Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds.

Various analogues of a new antidiabetic agent, pioglitazone (AD-4833, U-72107), were synthesized in order to study in more detail the structure-activity relationships of this class of drug. 5-(4-Pyridylalkylthiobenzyl)-2,4-thiazolidinediones (I), thia-analogues of pioglitazone, were prepared via Meerwein arylation of the alkylthioanilines (IV). 5-(4-Pyridylalkoxybenzylidene)-2,4-thiazolidinediones (IIa) and related heterocyclic analogues (IIb) were synthesized by Knoevenagel condensation of the aldehydes (VIII) with the corresponding azolidinones.

Radiorespirometric patterns of [14C]-substrates in rats. II. Differences with the nature and administration route of the injection fluid.

The effects on the 14CO2 expiratory patterns of the nature and administration route of the injection fluid containing [14C]-glucose were studied. In the case of rapid intravenous injection, no difference in the radiorespirometric pattern was found with different glucose concentrations and volumes of the aqueous injection fluid. With intravenous injection, lower P1 heights and longer plateaus were recorded with the [14C]-glucose blood mixture as compared to the aqueous injection fluid.

[Effects of halothane on membrane potential, Ca2+ current and intracellular cAMP content in single guinea pig ventricular myocytes].

In order to assess directly the actions of halothane on myocardium, especially on the Ca2+ channel we studied effects of halothane on electrophysiological and biochemical properties in single ventricular myocytes isolated enzymatically from guinea pig hearts. Membrane potentials and the slow inward Ca2+ current (ICa) were recorded with a suction microelectrode technique and a whole cell voltage clamp technique. The plateau duration of the action potential, maintained by ICa, and ICa was depressed by 2% halothane (to 58% and 29% of control respectively).

Effects of acetaldehyde on electrical activity during neuroeffector transmission in guinea-pig vas deferens.

The effects of acetaldehyde on electrical activity during sympathetic neuroeffector transmission were studied in the guinea-pig vas deferens. Application of 1 mM acetaldehyde produced a slow depolarization of the smooth muscle membrane. The amplitudes of facilitated excitatory junction potentials (EJPs) evoked by nerve stimulation were slightly decreased.

Effects of acetaldehyde on contractile response to nerve stimulation in guinea-pig vas deferens.

Twitch contractions of the isolated guinea-pig vas deferens induced by sympathetic nerve stimulation were augmented by acetaldehyde (0.1-10 mM). With high concentrations (5-10 mM), acetaldehyde produced a biphasic response consisting of an initial brief depression and a subsequent potentiation of the contraction.

[Effects of ketamine on voltage-dependent Ca2+ current in single smooth muscle cells from rabbit portal vein].

The effects of ketamine on membrane potentials and voltage-dependent Ca2+ current were studied in dispersed single smooth muscle cells from rabbit portal vein. The resting membrane potential (-56.2 +/- 1.

Effect of OPC-8490 on the membrane potentials and membrane currents of single guinea-pig myocytes.

The direct actions of OPC-8490 on mammalian myocardium were examined by determination of the drug's effects on the action potentials of isolated guinea-pig single ventricular cells and on the underlying ionic currents. OPC-8490 (10(-6) to 10(-4) M) did not alter the resting membrane potential, but rather produced a dose-dependent prolongation of the duration of the action potential. The amplitude of the action-potential plateau was also increased by OPC-8490.

Two distinct types of inwardly rectifying K+ channels in bull-frog atrial myocytes.

1. Single atrial myocytes were enzymatically isolated from the bull-frog as previously described (Hume & Giles, 1981), and patch-clamp techniques were used in an attempt to identify and separate two inwardly rectifying K+ channels in this tissue. 2.

Localization of the anti-allergic agent tranilast in the urinary bladder of rats as demonstrated by light microscopic radioautography.

Tranilast (N-(3,4-dimethoxycinnamoyl)anthranilic acid), an anti-allergic drug, has been developed and used for the treatment of anaphylactic hypersensitivity such as bronchial asthma in Japan. Recently, many cases with eosinophilic cystitis associated with administration of this drug have been reported. In a series of studies to elucidate the pathoetiology of this unusual cystitis, the distribution of tranilast in urinary bladder of rats was investigated.

Effects of TYB-3823, a new antiarrhythmic drug, on the electrophysiological properties of guinea-pig ventricular muscles.

1. The effects of TYB-3823 (B-GYKI 38233), a new antiarrhythmic drug, were electrophysiologically examined in the guinea-pig ventricular muscles. 2.

Studies on antidiabetic agents. Synthesis and hypoglycemic activity of 5-[4-(pyridylalkoxy)benzyl]-2,4-thiazolidinediones.

The synthesis of a series of 5-[4-(pyridylalkoxy)benzyl]-2, 4-thiazolidinediones is described. These compounds were evaluated for hypoglycemic and hypolipidemic activities in genetically obese and diabetic mice, yellow KK. 2-(2-Pyridyl)alkoxy derivatives were found to have much better hypoglycemic and hypolipidemic activities than 2-(3-pyridyl)- and 2-(4-pyridyl)alkoxy derivatives or even the previously reported compound, ciglitazone.

Electron microscopic radioautographic study of the localization of an anti-allergic agent, Tranilast, in rat mast cells.

We have previously reported that Tranilast, an anti-allergic agent, was rapidly taken into the cytoplasm of rat mast cells in vitro by means of light microscopic radioautography. The present study was performed at the electron microscopic level to elucidate the fine localization of this agent in the mast cells. The results revealed that the number of radioautographic silver grains in the cells increased by the incubation with 3H-labelled Tranilast for 0 to 60 min.

Enhancement of inflammatory reactions in a non-immunological air pouch model in rats.

In a carboxymethyl cellulose (CMC) air pouch inflammation model, accumulation of exudate decreased at a relatively rapid rate and almost disappeared 3 days after a 2% CMC injection into the preformed air pouch. After a second injection of 2% CMC solution into the 1-day-old CMC pouch on the day following the first CMC injection, the decrease in rate of exudate was similar to the change seen after the first CMC injection. In another group of rats, 3 days after the first CMC injection when inflammation had subsided, a second injection of 2% CMC solution into the 3-day-old CMC pouch resulted in a marked increase of exudate accumulation, inflammatory cell infiltration and vascular permeability.

Renal cell carcinoma: oncocyte type.

A case of oncocyte-type renal cell carcinoma was reported. The tumor had developed from the upper posterior portion of the left kidney and was well circumscribed. However, the tumor showed expansion into the intraparenchymal space, invasive growth, and venous invasion.

Radiorespirometric patterns of 14C-substrates in rats. I. Differences in kinds of 14C-substrates and their structural positions labelled with 14C.

Experiments were conducted by radiorespirometry to elucidate the relation between the respiratory 14CO2 wave pattern derived from intravenously injected 14C-substrates and the dispositional partition of these substrates in rats. Two types of 14C-methionine and 4 types of 14C-glucose molecules were used as the 14C-substrates. The respiratory 14CO2 wave patterns obtained in experiments using 14C-methionine substrates revealed different patterns based on differences in the labelled position and the amount of expired 14C-radioactivity as well as the wave height.

[Effects of ketamine on K+-contracture in isolated vascular smooth muscle from rabbit].

The effects of ketamine on contraction induced by depolarization of cell membrane (high K+-induced contracture) were studied in isolated vascular smooth muscle from rabbit portal vein. Ketamine in concentrations above 5 x 10(-4) M caused relaxation in phasic contraction, and above 10(-4) M caused relaxation in tonic contraction. These effects of ketamine at concentrations of between 10(-5) to 10(-3) M were dose dependent and reversible.

Effects of halothane on membrane ionic currents in guinea pig atrial and ventricular myocytes.

We studied the effects of halothane on membrane potentials and ionic currents in single guinea pig atrial and ventricular cells prepared by an enzymatic dispersion procedure. In both atrial and ventricular cells, action potential overshoot and its plateau phase were significantly decreased by halothane (2%) without change in resting potential. However, the duration of the ventricular action potential measured at 90% repolarization was markedly shortened by halothane (2%) (to 60% of control), whereas that of the atrial action potential did not change significantly.

Temperature-controlled perfusion apparatus for microscope using transparent conducting film heater.

We describe a novel temperature-controlled perfusion apparatus for electrophysiological studies on isolated cells or membrane patches. The apparatus uses a transparent conducting film of indium-tin-oxide as a heating element. The film heater deposited on a glass sheet allows us to construct a structurally simple apparatus that is able not only to heat directly the bath chamber but also to preheat the perfusion solution on the stage of an inverted microscope.

Radioautographic study on the localization of an anti-allergic agent, tranilast, in the rat liver.

In order to demonstrate the localization associated with metabolism of an anti-allergic agent, Tranilast, in the liver, light microscopic radioautography of the liver was performed. Rats were administrated orally with 3H-Tranilast, and were sacrificed at 15 minutes to 24 hours after the administration. The livers were taken out and fixed, embedded and processed for light microscopic radioautography.

Autoradiographic characterization of newly developed melanoic cell group different from the melanoic tumor piece embedded into a liver lobe of mice.

Secondary proliferous melanoic tumors grew at 100% of probability in a liver lobe of C57BL/6 mouse with a piece of B16 melanoma tumor embedded successfully in the lobe. Clear border between host liver tissues and the embedded tumor piece was observed 14 days after embedding. No division image was noted in cells of the embedded tumor piece.

Effects of halothane on membrane potentials and membrane ionic currents in single bullfrog atrial cells.

Halothane exerts negative inotropic and negative chronotropic actions on the isolated heart in experimental animals. In order to assess directly the actions of halothane in myocardium, we studied the effects of halothane on membrane potentials and transmembrane ionic currents in single isolated frog atrial cells obtained by the enzymatic dissociation method. The results show: (a) that the action potential is prolonged and its plateau phase and overshoot are depressed, but the resting potential remains unchanged; (b) that there is a significant inhibition of a time- and voltage-dependent outward K+ current and a slow inward Ca2+ current, with a slight decrease of a fast inward Na+ current following halothane (1.

Ultrastructural study on the meninx of the goldfish brain.

The cranial meninges of the goldfish were studied by means of transmission electron microscopy combined with the freeze-fracturing technique. The goldfish has three cranial meninges. The outer layer consists of flattened cells, which are stratified in 3 to 7 layers and are packed densely with many interdigitations of cell processes.

Light microscopic radioautographic study of the localization of an anti-allergic agent, Tranilast, in rat mast cells.

In order to demonstrate the localization of an anti-allergic agent, Tranilast, in the mast cells, light microscopic radioautography was performed. The mast cells collected from rat peritoneal cavity were incubated for 0 to 60 min in a medium containing 3H-Tranilast. After the incubation, they were fixed, embedded and processed for light microscopic radioautography.