Kenshi Kamei

Effects of Mitemcinal (GM-611), an Acid-Resistant Nonpeptide Motilin Receptor Agonist, on the Gastrointestinal Contractile Activity in Conscious Dogs

The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a motilin receptor antagonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via motilin receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.

ORAL MITEMCINAL (GM-611), AN ERYTHROMYCIN-DERIVED PROKINETIC, ACCELERATES NORMAL AND EXPERIMENTALLY DELAYED GASTRIC EMPTYING IN CONSCIOUS DOGS

1 We examined effects of orally administered mitemcinal, an erythromycin‐derived motilin agonist, on gastric emptying and antroduodenal motility in conscious normal dogs and conscious dogs with experimentally delayed gastric emptying. For comparison, we also examined the effects of orally administered cisapride. 2 Gastric emptying was assessed by adding paracetamol to the test meal and determining three of its pharmacokinetic parameters as indices of gastric emptying. Antroduodenal motility was assessed from the output of force transducers chronically implanted in the gastric antrum and duodenum. 3 In normal dogs, mitemcinal (0.25, 0.5 and 1 mg/kg) dose‐dependently accelerated gastric emptying, significantly increasing all three indices at doses of 0.5 and 1 mg/kg; cisapride (1, 3 and 10 mg/kg) had no significant effect. Mitemcinal also dose‐dependently stimulated antroduodenal motility in the interdigestive and digestive states. Cisapride, at 100‐fold the dose, produced similar effects in the interdigestive state, but mixed results in the digestive state. 4 In dogs with delayed gastric emptying induced by subcutaneous clonidine (0.03 mg/kg), mitemcinal (0.25, 0.5 and 1 mg/kg) dose‐dependently improved delayed gastric emptying, significantly increasing two of three indices at a dose of 1 mg/kg. Cisapride (1, 3 and 10 mg/kg) caused non‐significant increases in the indices of gastric emptying, with roughly bell‐shaped dose–response curves. The highest dose of mitemcinal (1 mg/kg) also stimulated antroduodenal motility. 5 In dogs with delayed gastric emptying induced by vagotomy, mitemcinal (0.125, 0.25 and 0.5 mg/kg) dose‐dependently improved delayed gastric emptying, significantly increasing all three indices at doses of 0.25 and 0.5 mg/kg. Cisapride (3 mg/kg) restored the indices to roughly prevagotomy levels, but none of the increases was significant. Mitemcinal, at a dose of 0.25 mg/kg, also stimulated antroduodenal motility. 6 Because delayed gastric emptying is the basic characteristic of gastroparesis, the fact that mitemcinal accelerated gastric emptying in dogs with normal and delayed gastric emptying much more robustly than cisapride adds to the evidence that mitemcinal is likely to be useful for the treatment of patients with gastroparesis.

An orally active motilin receptor antagonist, MA-2029, inhibits motilin-induced gastrointestinal motility, increase in fundic tone, and diarrhea in conscious dogs without affecting gastric emptying

The pharmacological properties of MA-2029, a selective and competitive motilin receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3-10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by motilin (3 microg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3-3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 microg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1-10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of motilin (3 microg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1-30 mg/kg, p.o.) reduced the incidence of diarrhea induced by motilin in a dose-dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating 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.

Mitemcinal (GM-611), an orally active motilin receptor agonist, improves delayed gastric emptying in a canine model of diabetic gastroparesis.

1 The aim of the present study was to evaluate the effects of mitemcinal (GM‐611), an orally active motilin receptor agonist, on delayed gastric emptying in a canine model of diabetic gastroparesis and to compare these effects with those of cisapride. 2 Moderate hyperglycaemia was induced by a single intravenous injection of a mixture of streptozotocin (30 mg/kg) and alloxan (50 mg/kg). Dogs that maintained moderate hyperglycaemia (fasting plasma glucose 200–300 mg/dL) without insulin treatment were selected and gastric emptying in these dogs was determined by the paracetamol method. 3 One year after the onset of diabetes, there was no difference in the gastric emptying of normal and diabetic dogs. However, after 5 years, the diabetic dogs showed delayed gastric emptying. The motor nerve conduction velocity of the tibial nerve was significantly lower in diabetic dogs comapred with normal dogs at both time points. 4 Histopathological examination at the end of the study showed that there were fewer nerve fibres in both dorsal vagal and tibial nerves of diabetic dogs comapred with normal dogs. The onset of delayed gastric emptying is thought to have occurred gradually, in parallel with abnormal autonomic nerve function induced by the long period of moderate hyperglycaemia. 5 Oral administration of mitemcinal (0.125, 0.25 or 0.5 mg/kg) dose‐dependently accelerated delayed gastric emptying, significant at 0.5 mg/kg, in diabetic dogs, whereas cisapride (1, 3 or 10 mg/kg) had no significant effect. These results add to the existing evidence that mitemcinal is likely to be useful for treating diabetic gastroparesis.

Mitemcinal (GM-611), an orally active motilin agonist, facilitates defecation in rabbits and dogs without causing loose stools

Abstract  The effects of mitemcinal (GM‐611), an orally active motilin agonist, on defecation were investigated in rabbits and dogs. In normal rabbits, within 0–3 h of dosing, orally administered mitemcinal (2.5–10 mg kg−1) increased stool weight in a dose‐dependent manner without causing loose stools. Sennoside (12–48 mg kg−1) also facilitated defecation within 2–9 h of oral administration, but the stools were significantly loosened. In the morphine‐induced constipation model, the stool weight of morphine‐treated rabbits (1 mg kg−1) was only 37.5% of that of untreated animals. Mitemcinal (0.5–20 mg kg−1) dose‐dependently increased stool weight without increasing stool water content. At the highest dose of mitemcinal, stool weight recovered to 83.9% of that of untreated animals. In normal dogs, mitemcinal (0.3–3 mg kg−1) reduced the time to first bowel movement after oral administration without inducing diarrhoea at any dose. These results indicate that mitemcinal facilitates defecation without inducing severe diarrhoea. It is suggested that mitemcinal may be a novel therapeutic agent for constipation that enables easier control of the timing of defecation because of the early onset and short duration of its action, compared with sennoside.

Hemodynamic and hormonal responses to nicorandil in a canine model of acute ischemic heart failure : A comparison with cromakalim and nitroglycerin

The pharmacologic profiles of nicorandil in the cardiovascular system have been characterized by K-channel opening and nitrate activities. However, the effects of nicorandil on acute heart failure have yet to be elucidated. To investigate the effects of nicorandil under such pathophysiologic conditions, we administered nicorandil intravenously to dogs with acute ischemic heart failure induced by coronary embolization and compared the results with those induced by cromakalim and nitroglycerin. The heart failure in this experiment was demonstrated by a reduction of mean blood pressure (MBP) from 143+/-3 to 129+/-2 mm Hg (p < 0.01); cardiac output (CO) from 2.18+/-0.10 to 1.06+/-0.05 L/min (p < 0.01); stroke volume (SV) from 12.7+/-0.6 to 6.8+/-0.3 ml/min (p < 0.01); Vmax, an index of the contractility of the left ventricle, from 105.5+/-4.4 to 49.9+/-1.8 1/s (p < 0.01), and an increase in right atrial pressure (RAP) from 2.9+/-0.3 to 5.3+/-0.3 mm Hg (p < 0.01); left ventricular end-diastolic pressure (LVEDP) from 2.5+/-0.4 to 26.0+/-1.4 mm Hg (p < 0.01); and T, time constant of left ventricular relaxation, from 38.3+/-0.8 to 62.4+/-2.8 ms (p < 0.01). Furthermore, plasma renin activity (PRA) and plasma atrial natriuretic peptide (ANP) increased (from 1.72+/-0.29 to 5.03+/-0.68 ng AngI/ml/h, p < 0.01; from 103.9+/-5.8 to 411.5+/-29.4 pg/ml, p < 0.01, respectively), whereas brain natriuretic peptide (BNP) remained unchanged (from 23.1+/-2.2 to 26.9+/-1.4 pg/ml). Nicorandil (10-40 microg/kg/min, i.v. infusion for 20 min for each dosing) or cromakalim (0.25-1 microg/kg/min) decreased MBP, systemic vascular resistance (SVR), RAP, and LVEDP, and increased CO, SV, and Vmax. However, the reduction of RAP in cromakalim was significantly smaller than those of nicorandil and nitroglycerin in comparison at similar hypotensive doses. Nitroglycerin (2.5-10 microg/kg/min) decreased MBP, RAP, and LVEDP, and increased Vmax but did not change CO or SV. Increased plasma ANP levels, an index of cardiac filling pressure after induction of acute ischemic heart failure, were decreased significantly by cromakalim and tended to decrease by nicorandil or nitroglycerin. Plasma BNP levels and PRA were not influenced by any of these drugs. These results suggest that nicorandil produces the reduction of both preload and afterload followed by an improvement of cardiac contractility in this model. The increase in CO may be mediated mainly by the drugs K-channel opening activities and the reduction of venous tone by its nitrate properties. Nicorandil may prove to be useful in the treatment of acute ischemic heart failure.

Regional and species differences in glyburide-sensitive K+ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim

1 The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol‐induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea‐pig and human airway smooth muscles. 2 In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentration‐dependent relaxation of the carbachol‐induced contraction. The IC50 values were 0.35 μm (pIC50: 6.46 ± 0.10, n = 9) and 0.55 μm (pIC50: 6.26 ± 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 μm (pICso: 6.73 ± 0.10, n = 7). However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (IC50 > 10 μm). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03‐1 μm) but not by charybdotoxin (100 nm). 3 Levcromakalim (1 μm) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 μm) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells. 4 Levcromakalim (10 μm) increased 86Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 μm) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 μm) prevented the hyperpolarization and the 86Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses. 5 Both KC 128 and levcromakalim relaxed the guinea‐pig isolated tracheal smooth muscles precontracted by carbachol (100 nm), histamine (3μm) or U46619 (10 nm). KC 128 was approximately 10 times more potent than levcromakalim for each agonist. 6 In human bronchial smooth muscles, levcromakalim but not KC 128 induced a concentration‐dependent relaxation of the carbachol‐induced contraction. 7 It is concluded that KC 128 has relaxant and hyperpolarizing effects in the dog bronchial and guinea‐pig tracheal smooth muscles, but not in the dog tracheal and human bronchial smooth muscles. On the other hand, levcromakalim acts consistently on all the above airway smooth muscle tissues. These results indicate that there are regional and species differences in distribution of K+ channels, and at least two different K+ channel opener‐ and glyburide‐sensitive K+ channels are present in the dog airway smooth muscles.

The effect of a novel benzopyran derivative, KC 399, on the isolated guinea-pig trachealis and human bronchi.

1. In isolated guinea-pig trachealis, KC 399, BRL 38227 and salbutamol suppressed the spontaneously generated tone in a concentration-dependent manner with pD2 values of 8.89 +/- 0.09 (n = 14), 6.18 +/- 0.07 (n = 11) and 7.72 +/- 0.12 (n = 8), respectively. 2. The bronchodilator effects of KC 399 and BRL 38227 were antagonized by glibenclamide but not by charybdotoxin or apamin. The effect of salbutamol was antagonized by charybdotoxin but not by glibenclamide or apamin. 3. KC 399 and BRL 38227 failed to inhibit the tone evoked by 90 mM K+ in guinea-pig trachealis, whereas salbutamol did inhibit it, in a concentration-dependent manner. 4. These bronchodilators also relaxed the tone of isolated guinea-pig trachealis supported by histamine, carbachol, U46619 or leukotriene D4. Their order of potency was always KC 399 > salbutamol > BRL 38227. 5. KC 399 and BRL 38227 relaxed isolated human bronchi contracted with histamine or carbachol. 6. We conclude that KC 399 is a potent relaxant of isolated guinea-pig trachealis and human bronchi in vitro. The relaxant action of KC 399 could be due to the opening of glibenclamide-sensitive K+ channels.

Effect of KC399, a newly synthesized K+ channel opener, on acetylcholine-induced electrical and mechanical activities in rabbit tracheal smooth muscle.

1 Effects of KC399, an opener of ATP‐sensitive K+ channels were investigated on membrane potential, isometric force and intracellular Ca2+ ([Ca2+]i mobilization induced by acetylcholine (ACh) in smooth muscle from the rabbit trachea. 2 In these smooth muscle cells, ACh (0.1 and 1 μm) depolarized the membrane in a concentration‐dependent manner. KC399 (1–100 nM) hyperpolarized the membrane whether in the presence or absence of ACh. When the concentration of ACh was increased, the absolute values of the membrane potential induced by the maximum concentration of KC399 were less negative. 3 ACh (0.1 to 10 μm) concentration‐dependently produced a phasic, followed by a tonic increase in both [Ca2+]i and force. KC399 (above 3 nM) lowered the resting [Ca2+]i and attenuated the ACh‐induced phasic and tonic increases in [Ca2+]i and force, in a concentration‐dependent manner. The magnitude of the inhibition was greater for the ACh‐induced tonic responses than for the phasic ones. Nicardipine (0.3 μm), a blocker of the L‐type Ca2+ channel, attenuated the ACh‐induced tonic, but not phasic, increases in [Ca2+]i and force. KC399 further attenuated the ACh‐induced tonic responses in the presence of nicardipine. 4 In β‐escin‐skinned strips, Ca2+ (0.3–10 μm) produced a contraction in a concentration‐dependent manner. KC399 (0.1 μm) had no effect on the Ca2+‐force relationship in the presence or absence of ATP with GTP. However, at a very high concentration (1 μm), this agent slightly shifted the relationship to the right and attenuated the maximum Ca2+‐induced contraction. 5 We conclude that, in rabbit tracheal smooth muscle, the membrane hyperpolarization induced by KC399 attenuates the ACh‐induced tonic increase in [Ca2+]i through an inhibition of nicardipine‐ sensitive and —insensitive Ca2+‐influxes, thus causing an inhibition of the ACh‐induced tonic contraction. The ACh‐induced phasic increase in [Ca2+]i and force are also inhibited, but less effectively than the tonic ones, suggesting that the action of such K+ channel openers on agonist‐induced responses may be slightly different in tracheal from vascular smooth muscle.