Adrenal medullary secretory response to stimulation of the medulla oblongata in the rat

In rats anesthetized with sodium pentobarbital, adrenal venous blood samples were collected and analyzed for epinephrine and norepinephrine by the fluorometric method. Stimulation of the inferior fovea or adjacent areas resulted in a significant increase in epinephrine secretion. Stimulation of some other areas of the floor of the fourth ventricle was associated with a significant decrease in norepinephrine secretion with or without significant decrease in epinephrine secretion. In no instance was observed a significant increase in norepinephrine secretion in response to the medulla oblongata stimulation.     

Effect of a protein meal in stomach and jejunum on gastric secretory response to pentagastrin in cats

A humoral gastrin potentiating mechanism was previously demonstrated in the upper intestine of cats. The present study was carried out on 10 cats with a gastric fistula (GF) and a Heidenhain pouch (HP). In five of the cats the duodenum and proximal jejunum dere excluded as a Roux-en-Y loop, and the other cats were provided with an isolated jejunal Thiry-Vella loop. In the Roux-en-Y loop cats, a protein-rich oral meal augmented the maximal HP acid response to pentagastrin but not the pepsin response. Protein-rich food in the Thiry-Vella loop did not stimulate acid secretion, nor did it augment the maximal GF or HP acid response to pentagastrin. Previous and present results suggest that an unknown humoral gastrin-potentiating mechanism is activated by a protein-rich meal in the stomach and the duodenum but not in the jejunum. The mechanism potentiates pentagastrin-induced acid, but not pepsin, secretion.This work was supported by grants from the Swedish Medical Research Council (No. 2324), the Karolinska Institute, and the Thuring's Foundation, Stockholm, Sweden.     

Quantitation and characterization of human plasma neurotensin-like immunoreactivity in response to a meal

The secretion and metabolism of endogeneous neurotensin-like immunoreactivities after a test meal were studied in five healthy human subjects. Intact neurotensin and the N-terminal metabolic fragment, neurotensin 1–8, were quantified by radioimmunoassay with C- and N-terminally directed antisera in conjunction with gel filtration of plasma samples obtained at timed intervals. Both C- and N-terminal neurotensin-like immunoreactivities rose after the meal, reaching a plateau level after 20 and 30 min, respectively. During the plateau phase, which lasted for the rest of the experimental period of 180 min, the molar ratio of intact neurotensin to neurotensin 1–8 remained approximately constant at 14.6. Meal-stimulated immunoreactive neurotensin appeared to be metabolized in a manner comparable to that of exogenously infused neurotensin in man. The results suggest that intact neurotensin is secreted at an approximately constant rate during the plateau phase. The relatively low plateau level of neurotensin 1–8, which has a much longer half-life than intact neurotensin in the circulation, implies that only a fraction of the secreted intact neurotensin is metabolized to neurotensin 1–8, indicating the existence of alternative pathways of neurotensin metabolism.     

Increased plasma norepinephrine response to yohimbine in elderly men

BACKGROUND: The effects of aging on sympathetic nervous system and adrenomedullary outflow were estimated by the measurement of plasma norepinephrine (NE) and epinephrine (EPI) responses to yohimbine and clonidine in healthy young and healthy older subjects. METHODS: Yohimbine (0.65 mg/kg), clonidine (5 microg/kg), and placebo were administered on separate days in random order to 5 healthy older men (age 74 +/- 1 years) and 18 healthy young men (age 26 +/- 1 years). NE and EPI were measured by radioenzymatic assay in plasma samples obtained before and 30, 60, and 90 minutes after drug administration. RESULTS: Plasma NE increases after yohimbine were greater in older men than in young men. but plasma NE decreases following clonidine did not differ between groups. Plasma NE and systolic blood pressure were higher in older men than in young men at baseline but no longer differed 90 minutes after clonidine. Plasma EPI increases after yohimbine and decreases after clonidine did not differ between groups. CONCLUSIONS: These results suggest increased sympathetic nervous system outflow in human aging that is not a function of reduced responsiveness of alpha-2 adrenoreceptor-mediated feedback inhibition.     

Selective stimulation of colonic motor response to a meal by sigma ligands in dogs

The influence of central vs. peripheral administration of sigma ligands (dl- and l-N-allylnormetazocine, 1-3-di-o-tolylguanidine, (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene and phencyclidine on colonic motility was investigated in fasted and fed dogs equipped with strain-guage transducers implanted on proximal and transverse colon. When injected intravenously at a dose of 0.25 mg/kg just before feeding, dl- or d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (but not phencyclidine) enhanced the colonic motor response to a meal by increasing the 0-4-hour motility indexes from 64.1%-159.3% in both the proximal and transverse colon but had no effect on colonic motility in fasted animals or animals injected intracerebroventricularly. The motor-stimulatory effects of d-N-allylnormetazocine (1 mg/kg), 1-3-di-o-tolylguanidine (0.25 mg/kg), and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (1 mg/kg) were abolished after previous treatment with haloperidol (0.5 mg/kg, intravenous) but not after sulpiride (0.1 mg/kg) or (+) R-(+)-8-chloro-2,3,4,5-tetrahydro-3- methyl-5-phenyl-1-H-3-benzozepine-OH. Prazosin (0.1 mg/kg, intravenous) and 1-methyl-3-(2-indolyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one (0.01 mg/kg) also suppressed the enhancement of the colonic motor response to eating induced by d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene whereas naltrexone did not affect their effects. It is concluded that d-N-allylnormetazocine, 1-3-di-o-tolylguanidine, and (+)cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene stimulate the postprandial colonic motility in dogs by acting selectively on sigma receptors located peripherally and probably by affecting the release of cholecystokinin octapeptide through a central adrenergic mechanism.     

Exocrine secretory responses of the pancreas to insulin and to a meat meal in dogs

Studies in five dogs with chronic pancreatic and gastric fistulae have shown that insulin-induced vagal stimulation of the pancreas (gastric fistula open) resulted in protein and bicarbonate outputs very much smaller than those obtained with a 400-g meat meal. However, when the insulin-activated gastric acid secretion was allowed access to the duodenum (gastric fistula closed) peak outputs of both bicarbonate and protein were observed which were closely similar to the response to the meal. These findings suggest that insulin-induced hypoglycaemia results in stimulation of the pancreas within the physiological range when gastric acid is allowed access to the duodenum with consequent release of secretin.     

Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis.

The secretory response to cholinergic stimulation was investigated in rectal biopsy specimens from children with cystic fibrosis and a control group using a modified Ussing chamber technique. Acetylcholine (10(-3) mol/l) increased the short circuit current in 12 control specimens by mean (SEM) 83.0 (16.4) microA/cm2, but samples from five children with cystic fibrosis failed to exhibit such a response (-1.4 (3.2) microA/cm2). Amiloride (10(-4) mol/l), which will inhibit electrogenic sodium absorption in viable tissues, caused similar reductions in the short circuit current of both control and cystic fibrosis tissues (control = -37.7 (7.7) microA/cm2; cystic fibrosis = -44.0 (9.3) microA/cm2). Thus, the failure of chloride secretion observed in the small intestine also exists in the rectal mucosa. This observation could be used both to aid diagnosis and to study the basic defect.     

The rapid ovarian secretory response to pituitary stimulation by the gonadotropin-releasing hormone agonist nafarelin in sexual precocity

We evaluated a GnRH agonist (GnRHa) as a potential single stimulus to both pituitary and ovarian secretion in 13 girls with true precocious puberty. We compared the GnRH agonist [6-D-(2-naphthyl)alanine]GnRH acetate (nafarelin, Syntex) administered as a single sc injection of 0.2 microgram/kg to GnRH infused iv in a dose of 2 micrograms/kg X h for 3 h and assessed the response of plasma steroid intermediates in estradiol (E2) biosynthesis. Although serum LH and FSH levels increased to similar peaks 3 h after commencing GnRH and nafarelin testing, they rose faster (P less than 0.01 at 1 h) and remained elevated longer (P less than 0.05 at 24 h) after nafarelin administration. At the third hour of testing with either agent, LH and FSH rose 8.8- and 3.4-fold, respectively (P less than 0.001 vs. baseline), whereas the rise in E2 was inconsistent and averaged only one third (P less than 0.02). However, plasma E2 increased later after nafarelin, but not after GnRH, rising from a baseline level of 30 +/- 6 (+/- SEM) to 115 +/- 13 pg/ml at 24 h (P less than 0.001). The least E2 response to nafarelin at this time was 150%. This rise is probably an underestimate of the maximum E2 rise, since a 6-fold response to nafarelin was found at 12 h in patients sampled then. Measurement of steroid intermediates from progesterone and 17 alpha-hydroxypregnenolone to E2 indicated that the response to nafarelin was typical of normal ovarian follicular secretion. That is, plasma levels of the intermediates in E2 biosynthesis rose less than 2-fold, and only the elevations in androstenedione, from 58 +/- 10 to 78 +/- 16 ng/dl (P less than 0.05), and estrone, from 14 +/- 3 to 38 +/- 7 pg/ml (P less than 0.02), at 24 h were significant. The greater effectiveness of nafarelin than GnRH in stimulating E2 secretion appears to be related to the more prolonged gonadotropin response. The magnitude, consistency, specificity, and rapidity of the gonadotropin and E2 responses to nafarelin indicate that this is a promising agent for rapidly testing pituitary and ovarian function simultaneously.     

Carbamazepine diminishes the sensitivity of the plasma arginine vasopressin response to osmotic stimulation

Carbamazepine, a drug used to treat manic-depressive illness, has been reported to possess antidiuretic properties, but its effects on arginine vasopressin (AVP) secretion are controversial. Consequently, we examined plasma AVP secretion during hypertonic (5%) saline infusion in seven manic-depressive patients while on placebo and after 3-5 weeks of carbamazepine treatment. We also measured carbamazepine's effects on basal levels of the hormone in cerebrospinal fluid. Carbamazepine significantly reduced the sensitivity of the plasma AVP response to osmotic stimulation without affecting the osmotic threshold for AVP secretion. Moreover, carbamazepine did not affect baseline weight, plasma osmolality, plasma sodium, urine output, plasma AVP, or cerebrospinal fluid AVP. Although the functional significance of these findings remain to be fully determined, the fact that carbamazepine significantly reduced AVP secretion without inducing diuresis supports previous suggestions that carbamazepine enhances renal responsivity to available AVP. In addition, since carbamazepine failed to affect the osmotic threshold, the reported cases of carbamazepine-induced inappropriate AVP secretion and water intoxication must be very uncommon and probably represent idiosyncratic responses.     

Influence of cholinergic stimulation on gastric secretory response to histamine in ex vivo isolated canine stomach

Totally isolated canine stomach, included into a perfusion system containing a living “supporting” dog, serving as an oxygenator, is able to secrete juice rich in H⁺ for several hours. Blood circulating in this system is homologous blood and the stomach may be stimulated by intraarterial continuous infusion of a secretion stimulant. The ex vivo preparation was used for the study of secretion stimulated by histamine and/or bethanechol chloride, a stable cholinergic drug. All combinations of histamine plus bethanechol chloride used in this study gave higher outputs of HCl and pepsin than could be accounted for on the basis of summation of stimulatory effects. Outputs of HCl and pepsin were higher when two agents were given together than the maximal output of either HCl or pepsin during stimulation by one agent. Potentiation with regard to acid and pepsin secretion was evident when a cholinergic drug, in various doses, was superimposed on histamine stimulation.     

Observations on plasma secretion levels by radioimmunoassay in response to duodenal acidification and to a meat meal in humans

The endogenous release of secretin in healthy human subjects was studied by measuring plasma secretin levels by radioimmunoassay (RIA) before, during, and following duodenal acidification and eating a meal. The sensitivity of our RIA was assessed by measuring plasma secretin levels during constant intravenous infusions of 4 graded doses of secretin. Our RIA detected significant increases (P<0.001) in plasma secretin with each dose, including a low dose of 0.125 U (41.3 ng)/kg hr. Intraduodenal infusion of 0.1N HCl resulted in marked increases (P<0.001) in plasma secretin levels whenever pH in the second portion of the duodenum was reduced to less than 3.5. In contrast, following a meal, pH in the second portion of the duodenum remained consistently greater than 4.5 and plasma secretin levels showed no changes from basal levels. These studies confirm that endogenous release of secretin depends on an acidic pH of the duodenum, and insignificant changes in the plasma secretin level following ingestion of a meal suggest that endogenous release of secretin in the postprandial period is probably too small in quantity to be detected by the present radioimmunoassay method.Presented in part at the Annual Meeting of the American Federation for Clinical Research, Atlantic City, New Jersey, May 4, 1975.This work was supported in part by Grant AMDD-16939 from the National Institutes of Health.