PubMed Health⌕ Search

Biomedical subjects

C A Sninsky

Publications and source records attributed to C A Sninsky.

At least 19 recordsLinked to original sources
PubMed1999

Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats.

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K+-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.

Adipocytes↗
PubMed1998

Diabetes and the gastrointestinal tract.

Gastrointestinal motility disorders are common in patients with diabetes. The entire gastrointestinal tract may be involved from the esophagus to the anal sphincter. Before instituting therapy, people with diabetes first require a careful diagnostic evaluation. Treatment includes tight glucose control and the use of antiemetics and prokinetic agents.

Diabetes Complications↗
PubMed1997

Evidence that hypothalamic neuropeptide Y gene expression and NPY levels in the paraventricular nucleus increase before the onset of hyperphagia in experimental diabetes.

Neuropeptide Y (NPY) is the most potent endogenous orexigenic signal. Several lines of evidence indicate that the site of NPY action in transducing feeding signal may reside in the paraventricular nucleus (PVN) and neighboring sites in the hypothalamus. To test the hypothesis that an increase in NPY activity in the ARC-PVN pathway precedes the onset of diabetic hyperphagia, we evaluated NPY levels in seven hypothalamic nuclei and NPY gene expression in the hypothalamus at 48, 72 or 96 h after streptozotocin (STZ) treatment in rat. In STZ-treated diabetic rats, NPY gene expression in the hypothalamus and NPY levels only in the PVN significantly elevated at 48 h, while hyperphagia occurred sometimes after 48 h post-injection. These results show that augmentation in NPY neuronal activity in the ARC-PVN axis precedes the onset of increased food intake produced by STZ-induced insulinopenia. These findings affirm the hypothesis that increased NPY neurosecretion in the PVN may underlie the diabetes-induced hyperphagia.

Animals↗
PubMed1997

Gastrointestinal myoelectric activity in a child with gastroschisis and ileal atresia.

Gastroschisis is frequently associated with intestinal atresia and alterations in gastrointestinal function. The authors studied gastric and small bowel myoelectric activity in a child who had a complex course and prolonged inability to tolerate oral intake after staged repair of gastroschisis and an associated ileal atresia. The child remained unable to tolerate oral intake after repair of the atresia and was reexplored 3 months later to rule out a partial small bowel obstruction, with simultaneous placement of serosal electrodes on the stomach and proximal small bowel. Persistent gastric dysrhythmias were observed postoperatively, and the child was unable to tolerate gastrostomy tube feedings. Abnormalities were also seen in small bowel motility, including retrograde propagation of activity fronts of the migrating myoelectric complex. However, the intestine converted to a fed myoelectric pattern with tube feedings, and the child was subsequently able to tolerate feedings via a tube placed directly into the small bowel. The authors conclude that myoelectric recordings via implanted electrodes are safe and feasible in children, and may give information regarding underlying motility alterations. The ultimate clinical role of myoelectric recordings in treating children with suspected motility disorders will require further study.

Abdominal Muscles↗
PubMed1997

Colchicine is an effective treatment for patients with chronic constipation: an open-label trial.

Chronic constipation is a common clinical condition that frequently does not respond to routine therapeutic measures. We hypothesized that colchicine would be effective in this condition because we reported that it stimulates intestinal motility in rats and commonly causes diarrhea in patients taking the drug for either gouty arthritis or Familial Mediterranean fever. We prospectively studied seven patients with chronic constipation who were refractory to medical therapy and treated them with oral colchicine 0.6 mg per os three times a day for eight weeks in an open-label pilot study. During the study, the mean number of spontaneous bowel movements significantly increased (P < 0.05) from 1.7 +/- 0.5 noted during routine therapy of constipation with laxatives and enemas to 6.4 +/- 0.7 per week; mean colonic transit time significantly (P < 0.05) decreased from 58.1 +/- 2.5 to 47.1 +/- 5.0 hr; and symptoms of abdominal pain, nausea, and bloating significantly (P < 0.05) improved during therapy with colchicine. Oral colchicine (0.6 mg three times a day) therapy appears to be an a promising treatment for chronic constipation and a placebo-controlled trial is indicated to confirm these findings.

Chronic Disease↗
PubMed1996

Metabolically programmed polyamine analogue antidiarrheals.

The design, synthesis, and testing of a novel class of antidiarrheal drugs based on a tetraamine pharmacophore are reported. While N1,N14-diethylhomospermine (DEHSPM) (5 mg/kg) completely prevents diarrhea in rodents, tissue distribution studies demonstrated that the principal metabolite of DEHSPM, homospermine (HSPM), accumulates and persists in tissues for a protracted period of time. This accumulation accounts for a large part of the chronic toxicity of DEHSPM. Thus a major objective was to develop a metabolically labile analogue of DEHSPM which retained the desirable biological properties of the parent drug. Hydroxyl groups, sites vulnerable to further metabolic transformation, were introduced into the external aminobutyl segments providing N1,N14-diethyl-(3R),(12R)-dihydroxyhomospermine [(HO)2-DEHSPM]. The design concept was assisted by molecular modeling, which predicted that (HO)2DEHSPM would have a Ki for polyamine transport essentially identical with that of DEHSPM. The experimentally measured Ki and also the observed values of other biological properties of (HO)2DEHSPM were in fact identical with those of DEHSPM, including IC50 against L1210 cells, impact on the NMDA receptor, and impact on L1210 native polyamine pools. Most significantly, however, there was no accumulation of the dideethylated metabolite in tissues from mice treated chronically with (HO)2DEHSPM, and (HO)2DEHSPM was 3-fold less toxic than DEHSPM. Finally, (HO)2DEHSPM completely prevented diarrhea in the castor oil-treated rat model at a dose of 5 mg/kg, just as did DEHSPM.

Animals↗
PubMed1996

Differential increase in neuropeptide Y-like levels and myenteric neuronal staining in diabetic rat intestine.

Neuropeptide Y is a regulatory peptide found in adrenergic and non-adrenergic neurons. Diabetes, which may cause autonomic neuropathy, induces an increase in hypothalamic neuropeptide Y (NPY) levels; thereby we measured the effects of chronic diabetes on neuropeptide Y in the intestine. Rats were injected with streptozotocin (65 mg/kg) and maintained for up to 20 weeks. Another group of rats was injected with 6-hydroxydopamine (50 mg/kg) x 2 to induce sympathectomy. Ileum and colon were harvested and both whole and microdissected intestine were (1) stained with antibodies to neuropeptide Y, vasoactive intestine polypeptide, and neurofilaments or (2) extracted for neuropeptide Y radioimmunoassay. Neuropeptide Y levels were similar under all conditions in the colon, but there was a trend toward an increase in the diabetic whole ileum. NPY levels were significantly increased in the dissected myenteric plexus ileal layer in diabetics. We noted an increase in the number of neuropeptide Y and vasoactive intestine polypeptide immunoreactive myenteric neurons in diabetics and after 6-hydroxydopamine-induced sympathectomy. Diabetes, and to a lesser extent sympathectomy, induced an increase in ileal neuropeptide Y levels and neuropeptide Y-staining myenteric but not submucosal neurons. Altered tissue levels of neuropeptide Y may account for certain of the gastrointestinal disturbances commonly seen in diabetes.

Animals↗
PubMed1996

Salsalate, morphine, and postoperative ileus.

BACKGROUND: Previously, we demonstrated that ketorolac, a nonsteroidal antiinflammatory drug (NSAID), prevented postoperative small bowel ileus in a rodent model. The aim of this study was to evaluate the effect of salsalate, an NSAID without antiplatelet effect, on postoperative ileus alone or in combination with morphine. METHODS: Forty-eight rats underwent placement of duodenal catheters and were then randomly assigned to one of eight groups (n = 6). Four groups had standardized laparotomy following drug administration, whereas 4 groups underwent the same treatment without laparotomy: control and morphine animals received 0.1 mL alcohol via the catheter, whereas salsalate and salsalate-plus-morphine animals received salsalate (15 mg/kg) dissolved in 0.1 mL alcohol. The animals also received 0.5 mg/kg morphine (morphine and salsalate plus morphine) or the same volume of saline (control and salsalate) subcutaneously. Transit was measured following the injection of a nonabsorbed marker via the duodenal catheter and is defined as the geometric center (GC) of distribution. An additional 20 rats had serosal electrodes placed on the jejunum, and were assigned to one of four treatment groups (control, salsalate, morphine, and salsalate plus morphine; n = 5 each group). Myoelectric activity was recorded until the reappearance of the migrating myoelectric complex (MMC) following laparotomy. RESULTS: Laparotomy and morphine independently reduced small bowel transit (P = 0.0006 and 0.006, respectively, by three-way analysis of variance [ANOVA]; GC 4.3 +/- 0.2 control versus 2.2 +/- 0.3 laparotomy versus 3.6 +/- 0.4 morphine), but morphine did not further worsen postoperative transit (GC 2.4 +/- 0.4; P = 0.42). Although salsalate did not alter baseline transit, pretreatment improved postoperative transit (P = 0.0002; GC 3.6 +/- 0.4). This effect was lost with the addition of morphine (GC 2.7 +/- 0.2; P = 0.21). The MMCs returned earlier after laparotomy in salsalate-pretreated rats (63 +/- 18 minutes salsalate versus 160 +/- 12 minutes laparotomy; P < 0.01, one-way ANOVA). However, this effect was also lost in animals receiving morphine (106 +/- 16 min; P > 0.05). CONCLUSION: Salsalate improves postoperative small bowel motility in a rodent model; however, this effect is masked by morphine.

Animals↗
PubMed1996

Metabolism and pharmacokinetics of N1,N14-diethylhomospermine.

The pharmacokinetics and metabolism of N1,N14-diethylhomospermine (DEHSPM) is described. Analysis of 15 min constant rate intravenous infusion data in dogs gave mean values of: plasma t1/2 = 1.04 hr; Vd = 0.514 liter/kg; CL = 0.343 liter/hr/kg; and AUC0-infinity = 43.2 mg/hr/liter. The renal t1/2 = 0.99 hr, with 36% of the drug recovered in the urine between 0-4 hr unchanged. In other experiments, the drug was administered to dogs by subcutaneous injection. Noncompartmental analysis of plasma concentration-time data showed a mean residence time (MRT) of 4.67 hr (subcutaneous) vs. 1.93 hr (intravenous). Mice and dogs received DEHSPM chronically to evaluate tissue distribution of DEHSPM and its metabolites. All tissues examined contained DEHSPM and its N-deethylated metabolites, N1-ethylhomospermine (MEHSPM) and homospermine (HSPM). On day 1 posttreatment, 35% of the total dose administered to mice was present in the liver (25%) and kidney (10%). The DEHSPM present declines rapidly (liver t1/2 = 1.6 days). The majority of the original dose was present as HSPM, which persisted in tissues for weeks (liver t1/2 = 15.4 days). These data suggest that DEHSPM and MEHSPM are metabolized by N-deethylation, but that HSPM is not susceptible to further degradation by polyamine catabolic enzymes that involves stepwise removal of aminopropyl equivalents by spermine/spermidine N1-acetyltransferase/polyamine oxidase. Thus, chronic DEHSPM dosing regimens in both dogs and mice may result in the accumulation of HSPM, which is retained by tissues for an extended period of time resulting in disruption of normal polyamine homeostasis in these tissues. These findings correlate with clinical and histopathological signs of toxicity in dogs and in mice.

Animals↗
PubMed1995

Vasoactive intestinal peptide and substance P receptor antagonists improve postoperative ileus.

Octreotide, a somatostatin analogue that inhibits the release of most gut peptides, hastens the resolution of experimental postoperative ileus, suggesting that gut peptides mediate this process. We studied the role of two gut peptides involved in the control of normal gut motility, vasoactive intestinal peptide (VIP), and substance P (SP), in the initiation and maintenance of postoperative small bowel ileus in rats by preoperative administration of VIP and SP receptor antagonists, (VIP-ra and SP-ra). Thirty male Sprague-Dawley rats (300-350 g) underwent laparotomy. One half underwent placement of a duodenal catheter for transit studies while the other half had serosal electrodes placed on the proximal jejunum for myoelectric recordings. Six days later, animals were separated into three treatment groups of five each. Control animals were pretreated with ip saline, while the others received either VIP-ra or SP-ra prior to standardized laparotomy. Following abdominal closure, [Na51]CrO4 was injected into the duodenum and the animals were sacrificed 25 min later. The small bowel was then excised and divided into 10 equal segments. Small bowel transit was calculated as the geometric center of [Na51]CrO4 distribution. The interval until the return of migrating myoelectric complexes (MMCs) was determined in animals with intestinal electrodes. VIP-ra-treated rats demonstrated a 67% improvement in the geometric center of radiolabel relative to controls and SP-ra-treated rats had a 23% improvement (3.67 +/- 0.06 VIP-ra vs 2.69 +/- 0.09 SP-ra vs 2.20 +/- 0.09 control, P < 0.01). MMCs returned 180 +/- 17 min in controls vs 99 +/- 14 min in VIP-ra-treated rats (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction.

Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20-33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2 +/- 0.3 AFs/4 hr, 2.7 +/- 0.7 min, and 85 +/- 23 min mm Hg to 4.1 +/- 0.8 AFs/4 hr, 5.5 +/- 0.7 min, and 152 +/- 24 min mm Hg, respectively (P < 0.05). Antral activity was decreased from 63 +/- 14 to 23 +/- 8% by octreotide (P < 0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

Adult↗
PubMed1995

The effect of Roux-en-Y diversion on gastric and Roux-limb emptying in a rodent model.

BACKGROUND: The "Roux stasis syndrome" is characterized by symptoms of upper gut stasis following Roux-en-Y gastrojejunostomy (RG). Whether symptoms result from delayed gastric emptying, altered Roux-limb transit, or both has never been settled, partly because of the difficulty of measuring Roux-limb transit. The aim of this study was to develop a model to simultaneously quantitate Roux-limb transit and gastric emptying. METHODS: Rats underwent vagotomy and antrectomy with RG or Billroth II reconstruction (B-II). Gastrointestinal transit of a solid meal (Technetium-99m sulfur colloid-labelled egg white) was assessed 0.5, 1, and 1.5 hours postprandial (pp). Transit of a liquid marker (Na51-CrO4 injected through an efferent-limb catheter) was measured at 25 minutes pp. RESULTS: Solid gastric emptying was slower in RG than in B-II rats at 60 and 90 minutes pp. More of the solid meal and of the liquid marker was retained in the Roux limb than the efferent limb of the B-II at all time points (P < 0.05). CONCLUSIONS: In a rodent model, Roux-en-Y gastrojejunostomy is associated with delayed gastric emptying and slowed efferent-limb transit of solids and liquids.

Analysis of Variance↗
PubMed1995

Insulin and insulin-like growth factor II suppress neuropeptide Y release from the nerve terminals in the paraventricular nucleus: a putative hypothalamic site for energy homeostasis.

It has been recently recognized that a distinct signaling pathway in the hypothalamus is involved in the stimulation of feeding in mammals. Neuropeptide Y (NPY), a member of the pancreatic polypeptide family, is the most potent orexigenic signal, and its secretion in discrete hypothalamic sites increases in response to insulinopenia produced by food deprivation or experimental diabetes. To establish the site of interaction between the hypothalamus and the pancreas, we examined the effects of insulin on NPY release in vivo and in vitro from hypothalamic sites known to be involved in feeding behavior. In the first study we evaluated the effects of peripheral insulin injections (1 U/kg.day, sc) on NPY levels in seven hypothalamic nuclei in food-deprived (FD) and ad libitum-fed rats. Whereas food deprivation for 3 days increased NPY levels in the medial preoptic area, paraventricular nucleus (PVN), and arcuate nucleus, insulin injections, which did not alter blood glucose levels, returned NPY levels to the control range selectively in the PVN. NPY levels in the hypothalamic nuclei remained unchanged after insulin injections in ad libitum-fed rats. The in vivo NPY release in the PVN of FD rats, evaluated by the push-pull cannula technique, also decreased in response to peripheral insulin injections. Finally, the effects of insulin, insulin-like growth factor I (IGF-I), and IGF-II on NPY release in vitro from the microdissected PVN and two central neighboring sites, the ventromedial nucleus and the median eminence-arcuate nucleus, of FD rats were evaluated. Both insulin (0.67 or 6.7 nM) and IGF-II (0.7 or 7.0 nM) decreased the release of NPY in a dose-dependent manner only from the PVN. On the other hand, IGF-I (0.07 or 7.0 nM) failed to alter the basal PVN NPY efflux. As the PVN is richly innervated by NPY-containing nerve terminals, the results of these in vivo and in vitro studies suggest that the site of insulin action on the hypothalamic NPY network may reside at the level of PVN nerve terminals or at the interneurons in contact with NPY nerve terminals. Although insulin may have a direct effect in reducing NPY release from the PVN, the effectiveness of IGF-II in decreasing NPY release from the PVN raises the possibility that insulin's action may also be mediated via hypothalamic IGF-II neuronal pathways.

Animals↗
PubMed1995

The impact of polyamine analogues on the blood pressure of normotensive and hypertensive rats.

The impact of the antineoplastic polyamine analogues N1N14-diethylhomospermine (DEHSPM) and N1N11-diethylnorspermine (DENSPM) on the blood pressure and heart rate of normotensive and hypertensive rats are described. DEHSPM was administered to both normotensive and spontaneously hypertensive rats (SHR), while the DENSPM analogue was given only to the normotensive animals. The intravenous administration of DEHSPM at doses of 5 or 10 mg/kg resulted in a profound and long-lasting drop in the test animals' blood pressure, with no appreciable change in their heart rate. This was true for both the normotensive and the hypertensive animals. When administered at equivalent molar dosages, DENSPM was one fifth as effective as DEHSPM at reducing blood pressure. The impact of NG-nitro-L-arginine-methyl ester (L-NAME) and L-arginine on the analogues' activity is consistent with the involvement of nitric oxide.

Amines↗
PubMed1994

Erythromycin enhances gastric emptying in patients with gastroparesis after vagotomy and antrectomy.

We studied the effect of erythromycin on gastric emptying in nine patients with gastroparesis following truncal vagotomy and antrectomy, and assessed their clinical response to chronic oral erythromycin. Gastric emptying was evaluated using a solid-phase radio-labeled meal. Patients were studied after erythromycin 200 mg intravenously (N = 9) and after an oral suspension of erythromycin 200 mg (N = 7) each given 15 min after ingestion of the meal. Three parameters of gastric emptying were analyzed: half-emptying time (T1/2), area under the curve, and percent gastric residual at 2 hr. Nine patients were subsequently placed on oral suspension erythromycin 150 mg three times a day before meals (range 125-250 mg three times a day) and symptoms of nausea, vomiting, postprandial fullness, and abdominal pain were assessed before and after erythromycin. Intravenous erythromycin markedly accelerated the gastric emptying (all three parameters studied) of solids (P < 0.01) in seven of nine patients with postsurgical gastroparesis [baseline T1/2 154 +/- 15 min; after intravenous erythromycin, T1/2 56 +/- 17 min (mean +/- SEM)]. Oral erythromycin enhanced (P < 0.05) the gastric emptying rate (T1/2, area under the curve) in five of seven patients (baseline T1/2 146 +/- 16 min; after oral erythromycin, T1/2 87 +/- 20 min). Of the nine patients who were placed on oral maintenance erythromycin, three showed clinical improvement after two weeks. In summary, erythromycin significantly enhances gastric emptying in many patients with vagotomy and antrectomy-induced gastroparesis; however, only a small subset of patients respond clinically to chronic oral erythromycin.

Administration, Oral↗