The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats.

Corticotropin releasing factor receptor 1 (CRF1) is the key receptor that mediates stress-related body responses. However to date there are no CRF1 antagonists that have shown clinical efficacy in stress-related diseases. We investigated the inhibitory effects of a new generation, topology 2 selective CRF1 antagonists, NGD 98-2 and NGD 9002 on exogenous and endogenous CRF-induced stimulation of colonic function and visceral hypersensitivity to colorectal distension (CRD) in conscious rats. CRF1 antagonists or vehicle were administered orogastrically (og) or subcutaneously (sc) before either intracerebroventricular (icv) or intraperitoneal (ip) injection of CRF (10 µg/kg), exposure to water avoidance stress (WAS, 60 min) or repeated CRD (60 mmHg twice, 10 min on/off at a 30 min interval). Fecal pellet output (FPO), diarrhea and visceromotor responses were monitored. In vehicle (og)-pretreated rats, icv CRF stimulated FPO and induced diarrhea in >50% of rats. NGD 98-2 or NGD 9002 (3, 10 and 30 mg/kg, og) reduced the CRF-induced FPO response with an inhibitory IC50 of 15.7 and 4.3 mg/kg respectively. At the highest dose, og NGD 98-2 or NGD 9002 blocked icv CRF-induced FPO by 67-87% and decreased WAS-induced-FPO by 23-53%. When administered sc, NGD 98-2 or NGD 9002 (30 mg/kg) inhibited icv and ip CRF-induced-FPO. The antagonists also prevented the development of nociceptive hyper-responsivity to repeated CRD. These data demonstrate that topology 2 CRF1 antagonists, NGD 98-2 and NGD 9002, administered orally, prevented icv CRF-induced colonic secretomotor stimulation, reduced acute WAS-induced defecation and blocked the induction of visceral sensitization to repeated CRD.

Cold ambient temperature reverses abdominal surgery-induced delayed gastric emptying and decreased plasma ghrelin levels in rats.

We investigated whether acute cold-induced vagal activation through brainstem thyrotropin-releasing hormone (TRH) signaling influences abdominal surgery-induced delayed gastric emptying (GE) in fasted rats. Laparotomy and cecal palpation or sham (short anesthesia alone) was performed 10 min before or 30 min after cold exposure (4-6°C) lasting 90 min. Non-nutrient GE was assessed during 70-90 min of cold exposure. Control groups remained at room temperature (RT). The stable TRH analog, RX-77368 (50 ng/rat) was injected intracisternally immediately before surgery and GE monitored 30-50 min postsurgery in rats maintained at RT. Plasma acyl (AG) and total ghrelin levels were assessed using the new RAPID blood processing method and radioimmunoassays. Desacyl ghrelin (DAG) was derived from total minus AG. In rats maintained at RT, abdominal surgery decreased GE by 60% compared to sham. Cold before or after surgery or RX-77368 normalized the delayed GE. In non-fasted rats, cold exposure increased plasma AG and DAG levels at 2 h (2.4- and 2.7-times, respectively) and 4 h (2.2- and 2.0-times, respectively) compared to values in rats maintained at RT. In fasted rats, abdominal surgery decreased AG and DAG levels by 2.4- and 2.1-times, respectively, at 90 min. Cold for 90 min after surgery normalized AG and DAG levels to those observed in sham-treated animals kept at RT. These data indicate that endogenous (cold exposure) and exogenous (TRH analog) activation of medullary TRH vagal signaling prevent abdominal surgery-induced delayed GE. The restoration of circulating AG levels inhibited by abdominal surgery may contribute to alleviate postoperative gastric ileus.

LPS inhibits fasted plasma ghrelin levels in rats: role of IL-1 and PGs and functional implications.

LPS injected intraperitoneally decreases fasted plasma levels of ghrelin at 3 h postinjection in rats. We characterized the inhibitory action of LPS on plasma ghrelin and whether exogenous ghrelin restores LPS-induced suppression of food intake and gastric emptying in fasted rats. Plasma ghrelin and insulin and blood glucose were measured after intraperitoneal injection of LPS, intravenous injection of IL-1beta and urocortin 1, and in response to LPS under conditions of blockade of IL-1 or CRF receptors by subcutaneous injection of IL-1 receptor antagonist (IL-1Ra) or astressin B, respectively, and prostaglandin (PG) synthesis by intraperitoneal indomethacin. Food intake and gastric emptying were measured after intravenous injection of ghrelin at 5 h postintraperitoneal LPS injection. LPS inhibited the elevated fasted plasma ghrelin levels by 47.6 +/- 4.9%, 58.9 +/- 3.3%, 74.4 +/- 2.7%, and 48.9 +/- 8.7% at 2, 3, 5, and 7 h postinjection, respectively, and values returned to preinjection levels at 24 h. Insulin levels were negatively correlated to those of ghrelin, whereas there was no significant correlation between glucose and ghrelin. IL-1Ra and indomethacin prevented the first 3-h decline in ghrelin levels induced by LPS, whereas astressin B did not. IL-1beta inhibited plasma ghrelin levels, whereas urocortin 1 had no influence. Ghrelin injected intravenously prevented an LPS-induced 87% reduction of gastric emptying and 61% reduction of food intake. These data showed that IL-1 and PG pathways are part of the early mechanisms by which LPS suppresses fasted plasma ghrelin and that exogenous ghrelin can normalize LPS-induced-altered digestive functions.

Complications of achalasia surgery.

The development of minimally invasive techniques have revolutionized the surgical therapy of achalasia and made myotomy with or without partial fundoplication the treatment of choice for most patients. Complications do occur, however, and every effort must be made to minimize their occurrence and identify and treat them effectively when they occur to maximize the likelihood of an excellent outcome in these patients who have a benign but incurable disorder. Further studies on the best location for the myotomy as well as the best type of fundoplication will help refine the procedure for future generations of patients.

Fluid and electrolytes in the aged.

OBJECTIVE: To review the physiological changes in fluid and electrolytes that occur in aging. DATA SOURCES: Data collected for this review were identified from a MEDLINE database search of the English-language literature. The indexing terms were fluids, intravenous fluids, fluid resuscitation, fluid management, perioperative, electrolytes, aged, elderly, hemodynamics, hyponatremia, hypernatremia, hypocalcemia, hypercalcemia, hypomagnesemia, hypermagnesemia, hypophosphatemia, hypokalemia, and hyperkalemia. Relevant references from articles obtained by means of the above search terms were also used. STUDY SELECTION: All pertinent studies were included. Only articles that were case presentations or did not specifically address the topic were excluded. DATA SYNTHESIS: The fastest-growing segment of the population in the United States is individuals 65 years or older. It is imperative that health care professionals review the physiological changes that manifest during the aging process. Fluids and electrolytes are important perioperative factors that undergo age-related changes. These changes include impaired thirst perception; decreased glomerular filtration rate; alterations in hormone levels, including antidiuretic hormone, atrial natriuretic peptide, and aldosterone; decreased urinary concentrating ability; and limitations in excretion of water, sodium, potassium, and acid. CONCLUSIONS: There are age-related alterations in the homeostatic mechanisms used to maintain electrolyte and water balance. Health care providers must familiarize themselves with these alterations to guide treatment of this growing population.

Corticotropin-releasing factor receptor 1-deficient mice do not develop postoperative gastric ileus.

BACKGROUND & AIMS: Corticotropin-releasing factor (CRF) signaling pathways play a key role in the stress response through the activation of CRF(1) and CRF(2) receptors. We investigated the CRF receptor subtypes involved in gastric postoperative ileus. METHODS: Adult male mice (C57BL/6, CRF(1)-deficient, and wild-type), fasted for 16-18 hours, were anesthetized for 10 minutes and had a midline celiotomy and cecal exteriorization and palpation for 30 or 60 seconds or no surgery (sham). Phenol red was given by gavage 100 minutes after anesthesia; 20 minutes later, gastric emptying and blood glucose level were measured. RESULTS: In C57BL/6 mice, cecal palpation for 30 or 60 seconds significantly reduced gastric emptying to 30.3% +/- 1.4% and 5.8% +/- 3.4%, respectively, compared with 58.5% +/- 4.4% in sham. The CRF(1) antagonist CP-154,526 (20 mg/kg subcutaneously) completely prevented the 30-second cecal palpation-induced delayed gastric emptying (53.0% +/- 7.9% vs. 28.0% +/- 4.0% in vehicle + surgery), whereas the CRF(2) antagonist astressin(2)-B injected subcutaneously had no effect. In CRF(1)-deficient mice, cecal palpation for 30 seconds did not delay gastric emptying (80.3% +/- 4.5% compared with 84.7% +/- 6.3% in sham); in wild-type mice, gastric emptying was decreased to 17.8% +/- 16.1% (P < 0.05 vs. sham 72.0% +/- 12.4%). Surgery increased glucose levels by 46% compared with sham in wild-type mice, while glycemia was not altered in CRF(1)-deficient mice. Basal emptying was similar in wild-type and CRF(1)-deficient mice and not influenced by CRF antagonists in C57BL/6 mice. CONCLUSIONS: These data show that CRF(1) activation plays an important role in mediating the early phase of gastric ileus.

Mechanisms and treatment of postoperative ileus.

OBJECTIVE: To review the pathogenesis and treatment of postoperative ileus. DATA SOURCES: Data collected for this review were identified from a MEDLINE database search of the English-language literature. The exact indexing terms were "postoperative ileus," "treatment," "etiology," and "pathophysiology." Previous review articles and pertinent references from those articles were also used. STUDY SELECTION: All relevant studies were included. Only articles that were case presentations or that mentioned postoperative ileus in passing were excluded. DATA SYNTHESIS: The pathogenesis of postoperative ileus is complex, with multiple factors contributing either simultaneously or at various times during the development of this entity. These factors include inhibitory effects of sympathetic input; release of hormones, neurotransmitters, and other mediators; an inflammatory reaction; and the effects of anesthetics and analgesics. Numerous treatments have been used to alleviate postoperative ileus without much success. CONCLUSIONS: The etiology of postoperative ileus can best be described as multifactorial. A multimodality treatment approach should include limiting the administration of agents known to contribute to postoperative ileus (narcotics), using thoracic epidurals with local anesthetics when possible, and selectively applying nasogastric decompression.