Morphine-neural interactions on canine intestinal absorption and blood flow.

Intestinal Na and H2O fluxes and blood flow were determined in extrinsically denervated or innervated ileum of fed dogs during intra-arterial (0.2, 2, 20 micrograms min-1) or intraluminal (4, 40, 400 micrograms ml-1) morphine sulphate infusion. 3H2O and 22Na were used to determine unidirectional fluxes and 3H2O clearances were used to determine total segmental and absorptive site blood flow. Net Na and H2O absorption decreased with time in innervated gut segments but were unchanged in denervated segments. Intra-arterial morphine prevented the decrease in net Na and H2O absorption in innervated segments due to increases in unidirectional absorptive fluxes. Intra-arterial morphine did not affect absorption in denervated segments. Intraluminal morphine increased net Na and H2O absorption from both innervated and denervated ileal segments due to increases in the unidirectional absorptive fluxes. Absorptive site blood flow was linearly related to unidirectional absorptive Na fluxes in each group although not with the same slopes. The increment in absorptive site blood flow vs. absorptive Na flux was greatest with luminal morphine, intermediate with intra-arterial morphine and in denervated segments without morphine and least in innervated segments. It was concluded that intra-arterial morphine inhibits an antiabsorptive effect of extrinsic nerves and that intraluminal morphine promotes an absorptive effect which could be direct or mediated through intrinsic nerves.

Differential effects of lumenal L-arginine and NG-nitro L-arginine on blood flow and water fluxes in rat ileum.

1. The role of endogenous mucosal nitric oxide (NO) in the local regulation of H2O absorption and blood flow in rat ileum was studied by perfusing L-arginine (L-Arg) (0.1-1.0 mM) and NG-nitro L-arginine (L-NOARG) (0.01-1.0 mM) through the lumen. D-Arginine (D-Arg) or L-Arg (1 mM), combined with L-NOARG, were used to determine if any of the measured intestinal effects of L-NOARG were exerted through NO formation. 2. Net and unidirectional H2O fluxes and effective mucosal blood flow were measured using 3H2O and [14C]-inulin in the perfusate. Mucosal NO formation was measured as the appearance of lumenal NO2-. 3. L-NOARG, beginning at a concentration of 0.1 mM, decreased net H2O absorption, but had only minor effects on unidirectional H2O fluxes or on blood flow. L-NOARG increased blood pressure, beginning at a concentration of 0.5 mM. 4. L-Arg had no significant effects on net H2O absorption or blood pressure, and only minor effects on unidirectional H2O fluxes and blood flow. 5. NO appearance in the lumen was marginally decreased by 1.0 mM L-NOARG, but not increased by L-Arg. 6. Mucosal blood flow resistance paralleled systemic blood pressure suggesting that vascular effects on the mucosa were exerted only after L-NOARG had reached the general circulation. 7. Lumenal L-Arg reversed the effects of lumenal L-NOARG on net H2O absorption and blood pressure, but D-Arg did not. 8. It was concluded that there is tonic NO production by the rat intestinal mucosa that promotes H20 absorption, but does not affect blood flow resistance. Mucosal NO production was not related to the observed effects on mucosal function.

Effects of atropine and tetrodotoxin on neurotensin-induced ileal sodium transport in the dog.

1. Neurotensin was infused intravenously, in the presence or absence of intravenous atropine or intraarterial tetrodotoxin, into dogs anaesthetized with sodium pentobarbitone. Net and unidirectional fluxes of sodium and blood flows in the ileum were measured. Arterial and mesenteric venous blood pressures, haematocrits and plasma total solids were also determined. 2. Neurotensin caused a transient increase in net sodium absorption which was not associated with significant changes in unidirectional fluxes. This was followed by prolonged net secretion which was associated with an increase in unidirectional sodium secretion and a smaller decrease in sodium absorption. Potassium secretion was also increased when net sodium secretion increased. 3. Neurotensin increased haematocrit and total solids and decreased arterial pressure at the same time that secretion occurred. 4. Atropine blocked all the cardiovascular effects of neurotensin and reduced its early effects on both absorption and secretion but not the later effects on secretion. Tetrodotoxin only blocked the increase in absorption but not the secretion or the cardiovascular effects. 5. It was concluded that there is a cholinergic step in the cardiovascular effects of neurotensin and that the early effects of neurotensin on secretion are due to active secretion supported by fluid leakage from the plasma. The later effects of neurotensin on secretion do not have a cholinergic step and are due primarily to an active secretion. The increased absorption is mediated partly through intrinsic nerves of the gut.

Effects of morphine on canine intestinal absorption and blood flow.

1 Intestinal absorption and blood flow were determined in anaesthetized fed or fasted dogs following rapid intravenous injections of morphine (0.01, 0.1, 1 mg/kg). 2 3H2O and 22Na were used to determine the unidirectional fluxes of Na+ and H2O from saline perfused through the ileal lumen and the clearances of 3H2O were used to determine total and absorptive site blood flow. 3 Net Na+ and H2O absorption were increased at each dose of morphine in fed but not in fasted dogs, due primarily to increased absorptive fluxes. 4 Arterial pressure was decreased by morphine but mesenteric vein pressure was little affected. Absorptive site blood flow was increased by morphine due to decreased blood flow resistance but total blood flow resistance was little affected by morphine. 5 The absorptive fluxes of Na+ and H2O were correlated with absorpitve site blood flow in both fed and fasted animals. The secretory fluxes of Na+ and H2O were correlated with estimated capiliary pressure in fasted dogs but morphine decreased the the secretory fluxes at a given capillary pressure in dogs which had been fed. 6 Naloxone (0.12 mg, i.v.) reversed the effects of morphine. The effects of morphine on the gut were reversed more slowly than on systemic blood pressure. 7 It was concluded that morphine can increase net absorption in fed dogs by a selective increase in intestinal absorptive site blood flow and thus increase absorptive fluxes by a washout effect but that there is also an epithelial effect, sensitized by feeding, which reduces the secretory fluxes of Na+ and H2O.

Modulation of hemorrhagic shock by intestinal mucosal NG-nitro-L-arginine and L-arginine in the anesthetized rat.

Maintaining intestinal function protects against shock of various origins. Nitric oxide (NO) can protect tissues. The present research examined whether the presence of 50 microM NG-nitro-L-arginine (NOLARG), a nitric oxide synthase (NOS) inhibitor, or L-arginine (LARG), the substrate of NOS, in the jejunal lumen of the anesthetized rat could affect the progress of hemorrhagic shock. The jejunal lumen was perfused with saline containing 14C-inulin and 3H2O to measure net H2O absorption and absorptive site blood flow (ASBF). Luminal NOx (NO3- +NO2-) secretion into the gut effluent and blood pressure (BP) were also measured. The animals were bled to and maintained at 40 mmHg for 60 min and then reinfused. Survival time was significantly decreased in luminally-perfused NOLARG animals, but was significantly increased in LARG perfused animals. Most deaths occurred during the hemorrhage periods. Animals perfused with LARG through the ileal lumen required significantly less blood to be reinfused to maintain blood pressure during the hemorrhage periods. There were not significant differences in BP among surviving animals. Net H2O absorption and ASBF were significantly decreased only in NOLARG-perfused animals in the period just before and after reinfusion. There were no significant differences in luminal NOx secretion among the groups. Thus, intestinal mucosal NOS substrates or antagonists modulate the progress of hemorrhagic shock, but the mechanism was not defined in these experiments.

Time- and surgery-dependent effects of lipopolysaccharide on gut, cardiovascular and nitric oxide functions.

Lipopolysaccharide (LPS) is considered a major effector of hypotension in septic shock, partly through increasing nitric oxide (NO) formation. LPS-activation of leukocytes that express cytokines which induce NO synthase (iNOS) has also been considered an important contributor to shock. However, LPS, cytokines, and NO are not necessarily associated with hypotensive shock. We investigated whether the timing of LPS injection after initial surgery could influence responses to LPS. E. coli LPS (17 mg/kg 0111:B4 and 026:B6 serotypes) was injected 15 or 120 min after tracheal and femoral cannulation in the anesthetized rat. LPS caused hypotension for 2 h when injected 15 min (early injection) after initial surgery. LPS decreased blood pressure for only 15 min when injected 2 h (late injection) after initial surgery. Plasma NO was increased and leukocytes were decreased after both the early and late LPS injection. Blood pressure responded the same when a second surgery (ileal cannulation and luminal perfusion) followed the early or preceded the late LPS injection. Ileal NO secretion increased and effective mucosal blood flow decreased when LPS followed gut surgery, but these did not change when gut surgery followed LPS. Plasma NO was increased and leukocytes were decreased when LPS followed gut surgery, but these did not change when gut surgery followed LPS. Ileal water absorption was not affected by LPS. These observations suggest that a desensitization to the hypotensive effect of LPS develops with time after an initial trauma. An additional gut trauma does not change the blood pressure response, but does have effects on leukocyte sequestration and NO synthesis. NO synthesis alone could not explain the effects on blood pressure.

Influence of the Ward colon tumor on the host response to endotoxin.

Cachexia and a decreased immune function are negative prognostic factors for cancer patients. While the decreased immunity results in a greater susceptibility to bacterial infection, the response of the host to the resulting infection is not clear. The experiments reported here were designed to evaluate the toxicity of endotoxin to rats with a transplantable Ward colon tumor (WCT) and to evaluate the mechanism of the observed increase in lethal toxicity. The lethal toxicity of endotoxin (lipopolysaccharide, LPS) at 5 mg/kg, i.p. was evaluated in the first of two experiments. Rats received LPS and were observed for morbidity and weight loss for a period of 11 days. A second experiment was done to evaluate the effect of LPS on the plasma nitrate/nitrite concentrations and plasma indicators of host tissue dysfunction. LPS was administered as previously described but blood and tissues were collected 5 h after LPS administration. LPS resulted in the death of 1 of 12 nontumor-bearing (NTB) rats and a transient weight loss in the survivors. This same dose of LPS, however, resulted in death for 10 of 12 WCT rats with tumor burdens less than 4% of body weight. The response of WCT rats 5 h after LPS was then compared with that of age-matched NTB rats. Plasma albumin concentrations were not affected by LPS in NTB rats but were significantly decreased in WCT rats. Peripheral blood gases were not consistently affected by LPS in either group. Peripheral blood white cell counts, except monocytes, were significantly decreased by LPS in both groups. Monocyte counts in peripheral blood were further reduced in WCT rats compared with NTB rats receiving LPS. The presence of the WCT significantly enhanced the LPS-associated increase in spleen weight. Liver weights were lower in LPS rats but there was no effect of the presence of WCT. The LPS-associated increase in plasma nitrate/nitrite concentration was enhanced by the WCT. The plasma arginine and citrulline concentrations were altered in a manner consistent with an increase in nitric oxide synthesis. An increase in plasma ornithine concentration suggests an increase in arginine metabolism by arginase. The plasma concentration of alanine aminotransferase was significantly elevated when WCT rats received LPS, suggesting enhanced hepatic dysfunction. The plasma blood urea nitrogen concentration was elevated by LPS to a greater extent in the WCT rats than in the NTB controls, indicating increased renal dysfunction. These results demonstrate that the Ward colon tumor increases the host lethal response to the endotoxin, a toxic product of bacterial infections. The mechanisms of lethality may include an increased nitric oxide synthesis in WCT rats and enhanced liver and renal toxicity.

Hypotension during septic shock does not correlate with plasma levels of nitric oxide metabolites in the conscious rat.

Hypotension following administration of lipopolysaccharide may be due to excessive production of the potent vasodilator nitric oxide brought about by induction of nitric oxide synthase. The purpose of this study was to determine in conscious, fasted rats what role nitric oxide played in lipopolysaccharide-induced hypotension. When examined by Western immunoblot analysis, inducible nitric oxide synthase immunoreactivity was detected in the aorta at 3 hours and increased over time following administration of intraperitoneal lipopolysaccharide (20 mg/kg). When compared with saline-treated control rats, significant hypotension was observed at 2, 4, and 6 hours following lipopolysaccharide treatment. Blood pressure at 2 hours did not differ significantly from that at 6 hours. Using the Griess reaction to quantify plasma levels of nitrates and nitrites as an index of systemic nitric oxide production, an augmentation in the formation of these nitric oxide metabolites was demonstrated at 4 and 6 hours but not at 2 hours. Subcutaneous administration of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (5 mg/kg) prevented lipopolysaccharide-induced hypotension, an effect reversed by subcutaneous L-arginine but not D-arginine (350 mg/kg). However, nitric oxide synthase inhibition did not attenuate the ability of lipopolysaccharide to increase plasma nitrate/nitrite levels. These data indicate that lipopolysaccharide-induced production of nitric oxide metabolites does not correlate with lipopolysaccharide-induced hypotension.

Effects of atropine and guanethidine on canine intestinal absorption and blood flow.

The possibility of tonic autonomic control over intestinal Na and H2O absorption and whether the cardiovascular system was involved was tested by administration of atropine or guanethidine. 3H2O and 22Na in saline perfused through the lumen were used to calculate unidirectional fluxes and total and absorptive site blood flow in canine ileum. Both atropine and guanethidine had qualitatively similar effects on absorption and blood flow with atropine being quantitatively greater. Net Na and H2O absorption were not increased significantly but their absorptive and secretory unidirectional fluxes were increased significantly. Total blood flow was not affected but absorptive site blood flow was increased and resistance decreased. The absorptive site blood flow was correlated with the absorptive Na fluxes similarly in all groups. The secretory fluxes of Na and H2O were correlated with estimated capillary pressure when all three groups were considered together. It was concluded that there is tonic cholinergic control over intestinal absorption which is mediated, in part, through cardiovascular effects. The findings were consistent with tonic parasympathetic activity having primarily a direct effect on gut absorption and blood flow but tonic sympathetic activity primarily modulating the direct effects of other regulatory mechanisms.

Effects of intraarterial, intravenous, and intraluminal neurotensin on canine ileal sodium and water absorption and blood flow.

Neurotensin is a regulatory peptide which is found primarily in the ileum and is secreted into the blood and lumen. The physiologic effects of neurotensin are uncertain but in certain pathologic states neurotensin increases to levels which can have effects on many organs. The effects of intravenous, intraarterial and intraluminal neurotensin (0.075-7.5 micrograms/min) on fed canine ileal sodium and water fluxes, potassium secretion, and blood flows were studied. Intravenous and intraarterial infusion of neurotensin increased net sodium, potassium, and water secretion, due to increased secretory fluxes, and increased hematocrits. Intraarterial neurotensin was not more effective than intravenous neurotensin except for stimulating potassium secretion. Neurotensin increased potassium secretion at 0.075 micrograms/min IA, increased sodium and water secretion at 0.75 micrograms/min IA and IV, and increased hematocrit at 7.5 micrograms/min IA and and IV. Total and absorptive site blood flows and arterial and venous pressures were not changed. Intraluminal neurotensin had no effects at any infusion rate. Neurotensin can increase potassium secretion at physiologic levels by a local effect and can increase sodium and water secretion at high physiological-pathological levels through a hormonal mechanism. The secretion is not dependent on cardiovascular changes.

Binding and solubility of oleic acid to laboratory materials: a possible artifact.

The possibility that significant amounts of fatty acids were dissolved in or bound to the surfaces of common laboratory materials was examined. The uptake or adsorption of radioisotopically labeled oleic acid and cholic acid by plastic tubing of Tygon, Teflon, and polyethylene, and Pyrex, and borosilicate glass, and steel was measured. 3H-oleic acid and 14C-cholic acid were used in the presence of different concentrations of unlabeled oleic acid, cholic acid, and/or bovine serum albumin. Concentrations, composition, pH, and perfusion rates were varied. Relatively large amounts (10-95%) of oleic acid (25 microM) were lost by dissolving in plastic and adsorption to glass or metal. The degree of losses decreased in the presence of compounds in the perfusion solution which could bind or dissolve oleic acid. In contrast, cholic acid was not lost to plastic, glass or metal. The magnitude of and influence of perfusion rate, composition, pH, and sequence of perfusion solutions on oleic acid losses were sufficiently large that the results of certain studies, such as those of unstirred water layers of albumin - stimulated fatty acid uptake by hepatocytes may need to be reexamined.

Effects of oleic acid and bile salts on canine villous motility.

The effects on canine villous motility of mucosal Tyrodes solution containing oleic acid (10 mM) and/or either taurocholic or cholic acid (15 mM) in the presence or absence of IV atropine (1 mg/kg) was used to assess the neural mediation of the effects of luminal nutrients. Villous motility was measured over 12 min periods by in vivo videomicroscopy of segments of jejunum. Neither bile salt had effects alone but villous motility increased after oleic acid was added to taurocholate and decreased after oleic acid was added to cholate. Villous motility increased when taurocholate and oleic acid were present initially and returned to control levels when removed. Villous motility was not affected by cholate and oleic acid but villous motility decreased when they were removed from the Tyrodes solution. Atropine blocked the increase in villous motility caused by taurocholate and oleic acid. Bile salts can modify the effect of oleic acid on villous motility and a cholinergic step is involved in the stimulation of motility.

Splenic sympathetic response to endotoxin is blunted in the fetal alcohol-exposed rat: role of nitric oxide.

This study was designed to test the hypothesis that nitric oxide (NO) mediates the blunted splenic sympathetic response to lipopolysaccharide (endotoxin) that occurs in young rats exposed to alcohol in utero (FAE). The subjects, 26-29-day-old rats, were progeny of pregnant dams fed an alcohol diet (35% of the calories were derived from ethanol) or their control and pair-fed (PFC) cohorts. We examined the effects of lipopolysaccharide (LPS) (0.5 mg/kg, i.p.) on splenic norepinephrine (NE) turnover, an index of sympathetic neural activity, splenic inducible NO synthase (iNOS) protein immunoreactivity, and NO metabolites nitrite/nitrate concentrations in plasma. In response to LPS, splenic NE turnover was increased by more than twofold in the PFC groups, but the increase did not occur in their FAE cohorts. The blockade of NOS with L-NAME (30 mg/kg, i.p.) reversed this difference. In both the PFC and FAE rats, basal levels of splenic iNOS protein immunoreactivity were equally barely detected and plasma NO metabolite levels were relatively low (25 microM in both groups). In response to LPS, however, iNOS protein displayed a marked increase in the PFC group and an even greater increase (by close to threefold) in the FAE rats. LPS also substantially increased plasma NO metabolite levels by close to eightfold in the control groups, but by 15-fold in their FAE cohorts compared to the basal levels. These findings support the hypothesis that in the FAE rat, an augmented NO formation accounts for the blunted sympathetic response to endotoxin.

Crystals in pulmonary cytologic preparations in association with aspiration of barium. A case report.

Crystals were found in a pulmonary cytologic preparation in association with the aspiration of barium. This type of event has not been described previously, although rare occurrences of crystals in pulmonary cytology specimens in association with Aspergillus infection and other situations have been reported. We recommend that patients suspected of aspiration be given no oral substances for at least 12 hours before bronchoscopy.

Cardiovascular and flux relationships in canine ileum.

Blood flow and pressure in denerved ileum of anesthetized dogs were altered by occlusion of the mesenteric artery or vein or by infusion of intra-arterial sodium nitroprusside (0.015-1.5 mg/min). Unidirectional Na and H2O fluxes were measured and absorptive site blood flow was estimated from the clearance of tritiated H2O. Net Na and H2O absorptions were reduced by mesenteric venous or arterial occlusion. Net secretion occurred with mesenteric venous occlusion. Nitroprusside reduced net absorption only at an infusion rate of 0.15 mg/min. The absorptive Na and H2O fluxes were reduced by both mesenteric venous or arterial occlusion, with venous occlusion being more effective. Nitroprusside reduced the absorptive Na flux at an infusion rate of 0.15 mg/min but not the absorptive H2O flux. The secretory flux of Na was increased by mesenteric venous occlusion but reduced by arterial occlusion and not changed by nitroprusside infusion. The secretory H2O flux was decreased by moderate degrees of mesenteric venous occlusion but was unchanged at greater levels. Arterial occlusion decreased secretory H2O fluxes. Nitroprossude infusion increased secretory H2O fluxes at an infusion rate of 0.015 mg/min. The absorptive and secretory Na and H2O fluxes were significantly correlated with absorptive site blood flow plus estimated capillary pressure. Absorptive site blood flow was primarily responsible for changes in absorptive fluxes and estimated capillary pressure for changes in secretory fluxes. Absorptive site blood flow affected the secretory and absorptive fluxes of H2O more equally than the Na fluxes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of vasoactive intestinal polypeptide on intestinal absorption and blood flow.

1. Intestinal absorption and blood flow in anaesthetized dogs was determined after I.V. infusion of vasoactive intestinal polypeptide (VIP) (1.75-175 ng/min) to determine the contribution of the cardiovascular changes to transport. 2. 22Na and 3H2O were utilized to determine the unidirectional fluxes of Na and H2O from saline perfused through the ileal lumen and the clearances of 3H2O were used to determine total and absorptive site blood flow. 3. Net Na and H2O absorption were reversed to secretion by VIP at 175 ng/min due to a significant decrease in unidirectional absorptive fluxes and smaller increases in secretory fluxes. 4. Arterial pressure and absorptive site blood flow were reduced in proportion to the changes in Na and H2O fluxes. 5. Total and absorptive site blood flow decreased and the blood flow resistances increased. 6. Prior treatment with guanethidine to suppress sympathetic effects did not greatly affect the responses to VIP. Prior treatment with atropine to suppress cholinergic effects inhibited most of the effects of VIP. 7. Absorptive site blood flow was linearly related to absorptive fluxes of Na and H2O but with different slopes for results from atropinized dogs as compared to those from dogs given VIP alone or VIP plus guanethidine. 8. It was concluded that VIP reduces gut absorption through a generalized cardiovascular effect and also through a mechanism which depends on the release of ACh by the gut.

Relationships between intestinal absorption and hemodynamics.

There are many interactions between intestinal blood flow and absorption. These include the support of transcellular transport by O2 delivery; the passive effects of Starling forces on absorption, secretion, and mucosal conductance; the washout of absorbed materials; and countercurrent exchange. Blood flow hemodynamics, and absorption interact. Regulatory mechanisms add a tertiary influence to these interactions. Further progress in this area would be greatly helped by techniques that could measure blood flow and hemodynamic factors at the absorptive and secretory sites more precisely.