There is increasing agreement about the atherogenicity of intermediate density lipoprotein (IDL). Our previous work demonstrated abnormal accumulation of IDL (Sf 12-60) in normocholesterolemic NIDDM. Diabetics under insulin treatment had no abnormal lipoprotein profile if they were normocholesterolemic. On the other hand, it is well recognized that hyperinsulinemia has a role in atherogenesis. In order to explore the possibility that there is any relationship between residual endogenous insulin response and IDL metabolism in NIDDM, an oral glucose tolerance test was performed in 61 patients. Forty-one of them were treated on diet and the other by sulphonylureas (SU). Patients who were hyperinsulinemic, with thyroid, renal or hepatic disease and those taking steroids or hypolipidemic drugs were excluded. Cholesterol (Ch) and triglyceride (Tg) levels were measured in three subclasses of Tg-rich lipoprotein fraction—very low density lipoprotein (VLDL): Sf 60-400, intermediate density lipoprotein1 (IDL1): Sf 20-60, IDL2: Sf 12-20. HDL fraction was separated from the plasma by precipitation.Oral glucose tolerance test performed in NIDDM on diet showed significant correlation between ΣIRI/ΣPG and IDL1-Ch/Tg or IDL1+2-Ch/Tg. Since hyperinsulinemic subjects were excluded from the study ΣIRI/ΣPG ratio may represent the insulin sensitivity rather than insulin resistance. The significant correlations shown here suggest the importance of insulin sensitivity for the metabolism of IDL. In SU treated group, there was an inverse relationship between insulinogenic index and HDL-Ch, suggesting the atherogenicity of endogenous insulin. Negative correlation between ΣIRI and HDL-Ch in all the diabetics in this study supports this suggestion. Thus, we demonstrate here the new evidence linking insulin with atherosclerosis.
This study was undertaken to determine the effect of hyperinsulinemia and/or sucrose-feeding on lipoprotein metabolism in rats. Sixty male Wistar rats with a mean body weight of 350g were used in this study. They received gradually increasing dose of NPH insulin subcutaneously for 11 days. There were four groups of rats; sucroseinsulin (SI), sucrose-control (SC), chow-insulin (CI) and chow-control (CC). SI and SC groups were given 5% sucrose solution as drinking water (to avoid hypoglycemia after insulin injection). The final insulin dose was 6U and 4U in SI and CI group, respectively. At noon time (approximately 17 hr after insulin injection) of day 11, blood was obtained with EDTA from the abdominal aorta of 3hr fasted rats anesthetized with sodium pentobarbital. Each separated plasma pool was prepared from two equal volume of rat plasma. Lipoprotein fractionation was done by preparative ultracentrifugation. Each floating fraction was obtained by slicing and served for triglyceride and cholesterol assay.There were no significant differences in plasma insulin and glucose levels between each experimental group and CC group. High density lipoprotein (HDL)-cholesterol concentration in SI group was the highest of all 4 groups and significantly differed from that of CC group. On the other hand, low density lipoprotein (LDL)-cholesterol in SI group was the lowest of all groups. CI group showed no remarkable differences in triglyceride and cholesterol concentration in each lipoprotein fraction compared to those of CC group.It was suggested from the present data that the combination of hyperinsulinemia and sucrosefeeding raises HDL-cholesterol and suppresses LDL-cholesterol level in rats. Such a kind of hyperinsulinemic rats can be a good model for experimental hyper-α-lipoproteinemia.
CS-514, a new inhibitor of endogenous cholesterol biosynthesis, has been shown to reduce plasma cholesterol concentration in both healthy and hypercholesterolemic subjects. In this study we compared the effect of CS-514 and probucol on plasma lipids in hypercholesterolemic subjects. After treatment with probucol, HDL-cholesterol as well as total cholesterol tended to decrease. After a washout period probucol was replaced with comparable doses of CS-514. All the patients showed decreased plasma cholesterol levels after CS-514 treatment. HDL-cholesterol levels increased significantly after CS-514. Plasma triglyceride levels showed no significant change throughout the study period. Thus, the two drugs differed in their effects on HDL-cholesterol.
Effects of oxybutynin on the urinary bladder and urethra were studied in comparison with atropine and flavoxate in cats and rabbits. Oxybutynin at 10 mg/kg, i.v., significantly inhibited the bladder contractions induced by electrical stimulation of the peripheral end in pelvic nerve. Oxybutynin was about one half the potency of atropine. On the contrary, 10 mg/kg of flavoxate, i.v., showed both effects of potentiation and inhibition. The bladder contractions induced by acetylcholine (ACh) and AHR-602 were markedly inhibited by oxybutynin and atropine. Oxybutynin was about one-fifteenth the potency of atropine. DMPP-induced contractions were inhibited by oxybutynin and atropine in a high dose, but oxybutynin was about two-fifths the potency of atropine. In addition, 3 mg/kg of oxybutynin, i.v., inhibited the contraction induced by hypogastric nerve stimulation, but 10 mg/kg of oxybutynin, i.v., significantly inhibited this contraction following initial potentiation. Oxybutynin showed an inhibitory effect on spontaneous rhythmical contraction, bladder tone and pelvic nerve discharge, similar to the effects of atropine. On the contrary, flavoxate potentiated this contraction and increased the bladder tone and pelvic and hypogastric nerve discharge. Urethra contractions induced by norepinephrine, ACh and hypogastric nerve stimulation were inhibited by oxybutynin, but not markedly. Oxybutynin and atropine dose-dependently increased the infusion volume, bladder volume capacity and micturition threshold pressure in the cystometrogram in rabbits. Flavoxate also increased them. From these results, it si suggested that oxybutynin is therapeutically a useful agent for pollakisurea nervosa.
Crude coumarin constituents of Peucedanum praeruptorum Duun. including praeruptorin A (=Pd-Ia)(2) and B (=Pd-II)(11) had an antagonistic effect on a specific platelet activating factor (PAF) in the platelet aggregation induced by several aggregating agents. This provides a new class of PAF antagonists. Studies of the structure-activity relationship with khellactone (1) derivatives and PAF antagonistic activity indicate that the cis isomers of 1 at the C-3' and C-4' positions are more favorable than trans isomers, and the acyl moiety at the C-3' position of 1 requires an appropriate molecular size.
The hexahydro-4-hydroxy-1-benzofuran-2-ones 3a, 4a, and 5a (related to the 6β-hydroxyeremophilenolides 1 and 2, which show anti-histaminic and anti-allergic activities) were synthesized from dimedone through the compounds 18a, 23a, and 24a, followed by dehydration reactions. Pharmacological investigations of 3a, 4a, 5a, 18a, 23a, and 24a showed that compounds 4a and 5a have anti-histaminic activity and cause marked inhibition in the Schultz-Dale reaction.
