Effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on postoperative ileus in dogs after laparotomy

The effects of SK-896, a new human motilin analogue ([Leu13]motilin-Hse), on digestive tract motility in postoperative ileus were evaluated in a dog model of ileus after laparotomy. SK-896 was intravenously administered at 0.17, 0.33 and 0.67 microg/kg starting soon after operation and then at 6-h intervals, for a total of 9 times. SK-896 progressively, dose-dependently and significantly increased the duodenal motility from 1 h after operation. The recovery time of the gastrointestinal-interdigestive migrating complex (GI-IMC) activity, which is an indicator of normal gastrointestinal tract activity after laparotomy, was 56.5 +/- 5.0 h in the control group. SK-896 significantly shortened this recovery time. On the other hand, the plasma SK-896 concentrations declined diexponentially after administration, and can be described by a linear pharmacokinetic model within the dose range used. In addition, the pharmacokinetics of SK-896 did not change significantly at any postoperative time. There was no correlation between the plasma SK-896 concentrations and the intensity of duodenal motility, because the activity in the duodenum decreased transiently 13 h after laparotomy and increased with time thereafter. The changes in the activity are considered to reflect the progressive changes in the state of ileus. In conclusion, SK-896 increased the duodenal motility significantly, shortening the recovery time of GI-IMC-like activity in dogs with post-laparotomy ileus. Therefore, it is expected from these results that SK-896 would be useful and effective for the treatment of gastroparalysis after abdominal surgery.     

Gastroprokinetic effect and mechanism of SK-896, a new motilin analogue, during the interdigestive period in conscious dogs

SK-896 [(Leu(13))motilin-Hse] is a new human motilin analogue synthesized from Escherichia coli using a biotechnological method. We investigated the gastrointestinal motor-stimulating effect of SK-896 and the mechanism of this effect using implanted force transducers in conscious dogs. Infusion of SK-896 during phase I in the interdigestive state induced interdigestive migrating contractions like motility in the gastroduodenum. The motility index (MI(0-20)) of gastric antrum motor activity induced by SK-896 was increased dose dependently (r = 0.830, p < 0.001), and the MI(0-20) induced by SK-896 at a dose of 0.25 microg/kg/h for 20 min was the same as that for spontaneous phase III contractions. The SK-896-induced MI(0-20) was significantly decreased by atropine, hexamethonium, dopamine, granisetron, and yohimbine. Conversely, ketanserin, phentolamine, timolol, and naloxone did not have significant effects on SK-896-induced MI(0-20). The effects of these drugs on human motilin (0.25 microg/ kg/h for 20 min) induced MI(0-20) were the same as those of SK-896. These results indicate that SK-896 induces gastrointestinal motility during the interdigestive period in dogs with regulation of acetylcholine release from the cholinergic nerve terminal via the parasympathetic nervous system in the same fashion as human motilin.     

Oral administration of MA-2029, a novel selective and competitive motilin receptor antagonist, inhibits motilin-induced intestinal contractions and visceral pain in rabbits

The pharmacological properties of MA-2029, a novel motilin receptor antagonist, were investigated. In vitro, MA-2029 (1 to 30 nM) competitively inhibited motilin-induced contractions in isolated rabbit duodenal longitudinal muscle strips, with a pA2 value of 9.17+/-0.01 (n=5). However, contractile responses to acetylcholine and substance P were unaffected even at 1 microM of MA-2029. MA-2029 concentration-dependently inhibited the binding of [125 I]motilin to motilin receptors in a homogenate of rabbit colon smooth muscle tissue and membranes of HEK 293 cells expressing human motilin receptors. The pKi of MA-2029 was 8.58+/-0.04 in the rabbit colon homogenate (n=4) and 8.39 in the HEK 293 cells (mean of duplicate experiments). In vivo, orally-administered MA-2029 (3 to 30 mg/kg) dose-dependently inhibited colonic contractions induced by motilin (3 microg/kg, i.v.) in conscious rabbits. Inhibition was caused by all doses at 30 min after administration and by 10 mg/kg or more at 4 h after administration. The plasma concentration of MA-2029 correlated with its inhibitory effect. Furthermore, the oral administration of MA-2029 (0.3 to 3 mg/kg) also inhibited abdominal muscle contractions (an index of the visceral pain) induced by intravenous infusion of motilin (3 microg/kg/h) during colorectal distension in conscious rabbits. These results indicate that MA-2029 is an orally active, selective and competitive motilin receptor antagonist. It is suggested that this compound may be useful for gastrointestinal disorders associated with disturbed gastrointestinal motility such as irritable bowel syndrome.     

In vitro pharmacological characterization of mitemcinal (GM-611), the first acid-resistant non-peptide motilin receptor agonist, in smooth muscle of rabbit small intestine

The pharmacological properties of mitemcinal (GM-611), the first acid-resistant non-peptide motilin agonist, were investigated in the smooth muscle of the rabbit small intestine and compared with porcine motilin (pMTL), erythromycin A (EMA) and its derivatives (EM-523, EM-574 and ABT-229). Mitemcinal, pMTL, EMA, EM-523, EM-574 and ABT-229 produced concentration-dependent contractions with approximately the same maximum contractions in the isolated rabbit duodenum longitudinal strips. The contractile response to mitemcinal or pMTL was competitively inhibited by a selective motilin antagonist, GM-109. The pA(2) values for GM-109 as an antagonist of mitemcinal and pMTL showed approximately the same values. However, the concentration-dependent contractile responses to mitemcinal or pMTL were not affected by pretreatment with atropine, tetrodotoxin, hexamethonium, naloxone or tropisetron. The removal of calcium ions from the medium and pretreatment with verapamil greatly suppressed the contractions induced by mitemcinal and pMTL. The contractile response to mitemcinal was not affected by preincubation in acidic solutions, while those of EM-523, EM-574 and ABT-229 were strongly diminished in the same condition. Mitemcinal as well as other motilin agonists displaced (125)I-pMTL bound to a homogenate of the rabbit duodenum muscle tissue. The displacement curves of all these compounds were parallel. These results indicate that mitemcinal is a selective and full motilin receptor agonist in the smooth muscle of the rabbit small intestine and that this agent has an excellent acid-resistant property.     

Effect of erythromycin on different parts of the rabbit intestine: Comparison with motilin

• 1.1. The effect of erythromycin on the rabbit intestinal smooth muscle was investigated and was compared to that of motilin.
• 2.2. Whole isolated segments from the duodenum, jejunum, ileum and ascending colon, as well as strips from the circular and longitudinal smooth muscle of the ascending colon were used.
• 3.3. Erythromycin was found to possess a concentration-dependent contractile effect on the above intestinal parts but in different degree of intensity.
• 4.4. The order of the sensitivity of the intestinal parts to erythromycin was duodenum = jejunum > ascending colon > ileum.
• 5.5. The circular smooth muscle of the ascending colon was found to be more sensitive than the longitudinal smooth muscle.
• 6.6. A similar contractile effect, but at lower concentrations, and the same regional specifity were observed with motilin.

     

Stimulating action of KW-5139 (Leu13-motilin) on gastrointestinal motility in the rabbit.

1. The gastrointestinal motor stimulating action of the motilin analogue, KW-5139 (Leu13-motilin), was investigated both in the anaesthetized rabbit and in rabbit isolated smooth muscle tissues. 2. KW-5139 (0.3-10 micrograms kg-1, i.v.) produced motor stimulating actions in the gastric antrum, ileum and descending colon, the excitatory responses of which were initiated at the same time but declined with different time courses. The rank order of the excitatory response was: descending colon > or = gastric antrum >> ileum. 3. Atropine (1-3 mg kg-1, i.v.) or naloxone (1 mg kg-1, i.v.) completely suppressed the excitatory response to KW-5139 in the gastric antrum, but only partially attenuated that in the descending colon. This suggests that the mechanism of the excitatory response is different in the gastric antrum and the descending colon, and that cholinergic neural pathway is involved in the response of the gastric antrum. 4. KW-5139 (0.1 nM-1 microM) caused concentration-dependent contractions of the gastric antrum, duodenum, jejunum, ileum and the descending colon in vitro. In the rabbit intestine, the contractile response to KW-5139 was strongest in the duodenum and weakest in the ileum. 5. The contractile response to KW-5139 in the intestinal segments were not affected by tetrodotoxin, but were decreased by verapamil, or pretreatment with a high concentration of porcine motilin, confirming the involvement of motilin receptors in the response to KW-5139. 6. The present results suggest that the rabbit is a suitable species for the investigation of motilin on gut motility, because of the high responsiveness of the descending colon as well as the upper gastrointestinal tract.     

Does motilin stimulate the gastrointestinal motility of the pig? In vitro study using smooth muscle strips and dispersed muscle cells

To clarify the physiological role of motilin in the pig gastrointestinal (GI) tract, effect of Leu¹³-porcine motilin (LMT) on the contractility of GI smooth muscle was investigated in studies using isolated muscle strips and dispersed muscle cells. LMT produced no contraction in either longitudinal muscle (LM) or circular muscle (CM) of the stomach (fundus, corpus, antrum), duodenum, ileum and colon even at 1 μM. Pretreatment with LMT (1 nM-1 μM) did not potentiate the contractile response to acetylcholine (ACh) in each muscle strip. Dispersed cells from the duodenum responded to ACh in a concentration-dependent manner (EC₅₀= 10 pM), but not to LMT even at a high concentration (10 μM). Electrical field stimulation (EFS) caused a frequency-dependent (0.2–10 Hz) contraction of the duodenal LM that was almost completely inhibited by atropine or tetrodotoxin. EFS caused the relaxation of duodenal CM in a frequency-dependent manner (0.1–10 Hz). This relaxation was not inhibited by atropine, propranolol, phentolamine or guanethidine, indicating the involvement of noncholinergic, nonadrenergic (NCNA) nerves. N^G-nitro l-arginine methylester (l-NAME, 100 μM) attenuated the EFS-induced relaxation and the inhibition at low frequency was larger than that at high frequency. l-Arginine prevented the inhibition by l-NAME but d-arginine did not. LMT (1 nM-1 μM) had no influence on EFS-induced cholinergic contraction of LM and EFS-induced NCNA relaxation of CM layer. The present in vitro studies indicate that motilin is ineffective in producing contraction and in modulating the autonomic neuroeffector transmission of the pig GI smooth muscle, and suggest that pig GI smooth muscle lacks functional motilin receptors.     

The effect of SK-896 on post-operative ileus in dogs: gastrointestinal motility pattern and transit

The aim of this study was to investigate the effect of SK-896 (Phe-Val-Pro-Ile-Phe-Thr-Try-Gly-Glu-Leu-Gln-Arg-Leu-Gln-Glu-Lys-Glu- Arg-Asn-Lys-Gly-Gln-Hse), a new motilin analogue, on gastrointestinal motility and transit in dogs with post-operative ileus, and to compare the effects of this agent on these parameters with the effects of prostaglandin F(2alpha), a well-known gastroprokinetic agent. We used chronically implanted force transducers to measure motility and radiography of radio-opaque markers to measure transit. Infusion of SK-896 1 microgram/kg/h, for 20 min twice a day induced interdigestive migrating contractions-like motility. Infusion of prostaglandin F(2alpha), 20 microgram/kg/h, for 1 h twice a day induced continuous contractions in the distal part of the small intestine. The time of first appearance of interdigestive migrating contractions in the stomach (gastric-interdigestive migrating contractions) and the gastric emptying time of the solid marker with the administration of SK-896 were significantly less than those noted with the administration of prostaglandin F(2alpha). It appears that gastric-interdigestive migrating contractions play an important role in the transit of substances, especially solid substances, in the gastrointestinal tract. We conclude that SK-896, which induced gastric-interdigestive migrating contractions, is effective to induce early recovery from post-operative ileus.     

The effects of diethylcarbamazine citrate on smooth muscle.

The effect of the anthelmintic drug diethylcarbamazine citrate (DECC) was examined on the guinea-pig isolated ileum, rabbit duodenum, chick oesophagus, rat portal vein and pig coronary artery. DECC contracted all the gastrointestinal smooth muscle preparations. The contractions were antagonized by hexamethonium and atropine but they were not affected by mepyramine or methysergide in concentrations that abolished, or markedly reduced, responses to histamine and 5-hydroxytryptamine. DECC inhibited the responses of the guinea-pig ileum to other spasmogens, namely, acetylcholine, histamine and nicotine. Physostigmine markedly potentiated the responses of the chick oesophagus and the rabbit duodenum to DECC. DECC relaxed the potassium chloride-induced contractions of the pig coronary artery strips; these relaxations were not modified by propranolol or calcium chloride. There was no evidence that DECC released histamine from skin or muscle.     

The effects of diethylcarbamazine citrate on smooth muscle

The effect of the anthelmintic drug diethylcarbamazine citrate (DECC) was examined on the guinea-pig isolated ileum, rabbit duodenum, chick oesophagus, rat portal vein and pig coronary artery. DECC contracted all the gastrointestinal smooth muscle preparations. The contractions were antagonized by hexamethonium and atropine but they were not affected by mepyramine or methysergide in concentrations that abolished, or markedly reduced, responses to histamine and 5-hydroxytryptamine. DECC inhibited the responses of the guinea-pig ileum to other spasmogens, namely, acetylcholine, histamine and nicotine. Physostigmine markedly potentiated the responses of the chick oesophagus and the rabbit duodenum to DECC. DECC relaxed the potassium chloride-induced contractions of the pig coronary artery strips; these relaxations were not modified by propranolol or calcium chloride. There was no evidence that DECC released histamine from skin or muscle.     

Motilin and erythromycin enhance the in vitro contractile activity of the sphincter of Oddi of the Australian Brush-tailed Possum

Summary Erythromycin has been shown to interact with gastrointestinal smooth muscle in a similar manner to motilin, and has been postulated as a motilin receptor agonist. We report that in isolated preparations from the biliary tract of thirty one Australian Brush-tailed Possums (Trichosurus vulpecula) erythromycin acts in a similar manner to motilin. In all muscle strips from the sphincter of Oddi, prepared in both the circular and longitudinal orientation, both synthetic porcine motilin (10^–10 M – 10^–6 M) and erythromycin (lactobionate) (10^–8 M – 10^–4 M) stimulated contractile activity in a concentration dependant manner, via a direct effect on the smooth muscle (the response was unaffected by tetrodotoxin, omega conotoxin GVIA or atropine). In strips prepared from the gallbladder neither agonist affected the contractile activity in 7 of 8 animals.Motilin was approximately 1000 fold more potent in stimulating contractile activity than erythromycin in both sphincter of Oddi circular strips [pD₂ for peak response to motilin 8.67 (mean) ± 0.06 (SEM) compared with erythromycin 5.67 ± 0.09] and sphincter of Oddi longitudinal strips [pD₂ for peak response to motilin 8.64 (mean) ± 0.28 (SEM) compared with erythromycin 5.45 ± 0.23]. The concentration response curves for motilin and erythromycin were similar and both agonists required the presence of extracellular calcium to elicit responses (responses were diminished by verapamil and abolished in calcium free Krebs solution).Our results support the hypothesis that erythromycin mimics the action of motilin in stimulating the sphincter of Oddi in vitro. Send offprint requests to J. Toouli at the above address     

Gastrointestinal hormone receptors on isolated smooth muscle cells from gastric antrum of the rabbit

The regulation by gastrointestinal polypeptide hormones of contraction and relaxation of functionally isolated smooth muscle cells from gastric antrum of the rabbit has been investigated. Gastrin, cholecystokinin (CCK-8) and motilin induced a rapid contraction of isolated cells: significant response occurred within a 5-sec incubation with these peptides and maximal response (40% decrease in cell length) after 30 sec. A higher sensitivity of smooth muscle cells to gastrin and CCK-8 than to motilin stimulations was demonstrated (EC50 = 10 pM for both gastrin and CCK-8 and EC50 = 1 nM for motilin). The minimal gastrin fragment required to get full contraction was the C-terminal pentapeptide amide common to gastrin and CCK. Proglumide inhibited gastrin- or CCK-8- but not motilin-induced contractions with an IC50 of 50 microM. contraction induced by gastrin and motilin required normal levels of extracellular calcium, whereas that due to CCK-8 seemed to be independent of extracellular calcium. Vasoactive intestinal polypeptide (VIP) caused a relaxation of smooth muscle cells maximally contracted by carbachol or CCK-8 or gastrin (EC50 = 2.2 nM) with a parallel increase in intracellular cAMP content.     

Characterization of angiotensin II antagonism displayed by SK-1080, a novel nonpeptide AT1-receptor antagonist

The pharmacologic profile of SK-1080, a nonpeptide AT1-selective angiotensin-receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in pithed rats. SK-1080 inhibited the specific binding of [125I]-[Sar1, Ile8]-angiotensin II to human recombinant AT1 receptor with a 12-fold greater potency than losartan [median inhibitory concentration (IC50): 1.01 and 12.3 nM, respectively], but it did not inhibit the binding of [125I]-CGP 42112A to human recombinant AT2 receptor (IC50: >10 microM for both). The Hill coefficient for the competition curve of SK-1080 against AT1 receptor was not significantly different from unity (0.96). Scatchard analysis showed that SK-1080 interacted with human recombinant AT1 receptor in a competitive manner, as with losartan. In functional studies with rat and rabbit aorta, SK-1080 competitively inhibited the contractile response to angiotensin II (pKB values: 9.97 and 9.51, respectively) with 15-25% decrease in the maximal contractile responses, unlike losartan, which showed competitive antagonism without any change in the maximal contractile responses to angiotensin II (pA2 values, 8.02 and 7.59, respectively). In pithed rats, SK-1080 (i.v.) induced a nonparallel right shift in the dose-pressor response curve to angiotensin II (ID50, 0.07 mg/kg) with a dose-dependent reduction in the maximal responses; this antagonistic effect was approximately 25 times more potent than losartan (ID50, 1.74 mg/kg), which showed competitive antagonism. SK-1080 did not alter the responses induced by other agonists such as norepinephrine, KCI, and vasopressin in isolated rabbit aorta and pithed rats. These results suggest that SK-1080 is a highly potent AT1-selective angiotensin II-receptor antagonist with a mode of insurmountable antagonism.     

Pharmacokinetic and pharmacodynamic studies of SK-896, a new human motilin analogue,in healthy male volunteers

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of SK-896 ([Leu(13)]motilin-Hse) after intravenous administration to healthy male volunteers. DESIGN AND SETTING: This was a non-blinded phase I study.Participants: Thirty male Japanese volunteers (mean age 30.6 years) participated in this study. The volunteers were divided into five groups receiving different doses of SK-896. METHODS: The pharmacokinetics and pharmacodynamics of SK-896 were evaluated after single intravenous infusions of doses of 10, 20, 40 and 80 micro g over 20 minutes to fasting volunteers, or after multiple intravenous infusions (twice a day for 3 days) of doses of 40 micro g over 20 minutes to volunteers in the morning (fasting) and afternoon (non-fasting). Plasma concentrations of immunoreactive SK-896 were determined by radioimmunoassay, and borborygmus was measured as an indicator of drug effect (acceleration of gastrointestinal motility) with an improved Holter electrocardiograph attached to the abdomen. RESULTS: When SK-896 was given by single intravenous infusion at each dose, the plasma concentration of immunoreactive SK-896 rapidly increased to a maximum at the end of the infusion. After the infusion was completed, plasma concentrations declined monoexponentially with an elimination half-time of 4.57-5.64 minutes. The area under the concentration-time curve and the maximum concentration (1.04-9.08 microg-equiv./L) increased in proportion to the dose, and there were no dose-related changes in plasma clearance (7.59-9.34 mL/min/kg), mean residence time (7.83-9.51 minutes) or steady-state volume of distribution (62.9-73.9 mL/kg), indicating that SK-896 plasma concentrations can be described by a linear pharmacokinetic model within the dose range of the present study. After beginning administration, an increase in borborygmus was observed. At doses of 40 and 80 micro g, the borborygmus did not continue even when the plasma concentration was maintained, suggesting that tachyphylaxis occurs at a higher dose. When SK-896 was given as multiple intravenous infusions, the pharmacokinetics did not change with repeated administration. The intensity of borborygmus was low with afternoon administration, reaching only one-third to one-half that with morning administration, suggesting that, like native motilin, SK-896 does not stimulate gastrointestinal motility in the non-fasting state. CONCLUSIONS: The appropriate dose and administration period (fasting or non-fasting) are important factors in stimulating and maintaining gastrointestinal motility when treating gastroparalysis with SK-896.     

Discovery of the first non-peptide antagonist of the motilin receptor

A first-in-class non-peptide antagonist of the motilin receptor was identified through electronic screening of our corporate database against a 3D pharmacophore. The pharmacophore was developed from the motilin 22 residue endogenous peptide using NMR structural data, principles of peptide folding, and peptide structure activity relationships. The NMR data supported helical content within the peptide, and both the hydrophobic staple and N-capping box motifs were identified in the motilin sequence. The conformational features of these motifs were imposed on the peptide structure, providing a constrained conformer as a starting point for database searching. A trisubstituted cyclopentene lead was identified directly from the electronic search. Compounds in this series inhibit the binding of 125I-motilin to human antral smooth muscle membrane and antagonize motilin-induced intracellular calcium mobilization in cells expressing the human motilin receptor. A potent compound developed through optimization, RWJ 68023, is active in binding and cell-based functional assays and is also effective in inhibiting motilin-induced contractility in segments of rabbit duodenum. This orally active compound is currently undergoing clinical evaluation for the treatment of gastrointestinal disorders associated with altered motility.     

Characterization of rat intestinal angiotensin II receptors.

In rat ileum and duodenum 125I-sarcosine1,isoleucine8-angiotensin II labels a single population of binding sites with comparable receptor densities of 98 and 94 fmol/mg protein, respectively. Radioligand binding was dose dependently antagonized by angiotensin II (AII) and related peptides. DuP 753, a selective antagonist for the angiotensin AT1 receptor subtype, potently inhibited radioligand binding in both tissues (Ki: 12.7 and 11.8 nM), while AT2-selective ligands like PD 123.177 or p-amino-phenylalanine6-AII were inactive in concentrations lower than 1 microM. The contractile response to AII (1 microM) in ileal longitudinal and circular smooth muscle preparations amounted to 96 and 16%, respectively, of the response to 100 microM methacholine. The contractile response to AII was inhibited by DuP 753 (pA2 7.53) but unaffected by PD 123.177 (pA2 less than 5). The AII effect in longitudinal duodenal preparations amounted to only 24% of the methacholine response and was totally abolished in the presence of 1 microM DuP 753. No contraction due to AII was observed in duodenal circular smooth muscle preparations. The results obtained demonstrate the existence of functional AT1 receptors in the rat ileum and duodenum. In the ileum these receptors are mainly located on the longitudinal smooth muscle and coupled to contraction. In duodenal smooth muscle AII receptors may be either less effectively coupled to contractile elements or involved in another, additional function.     

Relaxant effects of nifedipine on isolated, human myometrium.

Myometrial tissue was obtained from non-pregnant women subjected to hysterectomy because of various gynaecological disorders, and from women undergoing caesarean section. Strip preparations were dissected and isometric tension was recorded. Nifedipine (2.9 X 10(-8)--2.9 X 10(-6)M) inhibited spontaneous contractile activity, mainly by reducing the amplitude of contraction in both non-pregnant and pregnant myometrium. The drug also inhibited potassium induced contractions in a concentration dependent manner. This effect seemed to be more pronounced in pregnant than in non-pregnant tissue. In preparations of pregnant human myometrium, normally polarized or potassium depolarized, oxytocin induced a contractile activity that was effectively inhibited by nifedipine. Nifedipine also relaxed contractions induced by vasopressin in isolated non-pregnant myometrium. It is concluded that the relaxant effect of nifedipine on isolated pregnant and non-pregnant human myometrium can be explained by inhibition of calcium influx. The results thus support the view, that calcium influx is an important step in the initiation of contractile activity in human uterine smooth muscle.     

Peptides do not induce contractions in gastrointestinal smooth muscle in calcium-free solution.

1. Smooth muscle from six sites in the cat gastrointestinal tract was evaluated with respect to its ability to generate contractions in calcium-free solutions. 2. Membrane depolarization and carbachol, but not cholecystokinin or neurotensin, increased tension in smooth muscle segments of esophagus, corpus, duodenum, ileum, proximal colon and distal colon in calcium-free solution. 3. Substance-P produced a contractile response in the absence of calcium but only in the corpus and distal colon. 4. These findings indicate that peptide mediated release of intracellular calcium plays a minimal role in activation of cat gastrointestinal smooth muscle.     

红霉素对狗消化间期和餐后胃肠运动的影响及机制探讨

目的观察静脉注射红霉素对狗消化间期胃肠移行性复合运动（ＭＭＣ）和餐后运动的作用并探讨可能机制。方法应用低顺应性毛细管水灌注消化道腔内测压系统记录清醒狗胃肠收缩活动。在ＭＭＣＩ相和餐后静脉注射红霉素记录胃肠运动变化并抽血测定血浆胃动素浓度。结果①血浆胃动素随ＭＭＣ不同时相呈周期性波动,血浆胃动素浓度在 ＭＭＣⅢ相时最高,ＭＭＣＩ相时最低。②在 ＭＭＣＩ相时从静脉注射红霉素可以激发胃和十二指肠ＭＭＣⅢ相收缩,但不伴有血浆胃动素升高。引起狗ＭＭＣⅢ相收缩的最适红霉素浓度为０,５ｍｇ·ｋｇ－１体重;红霉素１０ｍｇ·ｋｇ－１引起胃肠持续收缩并出现十二指肠－胃逆蠕动,导致恶心呕吐。③阿托品明显抑制红霉素所致的胃和十二指肠ＭＭＣⅢ相收缩。④红霉素增强狗餐后胃窦和十二指肠的收缩活动。结论红霉素有促进胃肠动力作用,作用机制与胃动素释放无关,可能部分通过胆碱能神经介导。     

The stimulatory action of the calcium channel agonist Bay K 8644 on isolated duodenal muscle

Summary The action of the novel dihydropyridine analogue Bay K 8644 has been evaluated on the rat isolated duodenal muscle. Bay K 8644 (0.3 nmol/l to 1 pmol/l) increased both the tone and the phasic movements of the duodenum; the maximum response was about 60% of that to acetylcholine. Nifedipine (30 nmol/l) induced a parallel shift of the concentration-response curve to this compound to the right, without depressing the maximum response; conversely, verapamil (30 nmol/l) caused an unsurmountable antagonism. Incubation of the strips in Ca²⁺-free medium reduced the contractile response to the calcium agonist. The spasmogenic effect of Bay K 8644 was inhibited by atropine (0.1 pmol/l) which caused a significant reduction in the maximum response to the compound. The competitive interaction between Bay K 8644 and nifedipine is consistent with an action at the same dihydropyridine binding site in the calcium channel and suggests that these compounds could be selective probes for detecting the dihydropyridine receptor also in the intestinal smooth muscle. The sensitivity of the contractile effect of Bay K 8644 to atropine may indicate an action of this compound in the cholinergic system, probably mediated by a release of acetylcholine from the nerve terminal rather than due to a direct stimulatory action at muscarinic receptors in the smooth muscle.