Synchronizing, sedative and anticonvulsive effects of centrally administered somatostatin in the conscious rabbit

The effects of intracerebroventricular injection of somatostatin-14 on the cortical and deep structure electrical activity, somatic behavior and rectal temperature, were studied in 45 unanesthetized rabbits. In addition the antiepileptic action of the peptide was tested in these models: pentamethylenetetrazole-induced cortical spikes and waves, epileptic focus by topical application of strychnine and voltage-threshold for amygdala after-discharge. The results indicate that somatostatin exerts synchronizing, sedative and weak antiepileptic effects when centrally administered to rabbits.     

Influence of centrally administered peptides on ear withdrawal from heat in the rabbit

Certain neuropeptides previously linked to stress and implicated in CNS control of analgesia/algesia were tested using a recently developed analgesiometric model, the rabbit ear-withdrawal test. The latency to ear withdrawal increased in a dose-related manner after β-endorphin was injected intracerebroventricularly (IVC). Intermediate doses (0.5 and 1.0 μg) of adrenocorticotropic hormone (ACTH) caused hyperalgesia as indicated by decreases in latency. Corticotropin-releasing factor (CRF, 0.5 and 1.0 μg) also caused significant hyperalgesia late in the testing period. -Melanocyte stimulating hormone (-MSH, 0.25–2.0 μg), a molecule that shares the first 13 amino acid sequence with ACTH, and somatostatin (0.25–2.0 μg), caused no significant change in latency. However, 1.0 μg doses of each peptide antagonized the analgesic effect of β-endorphin (1.0 μg) in the following order of potency: ACTH = -MSH > CRF > somatostatin. The results support the idea that CNS peptides that are released during stress can exert opposing actions on acute pain, even though they may cause little effect alone.     

Effect of centrally administered somatostatin on pituitary thyrotropes in male rats

The effects of intracerebroventricularly administered somatostatin (SRIH-14 or -28) on growth and function of pituitary thyrotropes (TSH-cells) were examined in adult male Wistar rats. The animals were implanted with an intracerebroventricular cannula and after a recovery period, administered three 1g doses of SRIH-14 or -28 dissolved in 5l saline every second day. Controls were treated in the same way with the same volume of saline only. TSH-producing cells were studied using the peroxidase–antiperoxidase immunohistochemical procedure. Blood samples were collected for hormone (TSH) analyses 5 days after the last injection. Both SRIH-treatments significantly decreased (p < 0.05) all morphometric parameters obtained for TSH-cells in comparison with controls. The volume of TSH-cells decreased by 27%, nuclei by 44% and volume density by 33% in animals treated with SRIH-14. In animals treated with SRIH-28, these parameters were also significantly decreased (p < 0.05) (22%, 31%, and 25% respectively) compared to control rats. Serum concentrations of TSH were significantly decreased (p < 0.05) by 15% in SRIH-14- and by 12% in SRIH-28-treated animals in comparison with the controls. These observations suggest that centrally administered SRIH-14 or -28 is specifically involved in the control of growth and secretory activity of TSH cells.     

Absorption of intragastrically administered DDAVP in conscious dogs

Plasma concentrations of DDAVP were measured after intragastric administration and intravenous infusion in dogs. Oral ingestion of DDAVP led to a dose dependent increase in peak plasma concentrations as well as area under the curve (AUC). Intravenous infusion of DDAVP (0.13 pmol/l min) resulted in a mean steady-state level of 20.3 pmol/l. Elimination half-lives for oral DDAVP were 77.6 and 76.1 min for low and high doses respectively. T1/2 estimated from the ascending part of the i.v. infusion curve was 50 min. A metabolic clearance rate (MCR) of 3.9 ml/kg . min was assessed from the i.v. steady-state level.     

Hyperthermic effect of centrally administered natriuretic peptides in the rat.

The effects of atrial natriuretic peptide (ANP-28), brain natriuretic peptide (BNP-32) and C-type natriuretic peptide (CNP-22) on body temperature were investigated in rats. Intracerebroventricular administration of each peptide in doses of 400 or 1000 ng caused a dose-related elevation in colon temperature 30 and 60 min after injection. A 40 ng dose of ANP-28 was also hyperthermic at 60 min. An intramuscular (i.m.) injection of noraminophenazone (a cyclooxygenase inhibitor) abolished the natriuretic peptide-induced hyperthermia. The results show that natriuretic peptides may participate in thermoregulatory processes in the central nervous system, and that their hyperthermic effect may be mediated via a cyclooxygenase-involved pathway.     

Effects of atrial natriuretic peptides and furosemide in conscious dogs

Effects of ANF(8-33) and Auriculin A on renal variables were investigated in conscious water-diuretic dogs. The two substances were injected intravenously (1.08 micrograms/kg in 3 min) or ANF(8-33) was infused (0.2 microgram/kg X min in 20 min). The effects were compared to those of an equinatriuretic dose of furosemide (1.0 microgram/kg X min). Injections caused increases in sodium excretion, diuresis, and osmolar clearance. No significant change in exogenous creatine clearance (CCREA) occurred. Infusion of ANF(8-33) decreased blood pressure by 14% (P less than 0.01) and increased sodium excretion by a factor of 10 (P less than 0.01). The natriuresis was a function of increases in diuresis and urinary sodium concentration, the latter by a factor of 6 (P less than 0.01). Diuresis and free-water clearance (CH2O) increased by 60% (P less than 0.01), but urine osmolality did not change significantly. After the infusion a significant decrease in PAH clearance (CPAH) (P less than 0.01) was observed. Filtration fraction (FF) did not change. The furosemide natriuresis appeared later than that of ANF without significant deviations in diuresis, CH2O, CCREA, CPAH, and FF; urine osmolality increased by 35% (P less than 0.01). The effects of ANF(8-33) differ from those of furosemide in several ways. First, the onset of natriuresis is faster, second, the natriuresis is associated by marked increases in diuresis and free-water clearance but not in urine osmolality; and third, natriuresis is followed by a reduction in renal blood flow. The rapid natriuresis of ANF can occur without changes in glomerular filtration rate.     

Motilin release by intravenous infusion of nutrients and somatostatin in conscious dogs

to investigate the regulatory mechanism of motilin release, plasma motilin was measured by radioimmunoassay in healthy dogs during the fasting state and after intravenous administration of various nutrients and somatostatin. The fasting plasma motilin levels of these dogs were found to fluctuate intermittently. Intravenous glucose loading lowered plasma motilin, but immediately after the end of the glucose infusion as abrupt rise of plasma motilin was observed. Mixed amino acids administered intravenously abruptly inhibited motilin secretion, and plasma motilin levels remained low even 45 min after the end of the infusion. On the other hand, no remarkable change in plasma motilin was noted after the fat infusion. Following somatostatin infusion, plasma motilin was significantly decreased, remaining low even 30 min after the end of the infusion. These observations led us to conclude than motilin secretion is regulated by somatostatin and by nutrients coming through intravenous routes.     

Effect of somatostatin on intestinal absorption of nutrients the rat

Effects of somatostatin on absorption of D-glucose, L-leucine and triacylglycerols by the small intestine were studied in rats after treatment with the peptide in vivo and in everted jejunal segments in vitro.Absorption of glucose was not affected in vitro by somatostatin or the analogue [D-Trp⁸, D-Cys¹⁴]somatostatin at concentrations up to 0.006 mM. Addition of various peptidase inhibitors had no influence, suggesting that failure of somatostatins to inhibit absorption was not due to inactivation by peptidases. Glucose absorption in vitro by jejunum from rats treated with high doses of somatostatin in vivo was not different from that of untreated rats. The biguanide phenformin inhibited glucose absorption, whether added in vitro (IC₅₀ ≈ 1 mM) of after treatment in vivo (3–100 mg/kg per os). The blood glucose increase following oral glucose administration in fasted rats was not affected by somatostatin, but significantly suppressed by phenformin.Absorption of leucine in vitro was not affected by somatostatin (up to 0.03 mM) or [D-Trp⁸, D-Cys¹⁴]somatostatin (0.01 mM), but inhibited by phenformin (IC₅₀ = 2 mM).Absorption of acylglycerols (glycerol tri[1-¹⁴C]oleate) administered orally was significantly inhibited by somatostatin (twice 5 mg/kg subcutaneously) and phenformin (100 mg/kg per os).In rats — apparently in contrast to man — somatostatin does not decrease role of somatostatin in carbohydrate absorption remains controversial. Investigations in healthy [9] and diabetic [20] human subjects suggest that the peptide inhibits (directly or indirectly) the intestinal absorption of glucose in man. On the other hand, our results and those of others obtained in experiments in rats [4,11,21] and Rhesus monkeys [7] clearly do not support such a role in these species. Further studies are therefore needed to resolve this problem.     

Effect of vagotomy and atropine on plasma somatostatin response to a meal in conscious dogs

In 4 conscious dogs with gastric fistulas the somatostatin responses to a meal were measured and compared to the responses seen after i.v. infusion of atropine sulfate (20 and 50 micrograms.kg-1.h-1) or cimetidine (8 mg.kg-1.h-1). The experiments were repeated after truncal vagotomy. The somatostatin responses to bombesin (0.5 micrograms.kg-1.h-1) were also measured before and after vagotomy. Vagotomy decreased basal and postprandial somatostatin levels and reduced the somatostatin responses to feeding during the first 30-min period following the ingestion of the meal but not during subsequent periods. Bombesin-induced somatostatin release was increased after vagotomy. Atropine decreased the somatostatin responses to the meal before and after vagotomy. Cimetidine had no significant effect. These studies suggest that, in conscious dogs, somatostatin released into the circulation is partly under vagal control and that, as for gastrin release, vagal pathways for stimulation and inhibition are present. Our studies also suggest that cholinergic mechanisms are involved in the control of postprandial somatostatin release.     

Bombesin, somatostatin, and related peptides: actions on thermoregulation

Bombesin acts within the anterior hypothalamic preoptic area to interfere with thermoregulation in the rat. The body temperature (Tb) of animals receiving bombesin varies in parallel with ambient temperature (Ta). Bombesin-induced reduction of Tb in animals at low Ta is associated with a marked reduction of oxygen consumption (VO2). Some somatostatin-related peptides, e.g., desAA 1,2,4,5,12,13 [D-Trp8]-somatostatin (ODT8-SS), act within the brain to prevent bombesin-induced reduction of VO2 and Tb. ODT8-SS also produces hyperthermia not associated with an increase in VO2.     

Effect of cimetidine, ranitidine and omeprazole on postprandial gastrin and somatostatin release in conscious dogs

During a first series of experiments, the gastrin responses to a meal were measured and compared to the responses seen after administration of cimetidine (2.5 mg/kg/h) or omeprazole (2 mg/kg). During a second series of experiments the effects of cimetidine (2.5 mg/kg/h), ranitidine (0.5 mg/kg/h) and omeprazole (2 mg/kg) on post-prandial gastrin and somatostatin release were determined in experiments during which the intragastric pH was maintained close to 6.4. During a third series of experiments, the effects of cimetidine (2.5 mg/kg/h) and omeprazole (2 mg/kg) on basal gastrin and somatostatin release were estimated. Postprandial gastrin release was increased by cimetidine and by omeprazole. When acidification of the gastric content was prevented by intragastric titration, postprandial gastrin release was increased by about 100%. No further increase was observed when the animals were concomitantly treated with cimetidine, ranitidine or omeprazole. Intragastric titration did not alter postprandial somatostatin release. Concomitant administration of H2 blockers decreased the somatostatin response to the meal, while concomitant administration of omeprazole did not alter this release. No significant changes were observed in basal gastrin or somatostatin levels after administration of cimetidine or omeprazole.(ABSTRACT TRUNCATED AT 250 WORDS)     

Release of regulatory gut peptides somatostatin, neurotensin and vasoactive intestinal peptide by acid and hyperosmolal solutions in the intestine in conscious rats

The impact of exposure of the intestinal mucosa to acid and hyperosmolal solutions on the release of the inhibitory gut peptides somatostatin (SOM), neurotensin (NT) and vasoactive intestinal peptide (VIP) was studied in conscious rats during pentagastrin-stimulated gastric acid secretion. The animals were equipped with a chronic gastric fistula to measure acid secretion and a jejunal Thiry-Vella loop for intestinal challenge with saline, hydrochloric acid (HCl, 200 mmol L(-1)) or hyperosmolal polyethylene glycol (PEG, 1200 mOsm kg(-1)). Gut peptide concentrations were measured in intestinal perfusates, and in plasma samples collected during stimulated acid secretion, and at the end of experiments with luminal challenge of the loops. After pentagastrin-stimulation acid secretion was dose-dependently inhibited by intravenous administration of the gastrin receptor antagonist gastrazole, as well as ranitidine and esomeprazole by maximally 73+/-10%; 95+/-3%; 90+/-10%, respectively. Acid perfusion of the Thiry-Vella loop caused a prominent release of SOM both to the lumen (from 7.2+/-5.0 to 1279+/-580 pmol L(-1)) and to the circulation (from 18+/-5.2 to 51+/-9.0 pmol L(-1)) simultaneously with an inhibition of gastric acid secretion. The release of NT and VIP was not affected to the same extent. PEG perfusion of the loop caused a release of SOM as well as NT and VIP, but less. Simultaneously acid secretion was slightly decreased. In conclusion, intestinal perfusion with acid or hyperosmolal solutions mainly releases SOM, which seems to exert a major inhibitory action in the gut, as shown by inhibition of acid secretion. The other peptides NT and VIP also participate in this action but to a much lesser degree. The operative pathways of these gut peptides hence involve both endocrine (SOM) and paracrine actions (SOM, NT, VIP) in order to exert inhibitory functions on the stomach. The inhibitory action of gastrazole, was in a similar range as that of SOM implying that physiological acid-induced inhibition of gastric acid may primarily be exerted through inhibition of gastrin endocrine secretion.     

Influence of triamcinolone and somatostatin on morphometric parameters of cultured intestinal mucosa

Summary Mucosal biopsies from rabbit ileum were organ cultured for 24 h. The influence of triamcinolone and somatostatin on vilus height and diameter as well as crypt depth and the number of mitoses was measured at various times during 24 h of culture as indices of cell proliferation and tissue maintenance. It could be shown that triamcinolone reduced cell proliferation slightly but preserved mucosal structure in organ culture. Somatostatin inhibited crypt cell proliferation, without any effect on other morphological parameters.