Recovery of gastrointestinal motility from post-operative ileus in dogs: effects of Leu13-motilin (KW-5139) and prostaglandin F2 alpha.

Cyclical motor activity of the gastrointestinal tract, normally occurring during the interdigestive period in several mammals, is disrupted in the post-operative ileus. We determined the recovery from the disappearance of cyclical motor activity, from the stomach to the colon, in dogs after laparotomy with the force transducers. Moreover, we examined the effects of Leu13-motilin (KW-5139) and prostaglandin F2 alpha (PGF2 alpha), administered in the early post-operative period, on the gastrointestinal motility. Following laparotomy, the cyclical motor activity reappeared firstly in the ileum and the colon, then in the jejunum and the duodenum, and finally in the stomach. The reappearance time of the phase III contractions in the stomach was 105.8 +/- 10.6 h (n = 4). In the early post-operative period, KW-5139 (0.5 microgram kg-1, i.v.) induced phase-III-like contractions, whereas PGF2 alpha (50 micrograms kg-1, i.v.) induced simultaneously occurring contractions over the whole gastrointestine. The treatment with KW-5139 (0.5 microgram kg-1, i.v.) four times (twice daily on the first and the second post-operative day) significantly (P < 0.05) shortened the time required to recover the phase III contractions in the stomach (64.2 +/- 2.2 h, n = 4), whereas that with PGF2 alpha (50 micrograms kg-1, i.v.) four times did not (111.3 +/- 17.2 h, n = 4). The present results indicate that, after laparotomy, the cyclical motor activity recovers faster in the distal intestine than in the proximal intestine and the stomach, and that KW-5139, but not PGF2 alpha, shortens the reappearance time of the phase III activity in the stomach.

Protective effects of KW-3902, an adenosine A1-receptor antagonist, against cisplatin-induced acute renal failure in rats.

We investigated possible renal protective and therapeutic effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a novel and potent adenosine A1-receptor antagonist, on cisplatin-induced acute renal failure (ARF). ARF was induced in rats by a single injection of cisplatin-induced acute renal failure (ARF). ARF was induced in rats by a single injection of cisplatin (5 mg/kg, i.v.). Prophylactic treatment with KW-3902 (0.01-1 mg/kg, p.o., twice a day) significantly attenuated the increases of serum creatinine (S-CRE) and urea nitrogen (S-UN) induced by cisplatin. On the other hand, neither furosemide nor trichlormethiazide showed any ameliorating effects against the cisplatin-induced ARF. In the clearance study, the cisplatin-treatment induced marked decreases of glomerular filtration rate (GFR), renal plasma flow (RPF), and reabsorptions of water, sodium and potassium at tubular sites, in comparison with those in untreated normal rats. KW-3902 (0.1 mg/kg, p.o., twice a day) significantly improved these deteriorated glomerular and tubular functions. In the rats with established cisplatin-induced ARF, KW-3902 ameliorated the cisplatin-induced reductions of GFR, RPF, and reabsorptions of water, sodium and potassium at tubular sites. These results suggest that activation of adenosine A1-receptors is involved in the pathogenesis of cisplatin-induced ARF. The adenosine A1-receptor antagonist may be useful for the treatment of cisplatin-induced ARF.

Susceptibility to adenosine agonists of giant migrating contraction induced by glycerol enema in anesthetized rats.

The present study examined whether adenosine agonists influence the occurrence of giant migrating contractions (GMCs) induced by glycerol enema (65%, 2 ml/kg) in rats. Catheter pressure transducers were used to measure the colonic luminal manometric alterations. The adenosine A1 agonists (2S)-N6-(2-endo-norbornyl)adenosine ((S)-ENBA) (10 micrograms/kg, i.v.) and N6-cyclohexyladenosine (30 micrograms/kg, i.v.) abolished the GMCs, whereas the adenosine A2 agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680) (30-300 micrograms/kg, i.v.) failed to influence the GMCs. The suppressive action of (S)-ENBA on the GMCs was entirely counteracted by the peripheral adenosine antagonist 8-(p-sulfophenyl)theophylline (10 mg/kg, i.v.). The present observations suggest that the adenosine A1 agonist suppresses the GMCs via peripheral adenosine receptors.

Colonic giant migrating contractions induced by glycerol enema in anesthetized rats.

Colonic motility was measured with three catheter pressure transducers that were inserted into the descending colon at the distance of 4 cm, 6 cm and 8 cm from the anal verge in anesthetized rats. Colonic infusion of glycerol (65%, 2 ml/kg) induced large phasic pressure changes with high amplitude and long duration. Some of the pressure changes propagated over all the three recording sites, appearing to be equivalent to giant migrating contractions. These glycerol-induced large propulsions were abolished by lidocaine (5%, 2 ml/kg, intracolon), hexamethonium (10 mg/kg, i.v.) or clonidine (30 micrograms/kg, i.v.); and they were almost entirely suppressed by atropine (3 mg/kg, i.v.), suggesting the principal involvement of the cholinergic neural pathway.

Effect of benidipine hydrochloride (KW-3049), on cerebral ischemia induced by bilateral occlusion of the common carotid arteries in rats.

The effect of benidipine on experimental cerebral ischemia was investigated in rats subjected to occlusion of the bilateral common carotid arteries. Benidipine (30 micrograms/kg, i.p.) improved neurological symptoms such as ataxia, convulsion and loss of righting reflex, and prolonged survival time after occlusion of the bilateral common carotid arteries. In the nicardipine (100 micrograms/kg, i.p.)-treated group, a similar effect was observed, whereas nifedipine (100, 300 micrograms/kg, i.p.) and verapamil (300 micrograms/kg, i.p.) did not show any beneficial effect in this model. Furthermore, pretreatment with benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content 3 h after the occlusion. Nicardipine (100 micrograms/kg, i.p.) showed a tendency to reduce the increase in cerebral water content, though the effect was not statistically significant. Nifedipine (100 micrograms/kg, i.p.) produced no improvement. After occlusion of the bilateral common carotid arteries, depletion of adenosine triphosphate (ATP) and phosphocreatine (CP) and an accumulation of lactate occurred in a time-dependent manner. Prophylactic administration of benidipine (30 micrograms/kg, i.p.), 20 min before occlusion, attenuated the depletion of ATP and CP and the accumulation of lactate 3h after the occlusion. Furthermore, post-treatment with benidipine 30 min after occlusion also suppressed these metabolic disorders. In conclusion, the beneficial effects of benidipine in this severe cerebral ischemia model show that the compound has advantages over nicardipine, nifedipine and verapamil. Thus, these results suggest that benidipine may be useful in the treatment of acute ischemic cerebral damage.

Protective effects of benidipine hydrochloride (KW-3049), a calcium antagonist, against experimental arterial calcinosis and endothelial dysfunction in rats.

Protective effects of benidipine hydrochloride (KW-3049) against arterial calcinosis and its possible mechanisms of action have been investigated. Arterial calcinosis was induced in rats by combined administration of vitamin D2 (1050000 IU/kg, s.c.) and nicotine (12.5 mg/kg, p.o., b.i.d.) for 6 successive days. Calcium antagonists, benidipine or nifedipine, were given orally twice a day during the same period. The aortic calcium content in vitamin D2 and nicotine-treated (control) rats increased to about 25 times that in normal rats, accompanying an increase of serum calcium level. Benidipine (10 mg/kg, p.o., b.i.d.) reduced the aortic calcium content to about 18% of control rats without reducing the serum calcium level. Although the presence of aortic endothelial cells was observed under light microscopy in control rats, their surfaces were degenerated under scanning electron microscopy. Benidipine exerted a protective effect against these degenerative changes. Acetylcholine-induced endothelial dependent relaxation was attenuated in control rats, compared with that in normal rats. Benidipine significantly improved this attenuation of the relaxation. These results suggest that the anticalcinotic effect of benidipine is accompanied by its protective effect on endothelial cells.

Beneficial effect of the novel thromboxane A2 receptor antagonist sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate on collagen-induced coronary ischemia in guinea-pigs.

The effect of KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl) ethylidene]-6,11-dihydrodibenz[b,e] oxepine-2-carboxylate monohydrate, CAS 127166-41-0), a novel thromboxane A2 (TxA2) receptor antagonist, on collagen-induced coronary ischemia was studied in guinea-pigs. Under pentobarbital anaesthesia, intravenous injection (i.v.) of collagen (1 mg/kg) induced abnormal ECG changes such as ST-T changes, elevation of T-wave arrhythmia and cardiac arrest in severe cases. The changes of ECG (leads I, II and III) were recorded for 10 min following collagen injection. KW-3635 (25-50 mg/kg p.o.) remarkably improved the collagen-induced ischemic ECG changes. The effect of KW-3635 was more potent than those of daltroban, isbogrel and ticlopidine. Neither nifedipine nor propranolol had any effect. The plasma thromboxane B2 level in the KW-3635-treated animals was lower in comparison with those in both the control and daltroban-treated animals. These results suggest that TxA2 may play a role in this model of coronary ischemia and that KW-3635 is effective in the treatment of ischemic heart disease.

Antihypertensive effects of intravenous administration of benidipine hydrochloride and some other calcium antagonists in conscious, spontaneously hypertensive rats.

The antihypertensive effect of intravenously administered (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was examined in conscious, spontaneously hypertensive rats (SHR) and comparatively evaluated with those of nifedipine, nicardipine, nitrendipine, nisoldipine, verapamil and diltiazem. When nifedipine (10 and 100 micrograms/kg), nicardipine (10 and 100 micrograms/kg), nitrendipine (10 and 100 micrograms/kg), verapamil (100 and 1000 micrograms/kg) and diltiazem (100 and 1000 micrograms/kg) were intravenously administered to SHR, at their lower doses, only transient decreases of blood pressure were observed and, even at their higher doses, decreased blood pressures returned to the initial levels after 80 to 120 min. Nisoldipine at 10 micrograms/kg (i.v.) decreased the blood pressure (by 23 mmHg), lasting for 100 to 120 min, and the antihypertensive effect of 100 micrograms/kg (i.v.) of it (by 63 mmHg) lasted for longer than 240 min though a tendency of blood pressure to recover was observed. The peak effects of these 6 calcium antagonists were observed 1 min after the drug injection. When KW-3049 (1, 3, 10 and 30 micrograms/kg i.v.) was administered, a dose-dependent decrease of blood pressure (by 23 to 67 mmHg) was observed. The effect of KW-3049 was longer than those of the above 6 calcium antagonists, including nisoldipine. The maximal effects were attained 10 to 30 min after the drug injection and the decreased blood pressure did not return to an initial level even 180 min (at 1 and 3 micrograms/kg) and 240 min (at 10 and 30 micrograms/kg) after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effects of the new calcium antagonist benidipine hydrochloride in conscious, renal-hypertensive dogs.

The antihypertensive action of (+/-)-(R*)-2,6-dimethyl-4- (m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was evaluated in conscious, renal-hypertensive dogs. When KW-3049 (0.1, 0.3 and 1 mg/kg) was orally administered, antihypertensive action and increased heart rate with peak time after 60 to 120 min of administration were observed, and the duration of actions at the dose of 0.3 mg/kg (p.o.) or more lasted for more than 7 h. When nifedipine (0.3 and 1 mg/kg) and nicardipine (1 and 3 mg/kg) were orally given, the duration of antihypertensive action was shorter. Nitrendipine (1 and 3 mg/kg p.o.) showed antihypertensive action and increased heart rate with peak time after 45 to 60 min of administration, and the duration of action at 3 mg/kg (p.o.) lasted for 7 h or longer. The antihypertensive activity of KW-3049 at the action peak was 6.1, 12.1 and 8.9 fold as compared with those of nifedipine, nicardipine and nitrendipine, respectively. Also, when KW-3049 at 0.3 mg/kg (p.o.) was administered after 1 h of propranolol (20 mg/kg p.o.) administration, the increase of the heart rate was markedly inhibited while its antihypertensive action remained unchanged. From these results, it was demonstrated that KW-3049 shows potent and long-lasting antihypertensive action with gradual appearance of action, and was suggested that it may be an useful antihypertensive agent.

Antianginal effects of the new calcium antagonist benidipine hydrochloride in anesthetized rats and spontaneously hypertensive rats. Electrocardiographic study.

Antianginal effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in various experimental angina-pectoris models (anesthetized rats, spontaneously hypertensive rats (SHR] were compared with those of nifedipine, propranolol and hydralazine. Furthermore, the effects of these drugs on the pressure-rate product were evaluated. 1. Vasopressin test (SHR): The administration of KW-3049 at 10 micrograms/kg (i.v.) developed an inhibitory effect comparable to that of nifedipine at 200 micrograms/kg (i.v.) against the ischemic ECG changes caused by the intravenous administration of vasopressin at 1 U/kg. The effects of KW-3049 at 3 and 10 mg/kg (p.o.) lasted for 8 h or more. 2. Coronary occlusion test (rat): The rise of T-wave of epicardial ECG following ligation of coronary artery was inhibited by the administration of KW-3049 at doses of 30 and 100 micrograms/kg i.v. Nifedipine at dose of 200 micrograms/kg i.v. was slightly effective. 3. Isoproterenol (isoprenaline) test (rat): The fall of ST in ECG by the continuous infusion of isoprenaline (10 micrograms/kg/min) was almost completely prevented by propranolol (500 micrograms/kg i.v.). Also, KW-3049 (200 micrograms/kg i.v.) and nifedipine (200 micrograms/kg i.v.) significantly inhibited the decline of ST, in which the former was more effective than the latter. 4. Anoxia test (SHR): The fall of ST and rise of T-wave of ECG, induced by stopping artificial respiration of gallamine-immobilized SHR, were suppressed by the administration of KW-3049 at doses of 10 and 30 micrograms/kg i.v.(ABSTRACT TRUNCATED AT 250 WORDS)

Beneficial effects of the new calcium antagonist benidipine hydrochloride on myocardial dysfunction following coronary occlusion and reperfusion in anesthetized dogs.

The protective effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) on ischemic myocardium was examined comparing with that of nifedipine in anesthetized dogs subjected to a brief (10 min) coronary artery occlusion and reperfusion (2h). Occlusion of left anterior descending coronary artery elicited elevation of ST-segment and T-wave of epicardial ECG in the ischemic area. Regional myocardial contractile force in this area was depressed throughout the reperfusion period as well as during coronary occlusion period. LV max dp/dt, stroke volume and cardiac output tended to be reduced. In the dogs pretreated with 10 micrograms/kg of KW-3049 (i.v.) and 50 micrograms/kg of nifedipine (i.v.), both of which lowered the blood pressure to the same extent, elevation of ST-segment and T-wave was inhibited, and the prevention of irreversible depression of regional myocardial contraction observed at reperfusion periods was slightly more prominent in KW-3049 administration group. Stroke volume and cardiac output in both KW-3049 and nifedipine administration groups were maintained at higher levels than those in control group throughout coronary occlusion and the following reperfusion periods. LV max dp/dt of KW-3049 administration group was kept higher than that of the control group, while the value of the nifedipine administration group changed as that of the control group. These results demonstrate that KW-3049 as well as nifedipine exert protective effects on ischemic myocardium induced by coronary occlusion and reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)