Indapamide, a nonthiazide diuretic, exhibits direct vasodilator action as well as natriuretic and diuretic effects. Although calcium antagonist-like activity has been addressed so far, the mechanisms for vasodilator effect are still uncertain. To understand the wide range of indapamide actions, we examined the effects of indapamide on the vascular eicosanoid generation and investigated its mechanisms by using rat vascular smooth muscle cells in culture. Indapamide uniquely increased the prostacyclin generation in the vascular smooth muscle cells in a dose-dependent manner, whereas it did not affect the vasoconstrictor thromboxane A 2 . Thiazide diuretics lowered the prostacyclin generation, while nonthiazide derivatives did not affect the biosynthesis. Enzymatic analysis revealed that indapamide affected neither [ A n o-chlorobenzenesulfonamide molecule is a prototype of various diuretics including thiazide and nonthiazide diuretics (Figure 1). Although natriuretic and diuretic effects are mainly due to the common structure of o-chlorobenzenesulfonamide, varied side chains give the diuretics characteristic properties. In this context, indapamide diuretic comprises an indoline molecule and uniquely exhibits a direct vasodilator action as well as a natriuretic effect on the cortical collecting duct in the kidney. -4 The vasodilator effect is assumed to be caused by its calcium channel blocker-like activity 5 or endothelium-derived relaxing factor-mediated From the Second Department of Medicine (Y.U., T.N., T.I., H.M., T.S.), University of Tokyo, Tokyo, Japan, and Kyoto Pharmaceutical Industries, Ltd (H.S., S.M., S.O.), Kyoto, Japan.Supported in part by a Grant-in-Aid from the Ministry of Education, Science, and Culture of Japan (No. 62570384 and 01570469).Address for correspondence: Yoshio Uehara, MD, The Second Department of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.Received December 21, 1988; accepted in revised form September 12, 1989. mechanism.6 However, the exact mechanism is not fully understood.On the other hand, the biosynthetic system for eicosanoid (prostaglandins and thromboxanes) is well demonstrated in the vascular smooth muscle cells (VSMC) of rats. 7 -8 Prostacyclin (PGI 2 ), a major product of arachidonate metabolism in VSMC, has a powerful vasodilator action and attenuates the vasoconstrictor response to vasoactive substances. 9 The eicosanoid metabolism is a major component participating in the regulation of the constriction-relaxation mechanism of VSMC.To understand the wide range of indapamide effects, it seems important to disclose the relevance of the eicosanoid system in the vascular wall to the extrarenal indapamide effects. Thus in this study, we investigated the influences of indapamide on the eicosanoid generation in VSMC by using cultured VSMC of rats and attempted to define the mechanisms for its alteration. Methods Vascular Smooth Muscle Cell CultureVSMC were isolated from the thoracic aortas of 7-week-old Wistar rats according to the method of

Abstract-

Plasma levels of trimetazidine in rabbits, rats, and mice were determined. Plasma levels in animals showed unusual curve about 1 hr after oral administration and this reason was investigated by determining distribution of the drug in animal tissues and excretion of the drug in bile. Metabolic pathways of trimetazidine in rabbits were investigated qualitatively and it was ascertained by thin-layer chromatography that the methylene group connecting the benzene and piperazine rings is not severed by metabolism in rabbits.

No abstract

3-(4-Allyl-l-piperazinyl)-2, 2-dimethylpropyl methyl 1, 4-dihydro-2, 6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridine dicarboxylate dihydrochloride (NKY-7 22) produced a dose-dependent antihypertensive effect in conscious spontaneously hypertensive rats (SHR). In this respect NKY-722 was more potent and longer-acting than nicardipine. In canine isolated mesenteric arteries, exposed to a Ca2+-free medium containing high K+, NKY-722 inhibited Cat-induced contraction in concentration-dependent manner, suggesting the calcium antagonism as the mechanism of action.NKY-722 ; dihydropyridine derivative ; hypotensive effect ; Cat-antagonistic effect NKY-722 is a new water-soluble 1, 4-dihydropyridine derivative, which is expected to show good bioavailability and long-lasting pharmacological activity. The present article preliminarily reports the effects of NKY-722 on systemic blood pressure in conscious spontaneously hypertensive rats (SHR) and Cat-induced arterial contraction.Male SHR, with systolic blood pressure above 180 mmHg, were used. Blood pressure was continuously measured using a pressure transducer through a polyethylene catheter implanted into the femoral artery. When blood pressure was stable, NKY-722 (0.3, 1 and 3 mg kg) or nicardipine (3 mg kg) was orally administered.At doses larger than 0.3 mg kg, NKY-722 produced a dose-dependent decrease in blood pressure. The peak decrease in blood pressure recorded after administration of NKY-722 (at 3 mg kg) was 50=1-8 mmHg (n=5), while that with nicardipine (at 3 mg kg) was only 18±3 mmHg (n = 5). The hypotensive effect of NKY-722 lasted longer than 8 hr at 1 and 3 mg kg, while that of nicardipine was about 1 hr (Fig. 1).In order to study the Cat-antagonistic effect of NKY-722, helical strips of the canine mesenteric artery (15 X 2 mm) were used. The preparations were suspended in an organ bath containing Krebs-Henseleit solution bubbled with 95% 02 and 5% CO2 at 37°C, and 1.5 g tension was loaded. The arteries were exposed to a Ca2+-free medium containing KCl (25 mM) and the contractile response to Ca2+ was isometrically measured using a force-