Direct proabsorptive effect of octreotide on ionic transport in the small intestine.

Somatostatin is widely distributed within the nervous system and the gastrointestinal tract. Gastrointestinal actions of somatostatin include inhibition of hormone release, reduction of pancreatic secretion, inhibition of motility, and reduction of blood flow. The purpose of this study was to investigate the role of somatostatin and its analogue octreotide on water and electrolyte transport in the small intestine. Rabbit ileal segments (n = 17) were harvested and arterially perfused ex vivo with a nonrecirculating oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing carbon 14-labeled polyethylene glycol. Net fluxes of water, Na+, and Cl- were calculated for three 20-minute periods designated basal, drug infusion, and recovery. Three groups were studied: somatostatin at 10(-6) mol/L (n = 5), somatostatin at 10(-5) mol/L (n = 5), and octreotide at 10(-5) mol/L (n = 7). Somatostatin at 10(-5) mol/L yielded a proabsorptive effect on the flux of water and electrolytes. Octreotide at 10(-5) mol/L caused a significant (p less than 0.05) proabsorptive response in the fluxes of water, sodium, and chloride during the period of drug infusion, which returned to basal secretory levels during the recovery period. This proabsorptive effect occurred without alterations in vascular resistance and necessarily was independent of systemic hormone interaction, supporting a direct effect of octreotide on intestinal ionic transport.

Small-bowel origin of the signal for meal-induced jejunal absorption.

A meal stimulates the absorption of water and electrolytes from the proximal jejunal lumen. Neither sham feeding nor gastric distention alters this meal-induced jejunal absorption, implying no role for the cephalic or gastric phases of digestion. This study tested the hypothesis that the small bowel is the origin of the proabsorptive signal for meal-induced jejunal absorption. Twenty-five-centimeter canine proximal jejunal Thiry-Vella fistulas were constructed, and chronic duodenal catheters were placed. Jejunal absorption studies (n = 72) were performed by luminal perfusion of the jejunal segments with an isotonic buffer containing radioactive carbon-labeled polyethylene glycol. Each study consisted of a 1-hour basal period followed by a 3-hour experimental period. Ten groups were studied: control, orally ingested mixed meal, and 600 ml duodenal infusions of either water, saline solution, protein, lipid, carbohydrate, 150 mmol/L mannitol, 300 mmol/L mannitol, or 600 mmol/L mannitol, each delivered at 10 ml/min over 60 minutes. The control, water, and saline solution groups showed no significant changes in integrated 3-hour jejunal absorption above basal. The ingested mixed meal significantly increased water and electrolyte absorption (p less than 0.0001). The isovolumetric, isocaloric duodenal nutrient infusions of protein, lipid, and carbohydrate all significantly increased jejunal water and electrolyte absorption (p less than 0.0001). The poorly absorbed solute mannitol significantly increased absorption (p less than 0.0001) in a dose-dependent fashion. These results indicate that the proabsorptive signal for meal-induced jejunal absorption originates from or distal to the duodenum. This newly defined enteroenteric response occurs independently of nutrient composition and responds to increasing osmolarity of poorly absorbed solutes such as mannitol.

The proabsorptive effect of D-ala2-metenkephalinamide is mediated by naloxone-sensitive opiate receptors in the isolated perfused ileum.

Methionine-enkephalin is an endogenous opiate pentapeptide, originally isolated in the brain, that exists within enteric plexuses and enterocytes. The purpose of this study was to delineate the effects of the opiate agonist methionine-enkephalin on intestinal water and electrolyte transport, with the stable analog D-ala2-metenkephalinamide (m-ENK). Ileal segments from New Zealand white rabbits (n = 39) were harvested and vascularly and luminally perfused ex vivo. Net fluxes of H2O, Na+, and Cl- were calculated for three 20-minute periods: basal, drug infusion, and recovery. Six groups were studied: (1) control, (2-4) m-ENK at three doses, (5) naloxone, and (6) naloxone plus m-ENK. Oxygen consumption and arterial perfusion pressure were assessed as measures of metabolic activity and viability. The control and naloxone groups had no changes in the fluxes of water and electrolytes. Significant proabsorptive effects were demonstrated for the fluxes of H2O, Na+, and Cl- at increasing doses of m-ENK (p less than 0.05). Naloxone completely prevented m-ENK-induced absorption. These results with exogenous m-ENK suggest that endogenous methionine-enkephalin, serving as an enteric neurotransmitter and acting through naloxone-sensitive opiate receptors, may function as a physiologic modulator of intestinal water and electrolyte absorption.

Postreceptor mechanisms of small-bowel water and electrolyte transport.

Neurohumoral agents modulate intestinal transport by interactions with cell membrane receptors. Intracellular second messenger systems implicated in mediation of membrane receptor regulation of cellular events include the phosphoinositide and adenylate cyclase systems. In this study we have investigated the effects of direct postreceptor activation of key components of these systems on intestinal water and electrolyte transport. Rabbit ileal segments (n = 35) were arterially perfused ex vivo with an oxygenated sanguineous solution. The lumen was perfused with an isotonic solution containing 14C-polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- in six experimental groups were calculated for three 20-minute periods: basal, drug infusion, and recovery. The control group had no drug infusion. Two phorbol esters--phorbol 12, 13-diacetate (PDA; 10(-5) mol), and phorbol 12, 13-dibutyrate (PDB; 10(-5) mol)--were used to activate protein kinase C, an important component of the phosphoinositide system. The inactive 4 alpha-phorbol 12, 13-didecanoate (PDD; 10(-5) mol) served as a drug-infused control. Forskolin at two doses (FOR; 10(-5) mol and 10(-6) mol) was used to activate adenylate cyclase. The control and PDD groups had no changes in the flux of water and electrolytes. Both PDA and PDB had proabsorptive effects, with the more lipophilic and potent phorbol ester (PDB) having a more pronounced, significant effect (p less than 0.05). FOR caused significant secretion of H2O, Na+, and Cl- in a dose-dependent fashion (p less than 0.05). These results indicate that direct protein kinase C activation causes a proabsorptive effect and that direct activation of adenylate cyclase causes a secretory effect in the isolated small bowel. The activation status of these second messenger systems has a major influence on the transport state of the intestine.

The effect of pancreatic polypeptide infusion on glucose tolerance and insulin response in longitudinally studied pancreatitis-induced diabetes.

Glucose intolerance is often associated with pancreatitis. Pancreatitis-induced diabetes represents a different clinical syndrome than type I and type II diabetes mellitus. Patients with pancreatitis-induced diabetes may be extremely sensitive to exogenous insulin, rarely develop ketoacidosis, and rarely exhibit classic diabetic complications, such as retinopathy, nephropathy, or accelerated vasculopathy. Pancreatic polypeptide (PP) deficiency has been implicated in the defect of glucose homeostasis found after pancreatitis. This study evaluated intravenous and oral glucose tolerance and insulin response to glucose loading, in the setting of pancreatitis, with and without short-term PP replacement. Dogs (n = 7) underwent pancreatic duct ligation (PDL) and were studied with and without PP infusion (2 micrograms/kg/hr) before PDL and at 1 week, 6 weeks, and 4 months after PDL by means of intravenous and oral glucose tolerance tests. Basal and bombesin-stimulated PP levels at 4 months after PDL were subnormal, verifying PP deficiency in these animals with pancreatitis. PP levels during PP infusion reproduced normal postcibal levels, averaging 897 +/- 40 pg/ml. Glucose tolerance, expressed as the glucose decay constant for the intravenous glucose tolerance tests and as the integrated glucose response for the oral glucose tolerance tests, deteriorated over time and was not improved by acute PP replacement. The integrated insulin response to glucose was not affected by PP. The acute infusion of PP at a dose that reproduces normal postprandial PP levels fails to improve glucose tolerance or augment insulin release in this model of pancreatitis-induced diabetes.

Preoperative chemoradiation for marginally resectable adenocarcinoma of the pancreas.

Only 10% to 20% of patients with pancreatic cancer are considered candidates for curative resection at the time of diagnosis. We postulated that preoperative chemoradiation therapy might promote tumor regression, eradicate nodal metastases, and allow for definitive surgical resection in marginally resectable patients. The objective of this study was to evaluate the effect of a preoperative chemoradiation therapy regimen on tumor response, resectability, and local control among patients with marginally resectable adenocarcinoma of the pancreas and to report potential treatment-related toxicity. Patients with marginally resectable adenocarcinoma of the pancreas (defined as portal vein, superior mesenteric vein, or artery involvement) were eligible for this protocol. Patients received 50.4 to 56 Gy in 1.8 to 2.0 Gy/day fractions with concurrent protracted venous infusion of 5-fluorouracil (250 mg/m2/day). Reevaluation for surgical resection occurred 4 to 6 weeks after therapy. Fifteen patients (9 men and 6 women) completed preoperative chemoradiation without interruption. One patient required a reduction in the dosage of 5-fluorouracil because of stomatitis. Acute toxicity from chemoradiation consisted of grade 1 or 2 nausea, vomiting, diarrhea, stomatitis, palmar and plantar erythrodysesthesia, and hematologic suppression. CA 19-9 levels declined in all nine of the patients with elevated pretreatment levels. Nine of the 15 patients underwent a pancreaticoduodenectomy, and all had uninvolved surgical margins. Two of these patients had a complete pathologic response, and two had microscopic involvement of a single lymph node. With a median follow-up of 30 months, the median survival for resected patients was 30 months, whereas in the unresected group median survival was 8 months. Six of the nine patients who underwent resection remain alive and disease free with follow-up of 12, 30, 30, 34, 39, and 72 months, respectively. Preoperative chemoradiation therapy is well tolerated. It may downstage tumors, sterilize regional lymph nodes, and improve resectability in patients with marginally resectable pancreatic cancer. Greater patient accrual and longer follow-up are needed to more accurately assess its future role in therapy.

Endogenous opiates in the mediation of early meal-induced jejunal absorption of water and electrolytes.

The purpose of this study was to investigate the role of endogenous opiates in mediating meal-stimulated jejunal absorption. Jejunal Thiry-Vella loops, 25 cm long, were studied in awake conditioned dogs, using luminal perfusion with carbon-14 polyethylene glycol. Fluxes of water, sodium, and chloride were calculated every 15 minutes over a 1-hour basal period, followed by a 3-hour experimental period. The animals were divided into four groups: control, naloxone, meal, and meal plus naloxone. In the control and naloxone groups, the fluxes did not change over the 4-hour observation period. Meal alone immediately stimulated the absorption of water and electrolytes in the Thiry-Vella loop (p less than 0.05). The addition of naloxone infusion to the meal stimulus resulted in significantly reduced absorption during the first hour after the meal (p less than 0.05). We concluded that endogenous opiates play a role in meal-stimulated jejunal absorption.

Instant nutritional assessment.

Instant nutritional assessment of the hospitalized patient is described based upon admission serum albumin levels and total lymphocyte counts. Abnormalities of these parameters are associated with markedly increased morbidity and mortality in a series of 500 consecutively admitted patient. It is suggested that instant nutritional assessment be performed on all hospitalized patients with appropriate alterations and therapy being made to allow for nutritional repletion.

Feasibility of partial A2 and A4 pulley excision: residual pulley strength.

We investigated residual digital flexor pulley strengths after 75% excision of the A2 and A4 pulleys. For direct pull-off tests, A2 and A4 pulleys from cadaveric fingers were tested by pulling on a loop of flexor digitorum profundus tendon through the pulley. For functional loading tests, fingers were positioned with the metacarpophalangeal joint flexed to 90 degrees for A2 testing, and with the proximal interphalangeal joint in 90 degrees flexion for A4 testing (with all other joints in full extension). Excision of 75% of A2 and A4 pulleys reduced pulley strengths determined by both testing methods. For the functional loading tests, which are more clinically relevant, mean tendon forces at failure after partial excision of A2 and A4 pulleys were 224 and 131 N respectively, which is sufficient to withstand flexor tendon forces expected during activities of daily living.

Neurohumoral mechanism involved in augmentation of canine jejunal absorption following oral rehydration solutions.

Throughout the world diarrheal diseases kill over 5 million children annually. Oral rehydration therapy, initially using glucose-based solutions and more recently cereal-based solutions, prevents complications and death from dehydration. These experiments compared the effect of these two rehydration solutions and a mixed meal on jejunal water and ionic transport. Five dogs had 25-cm proximal jejunal Thiry-Vella fistulae constructed. Following recovery, jejunal absorption studies (N = 40) were performed using an isotonic electrolyte solution containing [14C]PEG to calculate net fluxes of water, sodium, and chloride. Each study consisted of a 1-hr basal period, followed by a 3-hr experimental period. Each animal was randomly studied in each of four study groups: control, mixed meal, glucose-based and cereal-based rehydration solution. In the mixed meal, glucose-based, and cereal-based solution groups there were significant increases (P < 0.0001) in jejunal Thiry-Vella fistula water and ion absorption following the stimuli, in the absence of direct luminal nutrient contact with the Thiry-Vella fistula. There were no differences between the observed responses to the glucose-based or cereal-based rehydration solutions. Glucose-based and cereal-based rehydration solutions were equally effective in stimulating jejunal absorption of water and electrolytes, but less effective than a mixed meal. Both food and oral rehydration solutions appear to increase jejunal absorption partially via a neurohumoral mechanism that is independent of luminal nutrient contact with the Thiry-Vella fistula.

Influence of meal composition on canine jejunal water and electrolyte absorption.

The absorption of water and electrolytes from the proximal jejunal lumen increases immediately after a meal. This meal-induced jejunal absorption occurs in jejunal segments out of normal gastrointestinal continuity. This study was designed to characterize the jejunal absorptive response to a series of isovolumetric gavage-delivered stimuli. Twenty-five-centimeter canine proximal jejunal Thiry-Vella fistulas were constructed, and jejunal absorption studies (n = 66) were performed by luminal perfusion of the jejunal segments with an isotonic buffer containing 14C-labeled polyethylene glycol. Each study consisted of a 1-hour basal period, followed by a 3-hour experimental period. Nine groups were studied, each receiving one of the following isovolumetric stimuli delivered via the gavage route: water, 0.9% saline, mixed meal, protein, lipid, carbohydrate, and mannitol (150 mmol/L, 300 mmol/L, and 600 mmol/L). The water and 0.9% saline gavage groups showed no significant changes in integrated postprandial water and electrolyte absorption above basal. The isocaloric mixed meal, protein, lipid, carbohydrate, and mannitol groups all had significantly increased integrated postprandial jejunal water and electrolyte absorption above basal (P less than 0.05). These results indicate that a proabsorptive signal for meal-induced jejunal absorption originates from or distal to the stomach. Meal-induced jejunal absorption occurs in response to nutrients of diverse composition and is also responsive to nonnutritive solutes such as mannitol. These findings support a new role for gastric or intestinal chemo- or osmo-receptors in stimulating the neurohumoral mechanisms that mediate meal-induced jejunal absorption.

Low-profile versus conventional metacarpal plating systems: a comparison of construct stiffness and strength.

Smaller, lower-profile plates for metacarpal fixation may have the potential to reduce extensor tendon irritation and adhesions, but their sufficiency for stabilizing metacarpal fractures has not been studied. We investigated the relative stiffness and strength of low-profile and conventional plating systems. For apex dorsal bending (bending closed), no plates broke or had notable plastic deformation. The conventional plates exhibited higher overall bending rigidity than all other plates, but had a lower maximum bending moment than the smaller plates. In apex volar bending (bending open) and torsion, the conventional plates were remarkably more rigid and developed remarkably higher torque. In vivo metacarpal loads are primarily apex dorsal bending, and all plates performed well in this mode. Thus, the smaller, low-profile plates may be sufficient for metacarpal fixation, although patient compliance and the use of supplemental stabilization with a cast or splint should be considered.

Passive and active rehabilitation for partial lacerations of the canine flexor digitorum profundus tendon in zone II.

The purpose of this study was to compare the effect of unrestricted active versus passive mobilization on the gliding function and structural properties (ultimate load and stiffness) of repaired and nonrepaired canine flexor digitorum profundus tendons following partial laceration at 1 week. Using a radiographic method, normalized tendon gliding of the flexor digitorum profundus tendon adjacent to the metacarpal bone and total joint rotation were shown to be significantly greater in passive than in active tendons. Each group differed from their control group, however, by an average of only 5%. Both rehabilitation (active vs. passive) and treatment (repair vs. nonrepaired) of the partial tendon laceration significantly affected gap formation. Both active rehabilitation and repair of the laceration significantly increased gap formation compared with passive rehabilitation and nonrepair of the partial laceration. Rehabilitation did not significantly affect the normalized ultimate loads and stiffness in the passive and active groups but the nonrepair groups displayed significantly higher ultimate loads and stiffness than the repair groups.

Neural blockade in basal and postreceptor-stimulated intestinal transport.

Postreceptor protein stimulation significantly alters the transport state of the ex vivo small intestine. This study investigated the effects of neural blockade on basal and stimulated ionic transport. Rabbit ileal segments (n = 46) were arterially perfused with an oxygenated sanguinous buffered electrolyte solution. The lumen was perfused with an isotonic solution containing [14C]polyethylene glycol as a nonabsorbable marker. Net fluxes of H2O, Na+, and Cl- were calculated. Tetrodotoxin (TTX) was used to block enteric neural transmission. Forskolin (FOR) was used to activate adenylate cyclase, and phorbol 12,13-dibutyrate (PDB) served to activate protein kinase C. Two groups were studied. Group A preparations had no TTX pretreatment, while group B preparations were pretreated with TTX. In the Group A preparations, TTX at 10(-6) M and PDB at 10(-5) M caused significant proabsorptive effects with a delta FH2O of +20 +/- 7 and +15 +/- 2 microliters/min, respectively (P less than 0.05), while FOR stimulated significant secretion with a delta FH2O of -14 +/- 3 microliter/min (P less than 0.05). In the Group B TTX-pretreated preparations, FOR did not cause secretion and PDB maintained an absorptive state. These results indicate that neural blockade with TTX reverses basal secretion in the ex vivo intestine, suggesting that an intact enteric nervous system maintains the secretory status of the intestine. FOR-induced adenylate cyclase-activated secretion does not occur in the presence of TTX, implying that intact neural transmission is required for the FOR effect. PDB-induced protein kinase C-activated absorption occurs despite neural blockade, suggesting that the PDB-induced proabsorptive effect is mediated without neural intermediaries.

Meal-stimulated absorption of water and electrolytes in canine jejunum.

After a meal, the absorption of water and electrolytes from the jejunal lumen increases. This meal-induced jejunal absorption occurs in jejunal segments out of normal gastrointestinal continuity. The experimental model used 25-cm proximal jejunal Thiry-Vella loops in awake dogs (n = 72 observations) to evaluate the mechanisms involved in meal-induced jejunal absorption, seeking to define the source or sources of the proabsorptive signal. Specifically, we evaluated the jejunal absorptive response to a standard meal, a standard meal plus cholinergic blockage using atropine, a sham-fed meal, a gavage-fed meal, and gastric distension with balloon and gavage water. Both the standard meal and the gavage-fed meal induced a prompt, sustained, and significant (P less than 0.0001) increase in the absorption of H2O, Na+, and Cl-. Atropine significantly reduced the magnitude of the postmeal absorptive response (P less than 0.05) compared with the standard meal alone. The sham-fed meal, gastric balloon distension, and gavage water did not alter jejunal absorption. Vagal nerve integrity after cervical esophageal manipulation was verified by gastric acid output and gastrin response to stimuli. These data support a role for cholinergic modulation of meal-stimulated jejunal absorption via a cephalic-phase-independent and gastric-distension-independent mechanism.

Luminal adrenergic agents modulate intestinal transport.

Intestinal transport is controlled by luminal solutes, neural pathways, and paracrine or humoral agents. The current study investigated the effect of luminally administered adrenergic agents on the intestinal transport of water and electrolytes. Dogs with 25-cm jejunal Thiry-Vella loops were studied. The loops were luminally perfused with an isotonic solution containing [14C]PEG, and the fluxes of H2O, Na+, and Cl- were calculated. Each experiment consisted of three 1-hr periods: basal, luminal agent infusion, and recovery. Luminal adrenergic agents did not alter heart rate. Norepinephrine (alpha 1 greater than alpha 2 and beta adrenergic agonist) and phenylephrine (alpha 1 adrenergic agonist) caused significant absorption of water and sodium. Clonidine (alpha 2 adrenergic agonist) and isoproterenol (beta adrenergic agonist) caused significant secretion of water, sodium, and chloride. Luminally administered adrenergic agents can influence small intestinal water and electrolyte transport. Alpha 1 agonists have a proabsorptive effect, while alpha 2 and beta agonists have a secretory effect. Luminally administered proabsorptive adrenergic agents may prove useful in pathologic secretory states such as diabetic diarrhea, small bowel transplantation, or diarrhea-associated endocrinopathies.