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Biomedical subjects

M J Zinner

Publications and source records attributed to M J Zinner.

At least 91 records · Page 5Linked to original sources
PubMed1989

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.

Animals↗
PubMed1988

Treatment of instrumental perforation of esophageal malignancy by transhiatal esophagectomy.

Perforation of esophageal malignancy secondary to instrumentation is an uncommon but catastrophic complication. Esophageal perforation at the site of an obstructing esophageal malignancy precludes simple operative repair and mandates esophageal resection with reestablishment of gastro-intestinal tract continuity. In the past the standard surgical approach has involved transthoracic esophageal resection via thoracotomy. We have successfully treated four patients with perforated esophageal neoplasms by transhiatal esophagectomy and cervical esophagogastrostomy, thus avoiding thoracotomy in high-risk patients. We consider transhiatal esophagectomy an advantageous alternative in the management of selected cases of instrumental esophageal perforation adjacent to an esophageal malignancy.

Adult↗
PubMed1988

Vagal release of serotonin into gut lumen and portal circulation via separate control mechanisms.

The mechanisms controlling vagally induced release of serotonin-like immunoreactivity (5-HTLI) into portal circulation and jejunal lumen were studied in individual cats. In control animals, electrical vagal nerve stimulation significantly enhanced both the endoluminal secretion rate of 5-HTLI and the release of 5-HTLI into the portal vein. The vagally induced release of 5-HTLI into portal circulation was blocked by pretreatment with propranolol or phenoxybenzamine, or by previous removal of the superior cervical ganglia, but was not blocked by atropine or hexamethonium. On the contrary, the luminal secretion of 5-HTLI after vagal stimulation was not blocked by adrenoceptor blocking agents or ganglionectomy, but instead was inhibited by cholinoceptor antagonists. Thus, in the same experimental animals it was shown that vagally induced release of 5-HTLI into portal circulation was mediated by adrenoceptor mechanisms, while endoluminal release of 5-HTLI was regulated via cholinoceptors. Based on indirect estimations, the apical release of 5-HT seems to be quantitatively small in comparison with the release into portal circulation.

Animals↗
PubMed1988

The effect of calcium channel blockade on basal- and substance P-induced intestinal secretion.

Calcium plays a central role in modulating many physiologic events. We have investigated the role of calcium channel blockade in the control of basal (n = 6)- and substance P-stimulated (n = 6) intestinal transport in the isolated perfused rabbit ileum. Twenty-centimeter segments of ileum, harvested from New Zealand rabbits, were arterially perfused at 1.5 ml/min with an oxygenated modified Krebs buffer solution containing washed human red cells (Hct = 15-20%) and 2.5 mM Ca2+. The intestinal lumen was perfused at 2 ml/min with an isotonic solution containing 1.2 mM Ca2+ and [14C]PEG as a nonabsorbable volume marker. The infusion of verapamil (1 microgram/min) significantly reduced (P less than 0.05) the basal secretion of H2O, and Cl-. Verapamil prevented the secretory effect of substance P infused at 0.25 microgram/min. Intraarterial verapamil had no effect on vascular perfusion pressure. These data indicate that calcium channel blockade has significant effects on basal- and substance P-stimulated intestinal secretion and suggest that transmembrane calcium fluxes function as major determinants of basal- and secretagogue-stimulated intestinal transport.

Animals↗
PubMed1988

The effect of norepinephrine on intestinal transport and perfusion pressure in the isolated perfused rabbit ileum.

Norepinephrine (NE) is an autonomic neurotransmitter and a potent vasoactive agent, with putative effects on intestinal absorption and secretion. To characterize the effects of NE on intestinal water and ion transport, independent of changes in intestinal blood flow, we studied the effects of three doses of NE (0.1, 0.4, and 2.0 microgram/min) on the isolated, vascularly perfused rabbit ileum at a constant vascular perfusion rate. Twenty-centimeter segments of New Zealand white rabbit distal ileum (n = 21) were vascularly perfused at a fixed rate of 1.5 ml/min using a modified Krebs buffer solution (37 degrees C) containing washed human red blood cells with a hematocrit of 15-20%. The intestinal lumen was perfused at 2 ml/min with a warm buffered isotonic electrolyte solution containing 10 microCi [14C]PEG as a nonabsorbable volume marker. Net fluxes of H2O, Na+, and Cl- were calculated during 20-min basal, NE infusion, and recovery periods. Perfusion pressure was monitored continuously. NE caused statistically significant graded increases in vascular resistance, as reflected by perfusion pressure, with increasing doses. NE stimulated absorption of H2O, Na+, and Cl- with a less distinct response to increasing dose. These data suggest that the separate effects of NE on absorption and hemodynamics may be mediated through different pathways or different receptors in the intestine.

Animals↗
PubMed1988

Resection of hepatic duct bifurcation and transhepatic stenting for sclerosing cholangitis.

Thirty-one patients with sclerosing cholangitis underwent reconstruction of their hepatic duct bifurcation and long-term stenting between 1980 and 1987. Indications for surgery were persistent jaundice in 29 and recurrent cholangitis in two. The mean serum bilirubin level before surgery was 10.4 mg/dl. Liver biopsy revealed that 26 patients had varying degrees of hepatic fibrosis, and five patients had progressed to secondary biliary cirrhosis. In 29 patients the major obstructive duct disease was at or near the hepatic duct bifurcation, and in two patients it was in the distal common duct. The operative procedure consisted of: (1) excision of the hepatic duct bifurcation and extrahepatic biliary tree, (2) dilatation of the intrahepatic ducts, (3) insertion of Silastic transhepatic biliary stents, and (4) bilateral hepaticojejunostomies. Two of the five patients (40%) with cirrhosis died after surgery. In contrast, only one of 26 patients (3.9%) with hepatic fibrosis died after operation. The 1-, 3-, and 5-year actuarial survival rates for patients with cirrhosis were 20%, 20%, and 20%, respectively. The only long-term survivor underwent a liver transplant. The 1-, 3-, and 5-year actuarial survival rates for patients with hepatic fibrosis were 92%, 87%, and 71%, respectively. In addition, the mean serum bilirubin levels of patients with hepatic fibrosis at 1, 2, 3, 4, and 5 years were 3.4 mg/dl, 2.9 mg/dl, 4.0 mg/dl, 5.4 mg/dl, and 4.3 mg/dl, respectively. Two of the long-term survivors subsequently underwent a liver transplant. Patients with sclerosing cholangitis, persistent jaundice, and biliary cirrhosis should be referred for consideration of liver transplantation. However, in the absence of biliary cirrhosis, if the major obstructive disease is at the hepatic duct bifurcation, primary biliary reconstruction and long-term stenting should be considered.

Adult↗
PubMed1988

Discrimination between alpha 1- and alpha 2-adrenergic receptors in the isolated perfused ileum.

Adrenergic control over intestinal homeostasis has been associated with changes in intestinal vascular resistance, motility, and transport. With the use of selective alpha-adrenergic agents, this study was designed to discriminate between the vascular and transport effects. Rabbit 20 cm ileal segments (n = 31) were vascularly perfused at a rate of 1.5 ml/min by means of a modified Krebs solution containing 15% to 20% red cells. The intestinal lumen was perfused with an isotonic solution containing carbon 14-polyethylene glycol as a nonabsorbable marker. Net fluxes of water and electrolytes were calculated during 20-minute basal, experimental, and recovery periods. Norepinephrine (mixed alpha 1- and alpha 2-agonist) significantly increased intestinal absorption and vascular resistance. Phenylephrine (alpha 1-agonist) significantly increased vascular resistance without altering transport. Clonidine (alpha 2-agonist) stimulated intestinal absorption without changing vascular perfusion pressure. Yohimbine (alpha 2-antagonist) prevented norepinephrine-induced absorption but had no effect on norepinephrine-induced increases in perfusion pressure. In this isolated perfused whole gut model, alpha 1-adrenergic stimulation was responsible for increases in vascular resistance, and alpha 2-adrenergic stimulation was responsible for increases in the absorption of water and electrolytes. The ability to discriminate between alpha 1- and alpha 2-effects has potential therapeutic implications in patients with malabsorption and diarrhea.

Adrenergic alpha-Agonists↗
PubMed1987

Regulatory mechanisms in endoluminal release of serotonin and substance P from feline jejunum.

The mechanisms controlling vagally induced 5-HT and SP release into the jejunal lumen were studied in the cat. In control animals, electrical vagal nerve stimulation doubled the rate of endoluminal secretion of 5-HT and SP. Propranolol pretreatment did not alter luminal secretion of these hormones. Atropine suppressed motor function and induced dose-related inhibition of vagal release of endoluminal 5-HT, but not of SP; the response to hexamethonium pretreatment was similar to that of atropine. In contrast, superior cervical ganglionectomy did not alter stimulated endoluminal 5-HT release but it completely abolished release into the portal vein. The portal 5-HT release was not affected by ganglionic blockade. The data suggest that vagally mediated 5-HT release into the lumen and the portal circulation are mediated by different neural mechanisms, the former cholinergic, the latter presumably adrenergic; and release of feline 5-HT and SP are independent, suggesting two intestinal sources, the EC cell for 5-HT and peptidergic neurons for SP.

Animals↗
PubMed1987

Intraluminal release of serotonin, substance P, and gastrin in the canine small intestine.

Several gastrointestinal hormones have been found in the intestinal lumen, but as yet their physiologic role is not yet clear. We have previously shown in anesthesized animals that electrical vagal stimulation provokes simultaneous intraluminal release of serotonin (5-HT) and substance P (SP). The aim of this study was to investigate if a physiologic stimulus, a meal, releases 5-HT, SP, and gastrin (G) into the canine jejunum. In 10 dogs, chronic jejunal Thiry-Vella loops were perfused with saline (37 degrees C) before and after: a test meal; atropine, 0.2 mg/kg intravenously before the meal; atropine alone at the same dose; propanolol, 0.5 mg/kg intravenously before the meal; and propanolol alone at the same dose. Effluent perfusates and peripheral blood samples were assayed by radioimmunoassay for concentrations of 5-HT, SP, and G. Large amounts of all three humoral agents were found intraluminally during the interdigestive period. The meal resulted in increased circulating levels of 5-HT, SP, and G, while intraluminal concentrations of 5-HT and SP but not G increased following the meal. Both atropine and propanolol pretreatment significantly reduced this response, while alone, these drugs did not affect basal values. We postulate that 5-HT and SP released into the intestinal lumen in response to a meal act as local neurocrine/paracrine modulators. Their release mechanisms appear to be under both cholinergic and adrenergic control.

Animals↗
PubMed1987

Vagal release of serotonin into gut lumen and portal circulation via separate control mechanisms.

The mechanisms controlling vagally induced serotonin-like immunoreactivity (5-HTLI) release into portal circulation and jejunal lumen were studied in individual cats. In control animals, electrical vagal nerve stimulation significantly enhanced both the endoluminal secretion rate of 5-HTLI and the release of 5-HTLI to the portal vein. The vagally induced release of 5-HTLI to the portal circulation was blocked by pretreatment with propranolol or phenoxybenzamine, or by prior removal of the superior cervical ganglia, but was not blocked by atropine or hexamethonium. On the contrary, the luminal secretion of 5-HTLI after vagal stimulation was not blocked by adrenoceptor blocking agents or ganglionectomy, but instead was inhibited by cholinoceptor antagonists. Thus, in the same experimental animal it was shown that vagally induced release of 5-HTLI to the portal circulation was mediated by adrenoceptor mechanisms, while the luminal release of 5-HTLI was regulated via cholinoceptors. Based on indirect estimations, the apical release of 5-HT seems to be qualitatively small in comparison with the release into the portal circulation.

Animals↗
PubMed1986

Effects of intraluminal perfusion with serotonin on jejunal motility.

Five dogs with chronic doubly cannulated proximal jejunal Thiry-Vella loops were studied to evaluate the role of luminal and circulating serotonin on intestinal intraluminal pressure quantitated using computer-assisted planimetry. Luminal perfusion with serotonin (50 micrograms/min) for 60 min resulted in a significant increase in luminal pressure. Upon cessation of infusion, intraluminal pressures rapidly returned to basal. While 4% lidocaine had no effect on basal intraluminal pressure, the drug almost abolished the pressure response to luminal serotonin. In contrast, atropine lowered mean baseline intraluminal pressures and also markedly inhibited the response to subsequent perfusion with serotonin. These data suggest that the motility response to intraluminal serotonin is neurally mediated. Intravenous serotonin infusion (3.3 micrograms/kg/min), which raised circulating levels of the amine to those noted after a standard meal, increased intraluminal pressures to a maximum similar to those noted after luminal perfusion; after cessation of infusion, pressures rapidly returned to basal. These observations support a physiologic role for serotonin in the modulation of intestinal motility.

Animals↗
PubMed1986

Effect of luminally administered serotonin and substance P on jejunal handling of water and electrolytes.

This study was initiated to evaluate the effect of luminally administered serotonin (5-hydroxytryptamine) and substance P on jejunal handling of water and electrolytes. Five dogs with chronic cannulated jejunal Thiry-Vella loops were studied. The isolated jejunal segments were perfused at 2 ml/min for 2 hours with an isosmotic, isothermic perfusate containing labeled polyethylene glycol for recovery calculation. Fluxes of water and sodium, chloride, and potassium were calculated during 30 minute baseline, 60 minute study, and 30 minute recovery periods. Substance P was administered intraluminally at 25 pg/ml, whereas serotonin was perfused at 600 ng/ml. Neither hormone was absorbed into the portal circulation. Intraluminal serotonin converted absorption to secretion of water from 43 +/- 23 to -105 +/- 25 microliters/min, sodium from 7.3 +/- 3.1 to -15.7 +/- 4.1 microEq/min, chloride from 4.4 +/- 3.4 to -16.4 +/- 3 microEq/min, and potassium from 0.16 +/- 0.20 to -0.86 +/- 0.17 microEq/min. Secretion ceased on cessation of serotonin perfusion. Substance P perfusion induced secretion of chloride (3.6 +/- 1.9 to -9.2 +/- 2.9 microEq/min) but only significantly decreased absorption of water (73 +/- 13 to 13 +/- 21 microliters/min) and sodium (8.1 +/- 1.9 to 0.2 +/- 3.1 microEq/min); in contrast, there was no significant change in jejunal handling of potassium.

Animals↗
PubMed1986

Verapamil reversal of serotonin-induced jejunal secretion of water and electrolytes in awake dogs.

Intestinal handling of water and electrolytes was monitored in 5 conscious dogs with chronic 25-cm Thiry-Vella loops of proximal jejunum using a neutral isosmotic perfusate containing [14C]polyethylene glycol as a recovery marker. Under basal conditions the animals absorbed water, Na+, and Cl-, and there was minimal nonsignificant secretion of K+. Intravenous serotonin infusion (30 micrograms/kg X min) increased circulating hormone levels to 937 +/- 131 ng/ml and induced significant secretion of water (-150 +/- 52 microliter/min), Na+ (-22.8 +/- 8.4 microEq/min), Cl- (-23.5 +/- 6.0 microEq/min), and K+ (-1.79 +/- 0.34 microEq/min). Simultaneous infusion of verapamil, a calcium channel blocker, at 8.3 micrograms/kg X min, reversed the intestinal secretion to absorption of all these parameters (144 +/- 32 microliter/min, 15.1 +/- 5.1 microEq/min, 10.3 +/- 3.0 microEq/min, and 0.12 +/- 0.23 microEq/min, respectively). This was accompanied by a significant improvement in the clinical appearance of the animals, decreased visible agitation, and cessation of defecation. Cessation of verapamil infusion (leaving the serotonin infusion unopposed) resulted in prompt return to the secretory state. Serum electrolytes did not change significantly, with the exception of potassium, which fell from 5.1 +/- 0.2 to 4.1 +/- 0.1 mg/dl. In control experiments (no serotonin), verapamil had an insignificant stimulatory effect on the absorption of water, Na+, and Cl- whereas the effect on K+ was significant (-0.2 +/- 0.2 to +0.4 +/- 0.1 microEq/min; p less than 0.05). These data support the role of calcium in modulating the effects of serotonin, and they suggest a new promising technology for the management of serotonin-induced intestinal secretion such as that seen in the carcinoid syndrome.

Animals↗
PubMed1986

Intraluminal release of serotonin during the interdigestive migrating complex in the canine small intestine.

Intraluminal release of serotonin (5-HT) was evaluated in relation to the interdigestive migrating complex (IMC) in the canine small intestine. Thirty-Vella loops (TVL) were constructed in the proximal jejunum of eight dogs. After recovery, the loops were continuously perfused with normal saline at 37 degrees C and changes in intraluminal pressure recorded. For each 10-min period, a motility index (MI) was calculated using computer-assisted planimetry and expressed in mm2/10 min. Serotonin contents in the effluent perfusates were measured by radioimmunoassay. A characteristic phasic motor activity was recognized in the TVL with periods of rest or minimal activity (MI = 406 +/- 45 mm2/10 min, Phase I) alternating with periods of vigorous activity (MI = 2082 +/- 134 mm2/10 min, Phases II and III). Serotonin was constantly found in the effluent perfusates in relatively high concentrations, but 5-HT levels did not vary significantly with intestinal activity; levels averaged 120 +/- 19 ng/ml during Phase I and 110 +/- 13 ng/ml during phases II and III. We conclude that intraluminal 5-HT plays no major role in the physiologic local regulation of the canine IMC in the small intestine.

Animals↗
PubMed1986

The effects of thyroid hormones on the formation of stress ulcers in the rat.

The Low T3 Sick Syndrome is a syndrome of low triiodothyronine (T3), low to normal thyroxine (T4), and a nonelevated thyrotropin despite the low T3 levels. This syndrome is frequently encountered in critically ill patients. These same patients are also at higher risk to develop acute stress ulcerations. The objective of this study was to access the effects of low circulating thyroid hormone levels on the development of stress ulcers in the rat. Rats having had previous surgical thyroidectomies were subjected to individual restraint stress; these animals had a significantly increased incidence of stress ulcers when compared to euthyroid stressed controls (1.6 +/- 0.4 ulcers vs 0.5 +/- 0.2 ulcers per animal, P less than 0.05). Surgically thyroidectomized (hypothyroid) animals who were given T3 replacement and then stressed, had ulcer rates similar to normal stressed controls (0.5 +/- 0.2 ulcers per animal). We conclude that low circulating thyroid hormones have an ulcerogenic effect, and that replacement of T3 in rats with surgical hypothyroidism reverses this effect.

Animals↗
PubMed1986

Studies on the mucosal hyperaemia of the feline small intestine observed at endoluminal perfusion with substance P.

Substance P-like immunoreactivity (SPLI) was found in the luminal contents of the feline small intestine. A physiological role for endoluminal substance P (SP) was explored in in vivo experiments, where feline jejunal segments were endoluminally perfused with saline or a low concentration of SP. A jejunal segment was initially perfused with saline, followed by SP in saline, and finally perfused with saline alone. The regional blood flow to the small intestine was determined by the microsphere technique. Endoluminal perfusion with SP caused a selective mucosal/submucosal hyperaemia of the experimental jejunum, which was normalized upon subsequent saline perfusion. Since neither acute vagotomy, local neural blockade (TTX, lidocaine), adrenergic blockade (phenoxybenzamine, propranolol), cholinergic blockade (hexamethonium, atropine), histamine - nor prostaglandin blockade - could antagonize the hyperaemic effects of luminally administered SP, it is suggested that this effect is directly paracrine in nature. Substance P may be released from SP nerves on physiological stimulation, that is, augmented vagal tone by a meal, and act at the effector cell, that is, vascular smooth muscle.

Adrenergic alpha-Antagonists↗