The alpha2-adrenergic receptor antagonist yohimbine improves endotoxin-induced inhibition of gastrointestinal motility in mice

Background: Sepsis inhibits gastrointestinal motility. Although the exactmechanism of this is unclear, lipopolysaccharide is known toactivate macrophages in the gastrointestinal wall, which upregulatetheir expression of inducible nitric oxide synthase (iNOS).This leads to an increased production of nitric oxide, whichrelaxes the gastrointestinal muscles. We studied endotoxaemicmice to determine whether yohimbine improved delayed gastricemptying and gastrointestinal transit. Methods: Male Balb/c mice (n = 49) were randomly allocated to two groups,and either yohimbine 25 µg or saline was injected s.c.Four hours later, mice in each group were further randomly allocatedto two groups, and either lipopolysaccharide 100 µg orsaline was injected intraperitoneally. Eight hours later, liquidcontaining fluorescent microbeads was infused into the stomach,and 30 min later, gastric emptying and gastrointestinal transitwere measured using flow cytometry. We also studied whetheryohimbine given after injection of lipopolysaccharide was effective(n = 22). In another group of mice (n = 32), iNOS in the gastrointestinaltract was measured using western blotting. Results: Lipopolysaccharide significantly inhibited gastric emptyingand gastrointestinal transit. Yohimbine, given before or afterlipopolysaccharide, significantly attenuated the inhibitoryeffects of lipopolysaccharide. Lipopolysaccharide increasedthe expression of iNOS in the small intestine and yohimbinesuppressed the effects of lipopolysaccharide. Conclusions: In endotoxaemic mice, yohimbine improved delayed gastric emptyingand gastrointestinal transit, possibly by downregulating lipopolysaccharide-inducedincreased expression of iNOS.     

Dual alpha(2)-adrenergic agonist and alpha(1)-adrenergic antagonist actions of dexmedetomidine on human isolated endothelium-denuded gastroepiploic arteries

The actions of dexmedetomidine (DEX) on human vascular smooth muscle are unclear. We investigated its effects on isolated, endothelium-denuded human gastroepiploic arteries in vitro and compared them with clonidine (CLO). DEX had little direct effect on resting tension, whereas CLO produced small contractile responses, an effect which is blocked by the alpha(1)-adrenergic antagonist prazosin. DEX markedly enhanced the high K(+) (40 mmol/L)-induced contraction, and this effect was reversed by the alpha(2)-adrenergic antagonists yohimbine and rauwolscine but unaffected by prazosin. However, CLO had little effect on the K(+) contractions. Interestingly, larger concentrations (>10(-7) mol/L) of both alpha(2)-adrenergic stimulants significantly inhibited the contractions elicited by the alpha(1)-adrenergic agonist phenylephrine (10(-6) mol/L) and, to a lesser extent, those elicited by the alpha(1)/alpha(2)-agonist norepinephrine (10(-6) mol/L). These results suggest the possibility that DEX and CLO each have a high affinity for alpha(1)-adrenoceptors in human isolated gastroepiploic arteries, resulting in a reduced efficacy of alpha(1)-adrenergic activation by alpha-agonists. The differing affinities of the drugs for alpha(1)- and alpha(2)-adrenoceptors may help explain their additional actions: 1) DEX enhances the high K(+)-induced contraction presumably through alpha(2)-adrenoceptor activation, and 2) CLO acts on alpha(1)-adrenoceptors as a partial agonist when present alone. IMPLICATIONS: Dexmedetomidine may not directly affect smooth muscle in human peripheral resistance vessels within the usual range of plasma concentrations (<10(-7) mol/L) achieved in clinical practice. However, in large doses, it could enhance the response to nonadrenergic vasoconstrictor agonists while antagonizing the vasoconstrictor response to alpha(1)-adrenoceptor agonists.     

Calcium channel modulation of alpha 1- and alpha 2-adrenergic pressor responses in conscious and anesthetized dogs.

The influence of halothane and isoflurane on alpha-adrenergic-mediated vasoconstriction before and following calcium channel modulation was investigated in chronically instrumented dogs. After ganglionic, cholinergic, and beta-adrenergic blockade, systemic hemodynamic responses following equieffective pressor doses of phenylephrine (0.6 micrograms/kg iv), a selective alpha 1 agonist, and azepexole [B-HT 933] (20 micrograms/kg iv), a selective alpha 2 agonist, were obtained. The calcium channel stimulator Bay k 8644 (0.5 and 1 micrograms.kg-1.min-1) was infused intravenously for 10 min and phenylephrine and azepexole administered at the end of each infusion. On different days, each dog was subsequently anesthetized with equihypotensive concentrations of halothane (1.7%) or isoflurane (2%) in oxygen and the same pharmacologic interventions were repeated in the presence of halothane or isoflurane. Twenty-one experiments (three groups) using seven chronically instrumented dogs were completed. Halothane and isoflurane produced significant (P less than 0.05) attenuation of the increase in arterial pressure after bolus administration of phenylephrine and azepexole. Bay k 8644 augmented the pressor responses mediated by both phenylephrine and azepexole in all three groups. Thus, halothane and isoflurane nonselectively reduced the pressor response to both alpha 1- and alpha 2-adrenergic receptor stimulation and this was probably not mediated by inhibition of transmembrane calcium flux through dihydropyridine sensitive channels.     

Effect of endothelin receptor antagonist (TAK-044) on autotransplanted perfused kidneys in dogs

BACKGROUND: Endothelin-1 (ET-1) is involved in some diseases, including renal disease. Recently, the role of ET-1 in postrenal transplantation has been demonstrated in experimental and clinical studies. A new endothelin receptor antagonist, TAK-044, blocks both, ETA and ETB receptors, and was useful in treating acute renal failure in rats. In this study, we evaluated the effect of TAK-044 on autotransplanted kidneys with 18 h of perfusion. MATERIALS AND METHODS: TAK-044 was injected subcutaneously at 15 mg/kg/day for 2 weeks in one group of dogs, and blood analysis and renal function, were evaluated. A control group was given saline in the same manner as that used for the TAK-044 group. Histopathological examination and immunohistochemistry for ET-1 were performed in the two groups. RESULTS: In the control group, 5 of the 7 dogs died of renal failure within 2 weeks after autotransplantation of the kidney. In the TAK-044 group, 5 of the 7 dogs survived and 2 died of renal failure within the same period. Although the histological changes in the tubules in both groups were severe due to the 18 h of perfusion, TAK-044 ameliorated these changes. Immunohistochemical staining for ET-1 was seen in tubules in the control group. CONCLUSION: These findings suggest that TAK-044 effectively reduces damage in autotransplanted perfused kidneys in dogs, and may be useful in limiting damage to the kidney by acute tubular necrosis after renal transplantation in humans.     

Effect of truncal vagotomy on sphincter of oddi cyclic motility in conscious dogs

OBJECTIVE: To evaluate the effects of truncal vagotomy at the diaphragmatic level on the sphincter of Oddi (SO) motility. SUMMARY BACKGROUND DATA: Cholelithiasis is a well-known late complication after gastrectomy and/or vagotomy. The mechanism of gallstone formation is only partly understood, and few studies address the effects of vagotomy on SO cyclic motility in conscious subjects. METHODS: In conscious dogs, SO motility was recorded by retrograde infusion manometry through a duodenal cannula before and after bilateral truncal vagotomy at the diaphragmatic level. Effects of cholecystokinin-octapeptide and feeding were also evaluated before and after vagotomy. RESULTS: SO cyclic motility and the gastroduodenal migrating motor complex continued to occur during postvagotomy fasting. Intermittent inhibitions of the SO and duodenal contractions disappeared during phase 3 of the migrating motor complex. SO basal pressure significantly decreased, whereas the amplitude significantly increased. Cholecystokinin-octapeptide inhibited SO contractions before and after vagotomy. The amplitude of SO contractions increased and their frequency decreased after feeding; however, these effects disappeared after vagotomy. CONCLUSIONS: SO cyclic motility and the effects of feeding change after truncal vagotomy at the diaphragmatic level. These facts may at least partly explain gallstone formation after gastric surgery and/or vagotomy.     

Effect of proglumide on gastrointestinal motility and gastric secretion in the conscious state

Proglumide suppressed neither phase III activity nor propagation of interdigestive migrating contractions (IMC) in the gastrointestinal tract. Furthermore, proglumide did not inhibit the gastric motor activity stimulated by pentagastrin, however, it suppressed the pH in Pavlov pouch stimulated by pentagastrin in the interdigestive state. On the contrary, in the digestive state, proglumide did not suppress the pH. That might be due to not only various gut hormones including gastrin, but also neural stimulation, mechanical stimulation and so on. In conclusion, antigastrin effect of proglumide is rather remarkable on the acid secretion not on the gastrointestinal motor activity. Proglumide may be an antacid without suppression of motor activity.     

The effects of the stereoisomers of the alpha 2-adrenergic agonist medetomidine on systemic and coronary hemodynamics in conscious dogs.

The alpha 2-adrenergic agonist medetomidine produces systemic hemodynamic effects that are mediated by both peripheral and central nervous system actions. The current investigation was designed to characterize coronary and systemic hemodynamic effects of the D- and L-stereoisomers of medetomidine in conscious, chronically instrumented dogs with and without autonomic nervous system blockade. Dogs were instrumented for measurement of aortic pressure, coronary blood flow velocity, cardiac output, left ventricular pressure, rate of change in pressure (dP/dt), and subendocardial systolic shortening. Administration of the D-isomer of medetomidine (doses of 1.25, 2.5, and 5.0 micrograms/kg, each administered over 10 min, with 60 min between doses) significantly altered systemic hemodynamics, in a biphasic fashion. A decrease in respiratory rate without change in arterial blood gas tensions occurred. With the 5 micrograms/kg dose of D-medetomidine, an initial pressor response was followed by secondary, significant (P less than 0.05), and dose-related decreases in heart rate (74 +/- 3 to 57 +/- 4 beats per min), mean arterial pressure (109 +/- 2 to 100 +/- 3 mmHg) and the rate-pressure product (10.5 +/- 0.4 to 7.0 +/- 0.5 beats.min-1.mmHg.10(3] accompanied by a reduction in plasma concentrations of norepinephrine. No changes in left ventricular end diastolic pressure or coronary blood flow velocity occurred. In contrast to the D-isomer, the L-isomer (1.25, 2.5 and 5.0 micrograms/kg) produced no changes in hemodynamics or plasma concentrations of norepinephrine. In dogs pretreated with hexamethonium (20 mg/kg), propranolol (2 mg/kg), and atropine methylnitrate (3 mg/kg) to produce autonomic nervous system blockade, D-medetomidine also produced an initial pressor response, but no secondary reduction in heart rate or arterial pressure occurred. The results indicate that the D-isomer of medetomidine is stereospecific for alterations in hemodynamics: the active D-isomer produces decreases in heart rate, arterial pressure, and the rate-pressure product via diminished sympathetic and/or augmented parasympathetic tone. This conclusion is supported by the absence of these changes after pharmacologic blockade of the autonomic nervous system.     

An experimental study of the gastrointestinal motility in conscious dogs with strain gauge force transducers

Interdigestive motor complex (IMC) from the stomach to the ileum and colonic migrating motor complex (CMMC), and the effects of motilin and PYY to them were studied in conscious dogs with strain gauge force transducers (SG). In fasted dogs, IMC cycle times were 100.5 +/- 7.5 min in from the antrum to the ileum and propagation velocity of the small intestine was fastest in the proximal jejunum (4.85 +/- 0.81 cm/min), slowest in the distal ileum (0.81 +/- 0.08 cm/min). The duration of postprandial interruption of motor complex (DIMC) was longer in the antrum and duodenum in 8 dogs of the twelves than the middle and lower intestines. Ileo-colonic propagation rates of IMC that reached to the terminal ileum were 95/116 (81.9%), but the frequency of CMMCs was about 4 times higher than that of IMCs. Each colonic motor complex were classified into four patterns, such as aboral migrating complex (A), oral migrating complex (O), discrete complex (D) and giant migrating contractions (G), and the starting point of migrating complex was marked with -, like A, O or G. Thus, independency index (I I) in each site was defined as: I I = (sum of number of A, O, G and D)/(total number of colonic motor complex). I I was highest in colon 1 (70-80%) and next in colon 4. Motilin (0.5 microgram/kg.hr) elicited IMC like activities in the antrum, duodenum and proximal jejunum, but no effects in the middle and lower small intestine, and the colon. PYY infusion caused dose dependent inhibitions of IMC in the antrum and duodenum, but no effects in the below intestines as same as motilin. These findings suggest that IMCs are basal rhythms of gastrointestinal motility and IMCs occurring from the antrum to the proximal jejunum are more sensitive to the factors as eating or gut peptides.     

Dexmedetomidine produces dual alpha2-adrenergic agonist and alpha1-adrenergic antagonist actions on human isolated internal mammary artery

OBJECTIVE: To investigate the direct effects of dexmedetomidine (DEX) on isolated human internal mammary artery (IMA). DESIGN: In vitro experimental study. SETTING: Cardiovascular Pharmacology Laboratory, Department of Pharmacology, Gulhane School of Medicine, Ankara, Turkey. PARTICIPANTS: IMA segments were obtained from 18 patients undergoing coronary artery bypass surgery. INTERVENTIONS: The response in IMA was recorded isometrically by a force displacement transducer in isolated organ baths. DEX-induced contractions were tested in the presence of the alpha2-adrenoceptor antagonist yohimbine (10(-7) mol/L) and the alpha1-adrenoceptor antagonist prazosin (10(-8) M). The effect of DEX (10(-7), 10(-6), and 10(-5) mol/L) on phenylephrine (10(-9)-3 x 10(-4) mol/L)-induced contactions was also tested. MEASUREMENT AND MAIN RESULTS: DEX (10(-9) mol/L-3 x 10(-5) mol/L) caused contraction in IMA segments. The contraction at lower concentrations of DEX (10(-9) mol/L-3 x 10(-7) mol/L) was attenuated by yohimbine (10(-7) mol/L), whereas prazosin (10(-8) mol/L) attenuated the contractions at higher concentrations of DEX (10(-6) mol/L-3 x 10(-5) mol/L). Incubation of IMA segments with high concentrations of DEX (10(-6) mol/L and 10(-5) mol/L) caused an inhibition of phenylephrine (10(-9) mol/L-3 x 10(-4) mol/L)-induced contraction. CONCLUSION: These data suggest that DEX causes contraction by activating alpha2-adrenoceptors at lower concentrations, but it may also activate alpha1-adrenoceptors at higher concentrations in IMA. The action of DEX on phenylephrine-induced contraction may be related to an alpha1-adrenoceptor antagonistic effect produced via partial alpha1-adrenoceptor agonistic action.     

Diurnal changes in colonic motility in conscious dogs

Daily profile of colonic motor activity was observed in 10 conscious dogs by means of extraluminal force transducers. Each dog was implanted with a set of seven strain, gauges, one on the terminal ileum and the remaining six on the colon equidistantly. The colonic motor activity was basically composed of migrating and non-migrating motor complexes at all six recording sites. Each motor complex was characterized by a tonic contraction superimposed by rhythmic bursts of phasic contractions. During fasted period these motor complexes recurred at a mean interval of 36 min, and a mean duration was 7 to 12 min. Those motor complexes which migrated over at least three recording sites were defined as "migrating", 72% of those observed at the most proximal sites (n = 2680) were migrating, and the remaining 28% were non-migrating. Of those migrating motor complexes 90.4% migrated caudad (iso-peristalsis), while only 9.4% migrated orad (antiperistalsis). During postprandial period the colonic motor complexes at all recording sites uniformly increased their frequency with shorter intervals. Different from the small intestine, the contractile patterns were essentially the same as those of fasted period. The postprandial acceleration of the colonic motor complexes seems to be compatible with gastrocolic response.     

Effects of trimebutine maleate (TM-906) on the gastrointestinal motility in anesthetized dogs

Effects of trimebutine maleate (TM-906) on the spontaneous motility of the gastrointestinal tracts were investigated in anesthetized dogs by means of force transducers. TM-906, administrated intravenously or intraduodenally, produced an inhibition followed by a potentiation of the spontaneous motility in the stomach, and caused a potentiation of the spontaneous motility in the duodenum, jejunum, ileum and colon. These effects of TM-906 were observed also in the vagotomized dogs as in the intact dogs. From these results, it is suggested that TM-906 modulates the spontaneous motility of the gastrointestinal tracts primarily through the peripheral mechanism.     

Effect of cisapride on the cholinergic control mechanisms of gastrointestinal motility in dogs

The action of cisapride on physiological and disturbed gastrointestinal motor function was investigated in conscious and anesthetized dogs and the mechanism of action involved. Regardless of the presence or absence of vagal innervation, administration of cisapride (0.2 mg approximately 1.0 mg/kg body weight, i.v.) during the quiescent period of interdigestive migrating contractions (IMC), induced non-migrating IMC-like motility in the entire gastrointestinal tract from gastric body to distal colon. Administration of cisapride in the digestive state resulted in the excitatory response of increased amplitude of digestive peristalsis and strong IMC-like motility was not observed. All of these excitatory responses in gastrointestinal motility disappeared by the administration of atropine (0.5 mg approximately 0.1 mg/kg body weight, i.v.). Furthermore, the excitatory response in gastrointestinal motility induced by cisapride in anesthetized dogs disappeared by the administration of TTX (10 micrograms/kg of body weight, i.v.). These results suggest that the excitatory action of cisapride on the gastrointestinal motility is based on its mechanism in which cisapride acts on the cholinergic neurones in the gastrointestinal wall to stimulate ACh release, resulting in the increase in gastrointestinal motility. Cisapride caused powerful IMC-like motility in the ileum of animal with pseudo-obstruction-like motor disturbance which had been seen after preparation of Thiry loop (ileum). This motility migrated from the proximal ileum to the Thiry loop and then to the distal ileum. Trimebutine maleate also demonstrated this effect, but metoclopramide and domperidone were ineffective. Administration of cisapride at the doses (0.2 mg approximately 1.0 mg/kg body weight, i.v.) causing stimulated motor response in the gastrointestinal tract did not induce significant secretion of gastric acid, pancreatic juice and bile.     

Changes in gastrointestinal motility after subtotal colectomy in dogs

Purpose: This study was conducted to examine recovery from diarrhea after subtotal colectomy by observing changes in gastrointestinal motility, neuropeptides, and autonomic nerves in the enteric nervous system in dogs. Methods: The moisture volume of intestinal matter recovered from the ileal side of the anastomosis was defined as the diarrhea index. Gastrointestinal motility was measured using strain gauge force transducers (SG) for 24 weeks after subtotal colectomy. Immunohistochemical changes in neuropeptides in the residual intestine, acetylcholinesterase activation of cholinergic fibers, and fluorohistochemical changes of adrenergic fibers in the myenteric plexuses were evaluated. Results: The digestive tract transit time returned to normal in the early postoperative period, but decreased moisture volume was seen in the intestinal matter after 8 postoperative weeks. Migrating contraction waves propagating beyond the site of anastomosis, signaling recovery of intestinal motility, were noted after 8 postoperative weeks, corresponding to reconstruction of cholinergic fibers in the anastomotic section. Transient activation of vasoactive intestinal polypeptide was seen in the residual intestine, but this had normalized by the eighth postoperative week. Lengthened villi in the residual intestine were also seen after 8 postoperative weeks. Conclusion: The decreased moisture volume in the intestinal matter is due to the improvements we observed in the eighth postoperative week. Received: October 25, 2001 / Accepted: July 2, 2002 Acknowledgments. An abstract of this report was presented at the 47th General Meeting of the Japan Society of Coloproctology. We wish to express our thanks to Dr. Yoshihisa Saida for his scientific advice and to Dr. Masakuni Onda for his technical assistance. Reprint requests to: Y. Jimba