Hybridization of non-sulfonylurea insulin secretagogue and thiazolidinedione-derived insulin sensitizer.

Hybrid compounds of non-sulfonylurea insulinotropic agents and thiazolidinedione-derived insulin-sensitizing agents were designed and synthesized. The benzylidenesuccinic acid derivative 24 was equal both to nateglinide in potency of insulin-releasing activity and to pioglitazone in insulin-sensitizing activity.

Effects of quinapril and losartan on insulin sensitivity in genetic hypertensive rats with different metabolic abnormalities.

This study was designed to investigate the effects of the angiotensin-converting enzyme (ACE) inhibitor quinapril and the angiotensin II-receptor antagonist losartan on insulin sensitivity in two types of genetic hypertensive rats with insulin resistance. Quinapril (3 mg/kg) and losartan (10 mg/kg) decreased the systolic blood pressure to almost the same extent in both spontaneously hypertensive rats (SHRs) and Dahl salt-sensitive (Dahl S) rats. Quinapril increased the glucose requirement for the euglycemic clamp test in both SHRs and Dahl S rats, whereas losartan increased it in SHRs but not in Dahl S rats. The severity of the metabolic abnormalities may be responsible for the failure of losartan to improve the insulin sensitivity in Dahl S rats because serum insulin, total cholesterol, triglyceride, and free fatty acids (FFAs) were higher in the Dahl S rats than in SHRs. A kinin antagonist, Hoe 140, inhibited the increase in the glucose requirement by quinapril without affecting the depressor effect of quinapril in SHRs. In conclusion, quinapril improved the insulin sensitivity more effectively than did losartan in the genetic hypertensive rats with insulin resistance and relatively severe metabolic abnormalities. Based on our findings, one of the mechanisms underlying the difference between quinapril and losartan may thus be endogenous kinins.

The augmentation of pituitary adenylate cyclase-activating polypeptide (PACAP) in streptozotocin-induced diabetic rats.

Pituitary adenylate cyclase activating polypeptide (PACAP), which was isolated from ovine hypothalamic extract, has been shown to have a physiological role in the regulation of insulin or islet functions. In streptozotocin (STZ)-induced diabetic rats, we examined the content of PACAP immunoreactivity and gene expression of three specific receptors. Four weeks after administration of STZ (50 mg/kg), plasma glucose levels increased 3.3-fold, and plasma insulin levels decreased to one-tenth as compared with the control. The content of PACAP immunoreactivity in the pancreas potently increased by 30%, but the content of vasoactive intestinal polypeptide (VIP) immunoreactivity was not changed. In the other tissues, the content of PACAP immunoreactivity did not significantly change except in the hypothalamus, which showed a 10% increment. In the expression level of PACAP/VIP receptors, semi-quantitative RT-PCR analysis revealed that VIP1/PACAP receptor mRNA significantly increased as compared with the other two types of receptors in the pancreas of STZ-induced diabetic rats. These findings suggest that PACAP and VIP1/PACAP receptor might be involved in the pathophysiology of diabetes mellitus.

Rat aortic smooth-muscle cell proliferation is bidirectionally regulated in a cell cycle-dependent manner via PACAP/VIP type 2 receptor.

In the cardiovascular system, vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have been well characterized as potent vasodepressors or vasodilators. However, their pathophysiological implication in proliferation of vascular smooth muscle cells has not yet been elucidated. In the present study, we have first identified PACAP/VIP type 2 receptor as a dominant type in rat vascular smooth muscle cell (VSMC) by RT-PCR. PACAP and VIP increased cyclic AMP accumulation with similar potency. In 24-h [3H]thymidine incorporation assay, PACAP or VIP exhibited a suppressive effect on the DNA synthesis of rat VSMC stimulated by serum when added at the late G1 phase. In contrast, when added at G0/G1 phase of the cell cycle, PACAP or VIP enhanced the serum-induced DNA synthesis. In 24-h incubation, PACAP alone has little mitogenic activity. However, when incubated up to 48 h, PACAP stimulated significantly the DNA synthesis and the cell proliferation of rat VSMC. These results suggest that PACAP and VIP regulate the proliferation of rat VSMC by enhancing or suppressing in a cell cycle-dependent manner and induce delayed mitogenesis and cell proliferation.

Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension.

Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments: the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase. The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro, but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-associated protein kinase, p160ROCK. Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.

Single-step synthesis of [18F]haloperidol from the chloro-precursor and its applications in PET imaging of a cat's brain.

We have established a convenient synthesis process for the synthesis of[18F]haloperidol using a single-step 18F-for-Cl exchange reaction and a new elution system for the preparative high performance liquid chromatography (HPLC) using C18 bonded vinylalcohol copolymer gel (ODP) and a basic eluent. We successfully applied the product to cat-PET study and got clear images of the striatum, showing the usefulness of this synthesis.