholestasis and liver damage in neonates maintained on prolonged TPN.

Animals↗
PubMed2005

Nitric oxide modulation of ET(B) receptor-induced vasopressin release by rat and mouse hypothalamo-neurohypophyseal explants.

Endothelin (ET) peptides stimulate vasopressin (AVP) secretion via ET(B) receptors at hypothalamic loci. Nitric oxide modulates the actions of ET in the cardiovascular system and also influences neurotransmission and specifically suppresses firing of magnocellular neurons. The purpose of these studies was to ascertain whether nitric oxide, generated in response to ET(B) receptor stimulation, buffers the stimulatory effect of ET and suppresses AVP release. Studies were performed using a pharmacological approach in hypothalamo-neurohypophyseal explants from rats, and an alternative strategy using explants from mice with an inactivating mutation of neuronal NOS (nNOS-/-) and their wild-type parent strain. Whole explants in standard culture or only the hypothalamus of compartmentalized explants was exposed to the ET(B) selective agonist, IRL 1620 (10(-13) to 10(-8) M). Rat and wild-type mouse explants displayed similar responses, although absolute basal release rates were higher from murine explants. Maximal AVP release at 0.1 nM IRL 1620 was 311 +/- 63 (rat) and 422 +/- 112% basal x explant(-1) x h(-1) (mouse). Sodium nitroprusside (SNP; 0.1 mM) suppressed maximal AVP release to basal values. N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.1 microM), which did not itself stimulate AVP secretion, more than doubled the response to 1 pM IRL 1620, from 136 +/- 28 to 295 +/- 49% basal x explant(-1) x h(-1) (P < 0.05) by rat explants. Explants from wild-type mice responded similarly. Explants from nNOS-/- mice had higher basal AVP secretory rate in response to 1 pM IRL 1620: 271 +/- 48 compared with 150 +/- 24% basal x explant(-1) x h(-1) (P < 0.05) from wild-type murine explants. In the nNOS-/-, SNP suppressed stimulated release, and L-NAME exerted no additional stimulatory effect: 243 +/- 38% basal x explant(-1) x h(-1). Thus nitric oxide inhibits the AVP secretory response induced by ET(B) receptor activation within the hypothalamo-neurohypophyseal system and is generated primarily by the nNOS isoform. The modulation of AVP secretion by ET and also nitric oxide can take place independently from their effects on cerebral blood flow, systemic hemodynamics, or the arterial baroreflex.

Animals↗