Hypotensive action of Nangapiry, a Paraguayan natural medicine, in rodents.

Hypotensive action mechanism of a cation exchange resin adsorbate (IR-120A) separated from a Paraguayan Natural Medicine, Nangapiry, was investigated. Blood pressures of normal and pithed rats and contractions of isolated thoracic aorta and atria of mice were measured. The blood pressure on normal rats was reduced by an intravenous injection of IR-120A (5 mg/kg). The hypotensive effect on the pithed rat appeared more lasting than that on normal rats by IR-120A. The IR-120A (100 microg-3 mg/ml) concentration-dependently depressed prostaglandin (PG) F2alpha (10 microM)- or KCl (40 mM)-induced aortic contractions and electrically-evoked contraction of left atria, and at a lesser extent spontaneous beating rate of right atria. The 50% inhibitory concentrations (IC50) for the PGF2alpha- and KCl-induced aortic contractions were 713 and 828 microg/ml, respectively, and the IC50 values for the muscle contraction and the beating rate were 1.04 and >3 mg/ml, respectively. These results suggest that the hypotensive action of IR-120A are peripherally elicited by the dilatation of artery and the depression of heart contraction, but not the reduction of heart rate.

The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice.

To determine the relationship between hypoglycemic activity and body weight gain induced by insulin sensitizers, we compared the effects of thiazolidinedione analogs (troglitazone and pioglitazone) and the oxadiazolidinedione analog (Z)-1,4-bis4[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phen oxy¿but-2-ene (YM440) in diabetic db/db mice. Oral treatment with YM440(100 mg/kg) for 28 days decreased the blood glucose concentration (control v YM440, 418 +/- 12 v243 +/- 44 mg/dL). The hypoglycemic activity of this agent was comparable to that of troglitazone (300 mg/kg) and pioglitazone (100 mg/kg). There were no changes in food intake among the groups. Troglitazone and pioglitazone, but not YM440, significantly increased body weight gain during treatment (control, 7.2 +/- 0.5 g; YM440, 7.5 +/- 0.8 g; troglitazone, 10.9 +/- 0.8 g; and pioglitazone, 14.5 +/- 1.1 g). To further assess whether the increase in body weight by troglitazone or pioglitazone was due to adipogenesis, the weight of intraabdominal fat tissue (epididymal, retroperitoneal, and perirenal) was determined. There were no differences in the total weight of visceral fat between the control and YM440 treatment (3.53 +/- 0.23 and 3.60 +/- 0.16 g). In contrast, troglitazone and pioglitazone significantly increased the fat weight (4.31 +/- 0.13 and 4.66 +/- 0.19 g). Thiazolidinediones are known as ligands for peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor responsible for adipogenesis. Troglitazone and pioglitazone activated PPARgamma and increased triglyceride accumulation and mRNA expression of fatty acid-binding protein (FABP) in 3T3-L1 cells. However, YM440 had no effect on these indices for adipocyte differentiation. These results suggest that the mechanism is different for the hypoglycemic action of YM440 versus the thiazolidinediones. YM440 ameliorates hyperglycemia without changing PPARgamma activity, adipocyte differentiation, or fat weight. Thus, YM440 could be a useful hypoglycemic agent for the treatment of non-insulin-dependent diabetes mellitus (NIDDM) without affecting body weight.

Effect of YM-126414 on glucose uptake and redistribution of glucose transporter isotype 4 in muscle cells.

We discovered a novel compound, YM-126414 [1,3, 3-trimethyl-2-(2-phenylaminovinyl)-3H-indolium perchlorate], which stimulates glucose uptake in skeletal muscle cells in vitro. This compound increased the rate of consumption of glucose by C2C12 mouse myoblast cells in a dose-dependent manner (EC(50)=10 nM). To investigate the mechanism of this stimulation, we determined the redistribution of insulin-regulatable glucose transporter isotype 4 (Glut4). When fully differentiated C2C12 cells stably expressing myc-tagged Glut4 protein were treated with YM-126414, redistribution was dramatically increased in a dose-dependent manner (EC(50)=21 nM). These results indicate that YM-126414 is a novel glucose uptake stimulator for muscle cells by causing up-regulation of Glut4 redistribution in differentiated muscle cells. Our findings for the in vitro effects of YM-126414 suggest a direction for the development of new drugs for the treatment of type 2 diabetes.

YM268 increases the glucose uptake, cell differentiation, and mRNA expression of glucose transporter in 3T3-L1 adipocytes.

The purpose of this study was to examine the effects of bis[4-[2,4-dioxo-5-thiazolidinyl)methyl]phenyl]methane (YM-268), a thiazolidinedione derivative, on glucose uptake, adipocyte differentiation through peroxisome proliferator-activated receptor gamma(PPARgamma), and phosphatidylinositol 3-kinase (PI 3-kinase) activity in cultured cells. YM268 and pioglitazone dose-dependently increased the 2-deoxyglucose uptake in 3T3-L1 cells. YM268 facilitated the insulin-stimulated triglyceride accumulation in 3T3-L1 adipocytes and increased the mRNA expression of fatty acid-binding protein. YM268, with and without insulin, increased the mRNA expression of glucose transporter isoforms such as GLUT1 and GLUT4, indicating enhancement of adipocyte differentiation. Additionally, YM268 and pioglitazone showed activity of the PPARgamma ligand, a member of the nuclear receptor superfamily responsible for adipogenesis. To examine the possible involvement of the increased activity of PI 3-kinase in YM268-stimulated glucose uptake, the enzyme activity was estimated by measuring the phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) concentration in human monocytic cells. Insulin dose-dependently increased the PI-3,4,5-P3 production but YM268 had no significant effect on the insulin-dependent and -independent PI 3-kinase activation. These results indicate that the mechanism by which YM268 increased glucose uptake, may be accounted for in part by the enhancement of GLUT1 and GLUT4 expression through PPARgamma activation.

In vivo effects of pioglitazone on uncoupling protein-2 and -3 mRNA levels in skeletal muscle of hyperglycemic KK mice.

Pioglitazone is a thiazolidinedione drug (TZD) which potently and specifically stimulates peroxisome proliferator-activated receptor gamma (PPAR gamma) and sensitizes cells to insulin. Since TZDs are thought to increase energy expenditure, changes in mitochondrial thermogenesis uncoupling protein-2 and -3 mRNA levels in response to pioglitazone treatment were measured in mouse skeletal muscle. Normally hyperglycemic and hyperinsulinemic KK/Ta mice were given pioglitazone for 2 weeks to treat this non-insulin dependent diabetes-like condition. During treatment, UCP2 mRNA levels increased to 185% of normal untreated control levels in soleus muscle. In contrast, UCP3 mRNA levels significantly decreased, up to 67% of normal untreated control levels. Interestingly, UCP3 mRNA levels correlated quite strongly with blood glucose levels, with r = 0.82 for gastrocnemius tissue and r = 0.92 for soleus tissue. These results may indicate that pioglitazone increases glucose catabolism by direct upregulation of muscle UCP2 gene expression in vivo. Therefore, UCP3 gene expression is controlled by a different mechanism than UCP2 expression.