Kanoo Hosoki

Involvement of dopamine D3 receptors in the area postrema in R(+)-7-OH-DPAT-induced emesis in the ferret

We investigated the possible involvement of dopamine D3 receptors in R(+)-7-hydroxy-2-(N,N-di-n-propylamino)tetraline (R(+)-7-OH-DPAT)-induced emesis in the ferret. The R(+)enantiomer of 7-OH-DPAT (0.03-1 mg/kg, s.c.) caused emesis in a dose-dependent manner, whereas the S(-)enantiomer, even at 1 mg/kg s.c. failed to induce emesis. Quinpirole (0.1-1.0 mg/kg) and apomorphine (0.3 mg/kg, s.c. only) also elicited an emetic response. S(-)-Eticlopride, which has a high affinity for the dopamine D3 receptor, antagonized R(+)-7-OH-DPAT (0.3 mg/kg, s.c.)-induced emesis (ID50 1.4 micrograms/kg, s.c.). R(+)-7-OH-DPAT (0.1-1.0 microgram) administered into the 4th cerebral ventricle dose dependently induced emesis within 1 min of dosing in ferrets. Intracerebroventricularly administered S(-)-eticlopride (0.01-1 microgram) also inhibited the emesis induced by s.c. administration of R(+)-7-OH-DPAT. The emetic effect of R(+)-7-OH-DPAT was unaffected by abdominal vagotomy but was markedly reduced by ablation of the area postrema. These results suggest that dopamine D3 receptors in the area postrema play an important role in R(+)-7-OH-DPAT-induced emesis in the ferret.

Antihypertensive effects of AJ-2615, a new calcium antagonist with α1-adrenergic blocking activity in experimental hypertensive animals

The antihypertensive effect of AJ-2615 [(±)-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluorophenyl)-1-piperazinebutanamide maleate], a novel calcium (Ca) antagonist having α1,-adrenergic blocking activity as well, was compared with that of the existing Ca antagonists (diltiazem, nifedipine, and nicardipine) in various hypertensive models of dogs and rats. When given orally to renal hypertensive dogs (RHDs) and spontaneously hypertensive rats (SHRs), AJ-2615 (RHDs, ED25 mm Hg = 6.0 mg/kg; SHRs, ED25 mm Hg = 24.9 mg/kg) was approximately as effective as diltiazem (RHDs, ED25 mm Hg = 6.3 mg/kg; SHRs, ED25 mm Hg = 54.7 mg/kg) in lowering the blood pressure. This antihypertensive effect was slower in onset and longer in duration (RHDs, ≧ 9 h; SHRs, ≧ 20 h) compared with any of the other reference drugs. AJ-2615 (10 mg/kg p.o.) given to RHDs once daily for 29 days significantly reduced the blood pressure measured 24 h after each dose and caused a stable antihypertensive effect without major diurnal variations. When given in single oral doses to RHDs and SHRs, AJ-2615 had no large effect on the heart rate while the reference drugs induced a large increase or decrease in heart rate in response to a blood pressure fall. These results suggested that AJ-2615 has potential as a long-acting (once daily dosage regimen) antihypertensive drug without causing a steep blood pressure fall and tachycardia.

Inhibitory effect of the new calcium antagonist AJ-2615 on progression of atherosclerosis in cholesterol-fed rabbits.

The effects of a new calcium antagonist, AJ-2615, on progression of atherosclerosis were investigated in rabbits fed a diet high in cholesterol and compared with those of prazosin, diltiazem, and their combination. In the AJ-2615 (30 mg/kg p.o. once daily) group, high cholesterol diet-induced increases in plasma concentrations of total cholesterol, free cholesterol, and phospholipid were significantly decreased. In addition, increases in aortic lipids and calcium content, as well as those in the atherosclerotic lesion area were clearly reduced by AJ-2615. On the other hand, prazosin (3 mg/kg p.o. twice daily) and diltiazem (50 mg/kg p.o. twice daily) groups displayed no such inhibitory effects. However, the group receiving the combination of prazosin and diltiazem at their respective dose levels exhibited a significant reduction in the increase in calcium content of the aorta and a slight decrease in the atherosclerotic lesion area, although there was no decrease in plasma or aortic lipid content. These results suggest that in addition to its calcium antagonistic and alpha 1-adrenoceptor blocking actions, some other yet-unidentified properties of AJ-2615 might contribute to the antiatherosclerotic effect of this agent.

Relative contribution of α1-adrenoceptor blocking activity to the hypotensive effect of the novel calcium antagonist monatepil

Summary: Monatepil, a novel calcium antagonist, has α1-adrenoceptor blocking activity; in the present study, we examined the relative contribution of this α1-blocking activity to its hypotensive effect. Monatepil and diltiazem produced dose-dependent hypotensive effects in anesthetized rats with the same potency. Prazosin and monatepil inhibited the L-phenylephrine (L-PE)-induced pressor response, whereas diltiazem scarcely did. The injection of prazosin produced a decrease in blood pressure (BP) in anesthetized rats. The decrease was recovered with angiotensin II (AH) infusion in a dose-dependent manner. We developed a new rat model by first intravenously injecting prazosin and then infusing All in anesthetized rats. In this model, diltiazem produced the same hypotensive effect as it did in pretreated conditions, although the hypotensive effect of monatepil was attenuated by 20–35% as compared with pretreated conditions. These results suggest that monatepil exerts α1-adrenoceptor blocking action in vivo and 20–35% of the hypotensive effect of monatepil is attributed to its α1-adrenoceptor blocking activity.

Possible involvement of endothelin in thromboxane A2 receptor agonist (U-46619)-induced angina in the rat

The thromboxane A2 receptor agonist, U-46619 ((5Z, 9 alpha, 11 alpha, 13E, 15(S))-9,11-(methanoepoxy)prosta-5,13-dien-1-oic acid) (10 micrograms/kg), induced a typical ischemic change (ST elevation) in the electrocardiogram on intracoronary arterial administration in the rat. The elevation of the ST segment induced by U-46619 was significantly reduced by pretreatment with anti-endothelin-1 rabbit serum. The plasma concentration of endothelin-1 dose dependently increased at the time of ST segment elevation after U-46619. These results indicate that endogenous endothelin-1 partly contributes to coronary spasmodic angina induced by thromboxane A2 in rats.

ANTI‐ARRHYTHMIC EFFECTS OF A NEW CALCIUM ANTAGONIST, MONOTEPIL, AJ‐2615, IN EXPERIMENTAL ARRHYTHMIC MODELS

1. To characterize the anti‐arrhythmic properties of a new calcium antagonist, monotepil, AJ‐2615, the preventive effects of AJ‐2615 were compared with those of the existing calcium antagonists, diltiazem and verapamil, in experimental models of arrhythmia.

Prevention by the new Ca2+ channel antagonist, AJ-3941, of loss of endothelium-dependent relaxation after subarachnoid hemorrhage in rats

AJ-3941 ((+/-)-(E)-1-(3-fluoro-6,11-dihydrodibenz[b,e]-oxepine-11-yl ) -4-(3-phenyl-2-propenyl)-piperazine dimaleate; CAS No. 143110-70-7), a cerebrovascular-selective Ca2+ channel antagonist having anti-lipid peroxidative action, was reported to prevent cerebral vasospasm following subarachnoid hemorrhage in rats. The present study was undertaken to determine whether AJ-3941 protects the impairment of cerebroarterial endothelium-dependent relaxation which is concomitantly induced with cerebral vasospasm. Subarachnoid hemorrhage biphasically suppressed the response to acetylcholine in rat basilar artery, at 0.5 h (n = 4; P < 0.06) and 1 day (n = 5; P < 0.05) after subarachnoid hemorrhage. The reduction of the responses was correlated significantly to the degree of vasospasm determined angiographically. This reduction was accompanied by a 49% increase of arterial lipid peroxide contents. Endothelium-independent relaxation in subarachnoid hemorrhage rats was preserved in response to 3-morpholinosydnonimine, sodium nitroprusside and papaverine. AJ-3941 prevented (n = 6-8, P < 0.05) the suppression of the acetylcholine-induced response and the increase in lipid peroxide content in subarachnoid hemorrhage rats. These results suggest that AJ-3941 could exert its vasospasmolytic effect by preserving endothelial function through its anti-lipid peroxidative action, in addition to its inhibition of vasospasmogen-induced vasoconstriction related to intracellular Ca2+ mobilization.

PREVENTIVE EFFECT OF A NEW CALCIUM ANTAGONIST, MONATEPIL, ON DRUG‐INDUCED ISCHAEMIC ELECTROCARDIOGRAPHIC CHANGES IN RATS

1. The preventive effects of monatepil, a new calcium antagonist with α1‐adrenoceptor blocking activity, on ischaemic electrocardiographic changes in rat models of vasospastic angina were evaluated and compared with those of the existing calcium antagonists (diltiazem, verapamil, nicardipine and nifedipine).

Inhibitory Effect of Monatepil Maleate on Acyl-CoA:Cholesterol Acyltransferase Activity in the Liver of Cholesterol-Fed Japanese Monkeys

We have previously demonstrated that monatepil maleate, AJ-2615, a new calcium antagonist endowed with alpha1-adrenoceptor blocking property, has antiatherosclerotic and plasma lipid-lowering effects in Japanese monkeys fed on a cholesterol-rich diet. To clarify the mechanisms on plasma lipid-lowering action, we investigated the effect of monatepil maleate in these monkeys on hepatic acyl-CoA:cholesterol acyltransferase (ACAT) activity. Both ACAT activity and esterified cholesterol content in the livers of monkeys fed on a cholesterol-rich diet for 6 months significantly increased about 7- and 16-fold, respectively, as compared with those in monkeys fed on a standard diet. Monatepil maleate (30 mg/kg/day for 6 months, orally) inhibited the increases of ACAT activity and esterified cholesterol content by 51% and 71%, respectively. In in vitro experiments, monatepil maleate inhibited ACAT activity in a concentration-dependent manner, whereas it did not affect 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity. A kinetic analysis revealed that monatepil maleate was a noncompetitive type inhibitor of ACAT. Hepatic ACAT activity was significantly correlated to hepatic esterified cholesterol content (r = 0.775, P < .0001), to plasma very low density lipoprotein (VLDL) content (r = 0.765, P < .0001) and to plasma total cholesterol content (r = 0.573, P < .005) in the monkeys. These results suggest that ACAT-inhibiting effect of monatepil maleate plays an important role in the reduction of hyperlipidemia.

U‐46619‐induced Ischaemic Electrocardiographic Changes in Rats: Preventive Effects of Prostacyclin and Nitroglycerin

Abstract— The anti‐anginal effect of nitroglycerin and prostacyclin was examined using, as an index, the ischaemic electrocardiogram (ECG) change (ST elevation) induced by intracoronary arterial injection of 9,11‐dideoxy‐11α,9α‐epoxymethano‐PGF2α (U‐46619), a stable thromboxane A2 agonist, in anaesthetized rats. The ST elevation induced by U‐46619 (5–20 μg kg−1, i.c.a.) was dose‐dependent and reproducible. U‐46619‐induced ST elevation was markedly prevented by the pretreatment of intravenous administration of prostacyclin (0·01 μg kg−1), and to a lesser extent by nitroglycerin (0·3 mg kg−1). Simultaneously, platelet count decreased significantly in the coronary arterial blood which indicated that platelet aggregation was enhanced by U‐46619. The decrease of platelet count in coronary arterial blood at the time of ST elevation was significantly suppressed by prostacyclin (0·1 μg kg−1, i.v.), but not by nitroglycerin (0·3 mg kg−1, i.v.). These results suggest that the ST elevation induced by intracoronary arterial injection of U‐46619 may be derived from spasm of coronary artery and platelet aggregation in the intracoronary artery in rats.