Bile acid transport in hypercholesterolemic resistant rabbits.

We examined bile acid transport and expression of the apical sodium-dependent bile acid transporter (ASBT) in ileal preparations to determine if alterations in bile acid excretion contributed to a hypercholesterolemia-resistant phenotype in rabbits (CRT/mlo). Taurocholate transport was not different between normal (NR) and CRT/mlo rabbits fed regular diet. However, feeding cholesterol-enriched diet reduced taurocholate transport significantly in CRT/mlo rabbits (0.53 + or - 0.06 pmol/microg protein) compared to regular diet (0.95 + or - 0.14 pmol/microg protein), but had no effect in NR rabbits. Cholesterol-enriched diet increased ASBT mRNA in CRT/mlo (2.6 + or - 0.7 to 5.4 + or - 0.1); no significant changes occurred in NR. Some CRT/mlo rabbits carry a polymorphism in ASBT at amino acid 333 (P333L). In transfected HEK293 cells, TC transport of P333L allele was significantly lower (0.08 + or - 0.01 vs 0.13 + or - 0.01 pmol/microg protein/15 sec, P< 0.05). This allele was not found in NR rabbits. The data suggest that the phenotype of the CRT/mlo rabbit is due to changes in bile acid transport as well as bile acid metabolism.

Peripheral mechanisms of intestinal dysmotility in the morphine tolerant and dependent rats.

Changes of intestinal motility and transit produced by tolerance to and dependence upon morphine have been partly attributed to peripheral mechanisms. We evaluated the effect of chronic peripheral morphine administration and peripheral mu-receptor blockade on vagal afferent activity (VAA) and c-Kit positive intramuscular cells of Cajal (ICCs). Ten rats were subjected to chronic subcutaneous morphine infusion for 72 h with subsequent VAA recording. Potential frequency was evaluated within recordings before and after mu receptor blockade by (D)-Phe -Cys -Tyr -(D)-Trp -Orn -Thr -Phe -Thr (CTOP) i.p. injections. Afterwards the rats were sacrificed and intramuscular c-Kit antigen expression was assessed by image analysis within removed fragments of duodenum and ascending colon. An equal group of rats served as a control for VAA and c-Kit expression. Analysis of VAA revealed similar frequencies of potentials in morphine tolerant / dependent rats before CTOP and in the controls. CTOP increased potential frequency in the morphine group which effect was visible mostly within the first 20 minutes (p=0.01). The morphine infused animals presented also higher c-Kit expression in both the duodenum (p<0.001) and the ascending colon (p<0.001) in comparison to the control group. Results of our study may indicate the involvement of both the intestinal wall and the long vago-vagal reflexes in tolerance to and dependence upon opioids.

Heme oxygenase-1 induction by hemin protects against gut ischemia/reperfusion injury.

BACKGROUND: We have shown that both intraischemic hypothermia and hypertonic saline resuscitation provide dramatic protection against gut ischemia/reperfusion (I/R) injury that is in part mediated by heme oxygenase-1 (HO-1). We therefore hypothesized that induction of HO-1 by hemin would lessen damage and improve function after gut I/R. MATERIALS AND METHODS: Male Sprague-Dawley rats were treated with 50 micromol/kg hemin (HO-1 inducer ferric protoporphyrin IX chloride) sq or vehicle 2 h before superior mesenteric artery occlusion for 60 min or sham laparotomy. After 6 h of reperfusion, transit was determined by quantitation of percentage of tracer in 10 equal segments of small intestine 30 min following injection into the duodenum (expressed as mean geometric center). Ileum was harvested for assessment of mucosal histologic injury (Chiu score 0-5 by blinded observer), myeloperoxidase activity (MPO, index of inflammation), and HO-1 protein expression. RESULTS: Hemin treatment was associated with increased HO-1 protein expression, lessened mucosal injury, decreased MPO activity, and improved intestinal transit following gut I/R. CONCLUSION: These data corroborate that HO-1 plays an important role in protecting the gut against I/R-induced injury.

Ischemia/reperfusion-induced disruption of rat small intestine transit is reversed by total enteral nutrition.

OBJECTIVES: A reduced blood flow to the gut is a consistent event after traumatic shock. Enteral nutrition support has been shown to reduce the septic morbidity after major trauma. We evaluated the effects of a transient ischemia followed by reperfusion (I/R) and an enteral nutrition support regimen on the motility of the small intestine of the rat. METHODS: A catheter was placed in the upper duodenum and the small intestine was then made ischemic by clamping the superior mesenteric artery for 45 min; the arteries of sham rats were isolated but not clamped. Intestinal transit was evaluated by measuring the amount of fluorescein isothiocyanate-dextran (12 000 MW) in each of 10 intestinal sections at 30 min after injection through the duodenal catheter. The mean geometric center of marker distribution (MGC) was calculated for each group and compared. In a second study, I/R was followed by infusion of saline or a complete nutrient solution overnight, and transit was determined. RESULTS: Intestinal transit (as the MGC) of I/R rats at 24 h after the beginning of reperfusion (3.5 +/- 0.2) and 48 h after the beginning of reperfusion (4.5 +/- 1.1) was significantly lower than that in the respective sham controls (5.1 +/- 0.3 and 5.9 +/- 0.5). The MGC for rats receiving a nutrient solution overnight during the reperfusion phase (6.0 +/- 1.1) was significantly increased compared with the MGC of 4.8 +/- 0.3 for rats receiving saline during the same period. CONCLUSIONS: These results demonstrate a long-term deleterious effect of a non-lethal ischemia on intestinal transit and may be one explanation for many of the sequelae occurring after ischemia. In addition, these results demonstrate that a nutrient infusion will prevent the delayed transit. This may provide a partial explanation for the beneficial effects of total enteral nutrition in the clinical situation of posttraumatic injury.

Migrating motility complexes persist after severe traumatic shock in patients who tolerate enteral nutrition.

BACKGROUND: Postinjury small bowel ileus is poorly characterized and may be an important factor in intolerance to enteral nutrition (EN). We, therefore, placed jejunal manometry catheters in high-risk trauma patients. Our hypothesis was that the presence of "fasting migrating motility complex (MMC)" activity and conversion to a "fed pattern" at goal rate of EN would be present in those patients who tolerate jejunal feeding. METHODS: After obtaining baseline fasting manometry pressure tracings, jejunal feeding was advanced stepwise to a set goal while tolerance was monitored and intolerance was treated by a standard approach. RESULTS: Of the 10 study patients, 7 were able to be maintained on EN. Five (50%) had "fasting MMCs" and had good tolerance to early advancement of EN. The remaining five patients did not exhibit "fasting MMCs" and four had poor tolerance to early advancement of EN. Overall, nine patients reached goal rate of EN of which four converted to a "fed pattern." This, however, was not associated with later tolerance to EN. CONCLUSION: EN is feasible following severe traumatic shock. Surprisingly, half of the patients had fasting MMCs. This requires intact neural and motor function and was associated with good tolerance of early EN.

Inducible nitric oxide synthase mediates gut ischemia/reperfusion-induced ileus only after severe insults.

Inducible nitric oxide synthase (NOS 2) is thought to play a role in gut motility disorders that occur under proinflammatory conditions. Clinically, ileus occurs after sepsis and shock-induced gut ischemia/reperfusion (I/R). The purpose of this study was to determine if NOS 2 mediates impaired intestinal transit in well-established models of both moderate and severe gut ischemia/reperfusion. At laparotomy, Sprague-Dawley rats had duodenal catheters placed. Small intestinal transit was determined by quantitating the percentage tracer (FITC-dextran) in 10 equal segments of intestine 30 min after catheter injection [expressed as the mean geometric center (MGC) of distribution]. Transit was assessed at 6 and 24 h after gut ischemia [45 or 75 min of superior mesenteric artery occlusion (SMAO) with sham laparotomy as control]. In a separate set of experiments, N(6)-(iminoethyl)-L-lysine (L-NIL), a selective NOS 2 antagonist, was administered 1 h prior to laparotomy and transit was determined after 6 h as described above. Ileal NOS 2 expression was assessed by Western immunoblot and quantitative "real-time" RT-PCR. We observed that both 45 and 75 min of SMAO decreased intestinal transit at 6 h of reperfusion compared to sham. Ileal NOS 2 mRNA and protein were increased after 75, but not 45, min of SMAO. In addition, L-NIL improved transit after 75, but not 45, min of SMAO. We conclude that (1) NOS 2 is upregulated in the gut only after more severe ischemic insults, and (2) ileus is mediated, at least in part, by NOS 2 under these conditions.

Down-regulation of inducible nitric-oxide synthase (NOS-2) during parasite-induced gut inflammation: a path to identify a selective NOS-2 inhibitor.

Nitric oxide (NO) possesses potent anti-inflammatory properties; however, an over-production of NO will promote inflammation and induce cell and tissue dysfunction. Thus, the ability to precisely regulate NO production could prove beneficial in controlling damage. In this study, advantage was taken of the well characterized inflammatory response caused by an intestinal parasite, Trichinella spiralis, to study the relationship between intestinal inflammation and the regulation of nitric oxide synthase-type 2 (NOS-2) expression. Our study revealed that a specific gut inflammatory reaction results in inhibition of NOS-2 expression. Characteristics of this inhibition are: 1) local jejunal inflammation induced by T. spiralis systemically inhibits NOS-2 gene transcription, protein expression, and enzyme activity; 2) the inhibition blunts endotoxin-stimulated NOS-2 expression; 3) the inhibition does not extend to the expression of other isoforms of NOS, to paxillin, a housekeeper protein, or to cyclooxygenase-2, another protein induced by proinflammatory cytokines; 4) the inhibition is unlikely related to the formation of specific anti-parasite antibodies; and 5) the inhibition may involve substances other than stress-induced corticosteroids. Elucidation of such potent endogenous NOS-2 down-regulatory mechanisms could lead to the development of new strategies for the therapy of inflammatory conditions characterized by the overproduction of NO.

Post-injury multiple organ failure: the role of the gut.

Despite intensive investigation, the pathogenesis of post-injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas-Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post-injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis-associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

Ileal mucosal response to bacterial toxin challenge.

BACKGROUND: The cause of postinjury intestinal mucosal barrier disruption remains obscure. The present study examines the hypothesis that the bacterial toxin formyl-methionyl leucyl phenylalanine (FMLP) plays an initial role in this process. METHODS: Mucosal permeability to fluorescein isothiocyanate-labeled dextran (4,400 molecular weight) was measured in perfused distal rat ileum with and without FMLP. Dextran and myeloperoxidase appearance in the lumenal perfusate was assessed in response to surrogates of traumatic stress: ischemia/reperfusion, total abdominal irradiation, and total parenteral nutrition. Recovery of FMLP in the effluent of static closed and perfused ileal loops was determined by mass spectrometry. Release of mast cell mediators in the presence of FMLP was determined in ileal everted sacs. RESULTS: Seventy-five percent of FMLP was recovered in perfusion effluent in contrast to 5% in closed loops. There was a transient increase in ileal permeability in FMLP/perfused, untreated rats, and in ischemia/reperfusion and total parenteral nutrition treated rats that was recorded with a concomitant increment in myeloperoxidase (inflammatory marker) in all experimental models except irradiated rats, which were unresponsive to FMLP. FMLP responsiveness was associ. ated with a significant rise in release of serotonin (mast cell mediator). CONCLUSION: These results suggest that mast cells and other resident inflammatory cells within the gut wall are involved in FMLP-induced changes in mucosal barrier permeability and raise the possibility that under conditions of traumatic stress, proinflammatory mediators within the gut wall might be activated by toxic factors in the gut lumen.

Temporal expression of tumor necrosis factor-alpha and nitric oxide synthase 2 in rat small intestine after endotoxin.

Temporal changes in tumor necrosis factor-alpha (TNF-alpha) and nitric oxide synthase 2 (NOS 2) were evaluated in segments of duodenum, jejunum, and ileum removed from male Sprague-Dawley rats 30, 60, 120, 180, and 240 min after lipopolysaccharide (LPS), 5 mg/kg, intraperitoneally. Plasma was assayed for TNF-alpha and for nitrate/nitrite (NOx). Intestinal and plasma TNF-alpha were elevated by 60 min after LPS and were back to control levels by 180 min. For control rats, NOS 2 was detected in the ileum, but not in the duodenum or the jejunum. In rats treated with LPS, NOS 2 was detected in all areas of the intestine at 120 min and was greatest at 240 min. Plasma NOx was elevated at 120 min and continued to increase to 240 min. The time course of changes in intestinal TNF-alpha and NOS 2 were similar to those reported for other tissues and suggest that the early and late actions of the LPS on the intestine may involve both mediators.

Roles of IL-1 and TNF in the decreased ileal muscle contractility induced by lipopolysaccharide.

Gastrointestinal stasis during sepsis may be associated with gastrointestinal smooth muscle dysfunction. Endotoxin [lipopolysaccharide (LPS)] impairs smooth muscle contraction, in part through inducible nitric oxide synthase (NOS II) and enhanced nitric oxide production. We studied the roles of tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) in this process by using TNF binding protein (TNFbp) and IL-1 receptor antagonist (IL-1ra). Rats were treated with TNFbp and IL-1ra, or their vehicles, 1 h before receiving LPS or saline. At 5 h after LPS, contractility was measured in strips of ileal longitudinal smooth muscle, and NOS II activity was measured in full-thickness segments of ileum. LPS decreased maximum stress (mean +/- SE) from 508 +/- 55 (control) to 355 +/- 33 g/cm2 (P < 0.05). Pretreatment with TNFbp plus IL-1ra prevented the LPS-induced decrease. Separate studies of TNFbp alone or IL-1ra alone indicated that, at the doses and timing used, TNFbp was more effective. LPS also increased NOS II activity by >10-fold (P < 0.01) over control. This increase was prevented by TNFbp plus IL-1ra (P = not significant vs. control). We conclude that the LPS-induced increase in NOS II activity and the decrease in ileal muscle contractility are mediated by TNF and IL-1.

Ileal nitric oxide formation is altered in the young rat in response to endotoxin: effects of exposure to alcohol in utero.

This study was designed to test the hypothesis that the activity and expression of iNOS in the ileum will be altered in young rats exposed to alcohol in utero (FAE). The subjects, 26-29-day-old rats, were progeny of dams fed an alcohol diet during gestation and their pair-fed/control cohorts. We determined the effects of endotoxin administration on ileal iNOS enzymatic activity and on ileal iNOS immunoreactivity. The basal levels of the measured variables were not significantly different between the groups. In response to LPS, however, FAE animals responded with a greater increase in ileal iNOS activity and immunoreactivity. The findings indicate that ileal iNOS is augmented in response to immune signals, which may partly account for the altered gut functions associated with FAE.

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.

Decreased ileal muscle contractility and increased NOS II expression induced by lipopolysaccharide.

This study was designed to determine if an increase in nitric oxide synthase (NOS) activity induced by lipopolysaccharide (LPS) is associated with increases in NOS II protein and mRNA abundance and with altered ileal longitudinal muscle contractility. Strips of muscle taken from LPS-treated, but not control, animals exhibited reduced in vitro contractility when L-arginine was a component of the physiological salt solution. This reduction was reversed by N omega-nitro-L-arginine (L-NNA), a competitive inhibitor of NOS. Full-thickness segments of jejunum, ileum, and colon taken 5 h after LPS injection exhibited increased NOS activity, NOS II immunoreactivity, and NOS II mRNA abundance. Increased NOS II immunoreactivity and mRNA abundance also were detected in ileal muscle strips taken from LPS-treated animals. These data confirm the reported effects of LPS on intestinal NOS activity and indicate that it can be attributed, at least in part, to an increase in NOS II mRNA and protein abundance. Furthermore, the data suggest that an LPS-induced increase in NOS II may lead to a decrease in ileal muscle contractility.

Gallbladder contractility in aspirin- and cholesterol-fed prairie dogs.

BACKGROUND/AIMS: Whether aspirin prevents cholesterol gallstone formation is controversial. This study aimed to investigate this issue and determine the depression of gallbladder smooth muscle contractility associated with cholesterol feeding in the prairie dog. METHODS: Prairie dogs were divided into four subgroups. Animals were fed control or 1.2% cholesterol diet and treated with placebo or aspirin for 2 weeks. The presence of crystals and stones was determined, and contractile force in response to cholecystokinin octapeptide (CCK-8) of gallbladder muscle strips was measured. RESULTS: Maximal stress of 2.66 +/- 0.23 x 10(4) N/m2 was measured in muscle strips from animals on control diet. Maximal stress was significantly lower in strips from animals on high-cholesterol diet, being 1.49 +/- 0.16 x 10(4) N/m2 with placebo and 1.62 +/- 0.23 x 10(4) N/m2 with aspirin. The difference in maximal stress between aspirin-treated and placebo-treated animals was not significant. Although none of the animals on control diet had crystals or stones, all animals on the high-cholesterol diet, whether receiving placebo or aspirin, had crystals in the bile, and more than 65% had cholesterol stones. CONCLUSIONS: Aspirin has no effect on stone formation, nor does it prevent the decrease in contractility despite a profound decrease in endogenous gallbladder prostanoid synthesis.

Structural and molecular changes in intestinal smooth muscle induced by Trichinella spiralis infection.

Infection with Trichinella spiralis in the rat causes altered intestinal motility and jejunal smooth muscle contractility by day 6 postinoculation. The purpose of this study was to determine structural and molecular changes in the smooth muscle that could account for the functional changes that have been reported. By day 6 postinoculation, there was an increase in thickness of both muscle layers of the jejunum. This increase in mass was accompanied by an increase in total protein content of the seromuscular tissues. When specific proteins were analyzed, increases in actin and myosin heavy chain contents were found. On the other hand, there was no increase in collagen content. Alterations in gene expression at the pretranslational level were determined by monitoring total RNA and the proportion of mRNA that codes for alpha-smooth muscle actin. There was an increase in both parameters in longitudinal muscle from the jejunum of infected animals. The increase appeared to be site selective because there were no increases in either parameter in longitudinal muscle of the distal intestine. These results indicate that pretranslational upregulation of gene expression for actin isoforms occurs in smooth muscle of the proximal but not distal intestine during the early enteric phase of infection with T. spiralis. Thus the altered smooth muscle contractility that has been reported in experimental trichinosis may be related in part to an increased expression of smooth muscle protein.

Nitric oxide is involved in muscle relaxation but not in changes in short-circuit current in rat ileum.

L-Arginine (L-Arg)-nitric oxide (NO) pathways in rat ileum were studied in an Ussing chamber modified so that a strain gauge transducer could be attached longitudinally on the serosal side of the intestine. Ileal segments from 22 rats were mounted as flat sheets and voltage clamped at zero transmural potential (PD). Changes in short-circuit current (delta ISC) in the absence of carbachol and longitudinal muscle relaxations in the presence of carbachol in response to transmural field stimulation (TMS; 5-s trains of impulses, 0.4-ms impulse duration, 1-10 Hz) were recorded during a control period, in the presence of N omega-nitro-L-arginine (L-NNA; 10(-4) M), and in the presence of L-Arg after treatment with L-NNA. In the control period, the delta ISC and muscle relaxation were frequency dependent with maximal responses generated at a frequency of 10 Hz. Tetrodotoxin (5 x 10(-6) M) blocked muscle relaxation and decreased delta ISC by 94% during TMS at 10 Hz. L-NNA blocked the muscle relaxation induced by TMS but failed to alter delta ISC. Muscle relaxation to TMS was restored dose dependently by L-Arg. In segments from another group of eight rats, saturated NO solutions relaxed the muscle but failed to change ISC either in the presence or absence of carbachol. These results support a role for NO as a neurotransmitter mediating relaxation of ileal smooth muscle but not mediating changes in epithelial ISC.

Endotoxin, interleukin-1 beta, interleukin-6, or tumor necrosis factor-alpha do not acutely stimulate isolated murine myometrial contractile activity.

OBJECTIVES: Endotoxin, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha have been implicated in the pathogenesis of preterm labor, but their acute effect on myometrial contractile activity is unknown. The objective of this study was to determine their effect on isolated pregnant murine myometrial contractile activity. STUDY DESIGN: Isometric contractions were measured in myometrium isolated from pregnancy day 18 Swiss-Webster mice. Frequency, duration, amplitude, and integrated area were compared before and after the addition of endotoxin (10(3) and 10(4) ng/ml) (n = 6), interleukin-1 beta (10 and 10 ng/ml) (n = 6), interleukin-6 (1 and 10 ng/ml) (n = 6), and tumor necrosis factor-alpha (1 and 10 ng/ml) (n = 6). Results were analyzed with the Wilcoxon rank-sum test. RESULTS: The addition of endotoxin, interleukin-1 beta, interleukin-6, or tumor necrosis factor-alpha did not result in a change in the contractile activity of isolated pregnant murine myometrium compared with control. CONCLUSION: Endotoxin, interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha do not acutely increase isolated murine myometrial contractile activity.

Cocaine acutely increases rat myometrial contractile activity by mechanisms other than potentiation of adrenergic pathways.

OBJECTIVE: We hypothesized that cocaine acutely increases contractile activity in isolated rat myometrium and that this effect is solely caused by potentiation of adrenergic pathways. STUDY DESIGN: Isometric contractions were measured in myometrium isolated from virgin and day-18 pregnant Sprague-Dawley rats. Frequency, duration, amplitude, and integrated area were compared before and after the addition of cocaine (10(-6) to 10(-4) mol/L) by means of analysis of variance and Duncan's multiple-range test. The effects of alpha-adrenergic receptor antagonists (prazosin 10(-6) mol/L and yohimbine 10(-6) mol/L) and beta-adrenergic receptor antagonist (DL-propranolol 2 x 10(-6) mol/L) were assessed. RESULTS: Contraction duration, expressed relative to control, increased acutely after cocaine (10(-5) mol/L) administration in pregnant (1.70 +/- 0.20) and nonpregnant (1.36 +/- 0.24) myometrium (mean +/- SE, p < 0.05), as did integrated area (pregnant 3.47 +/- 0.97, nonpregnant 2.48 +/- 0.66) (mean +/- SE, p < 0.05). These effects were not completely inhibited by adrenergic blockade. CONCLUSION: Cocaine acutely increases the duration and integrated area of spontaneous contractions in isolated rat myometrium by mechanisms not completely explained by inhibition of catecholamine reuptake and potentiation of adrenergic pathways.

The acute effect of cocaine exposure on pregnant human myometrial contractile activity.

OBJECTIVE: The objective of this study was to test the hypothesis that cocaine acutely increases contractile activity in isolated pregnant human myometrium. STUDY DESIGN: Myometrial samples were obtained from the lower uterine segment at elective cesarean section from five women at term who were not in labor and who had no perinatal risk factors. Myometrial strips were suspended in contractile buffer, and isometric contractions were measured. Frequency, amplitude, duration, and integrated area (mean +/- SE) were compared before and after the addition of cocaine (10(-6) to 10(-4) mol/L) by means of analysis of variance and Duncan's multiple range test. RESULTS: Contraction duration, expressed relative to control, increased acutely after addition of cocaine (10(-5) mol/L, 2.0 +/- 0.29; 10(-4) mol/L, 2.8 +/- 0.64) (p < 0.001). Integrated area of contractions also increased relative to control (10(-6) mol/L, 1.6 +/- 0.18, p < 0.05; 10(-5) mol/L, 2.4 +/- 0.16 and 10(-4) mol/L, 3.5 +/- 0.23, p < 0.001). These effects were dose dependent. CONCLUSION: Cocaine acutely increases contractile activity in myometrium isolated from pregnant women.