Differences in enhancing effects of zolpidem and benzodiazepine drugs on recurrent inhibition in rat hippocampal slices

It has been reported that the clinical and electroencephalographic profiles of zolpidem, a non-benzodiazepine drug which binds preferentially to the ω₁ benzodiazepine recognition sites located within the GABA_A receptor complex, are different from those of benzodiazepine drugs, which bind non-selectively to the ω₁ and ω₂ sites. In order to clarify the electrophysiological mechanism underlying the unique profile of zolpidem, the present study compared the enhancing effects of zolpidem and two benzodiazepine drugs, triazolam and diazepam, on recurrent inhibition. This inhibition was expressed as suppression of the orthodromically induced population spikes by the preceding antidromic stimulation of the alveus in the CA1 region of rat hippocampal slices. The rank order of potency for enhancing recurrent inhibition was triazolam > diazepam > zolpidem. From the present results and previously reported findings that zolpidem has a lower affinity for the ω₂ sites than diazepam while both have the same affinity for the ω₁ sites, we concluded that the hippocampal recurrent inhibition appears to be enhanced mainly by activation of the ω₂ sites, but not by that of the ω₁ sites. Furthermore, the lower potency of zolpidem for enhancing recurrent inhibition may underlie its unique profile in terms of its clinical and electroencephalographic effects. Received: 1 November 1996/Final version: 22 January 1997     

Alleviation of gallbladder complications by treatment of hepatic arterial embolization with caerulein

Transcatheter arterial embolization (TAE) with the concurrent use of caerulein was assessed for the purpose of preventing gallbladder complications often seen after TAE of hepatic carcinoma. Ninety-six cases with primary hepatic carcinoma, who had undergone TAE in the right hepatic arterial region over the past 4 years, were divided into three groups: 22 cases for which embolization was possible on a selective basis by passing the catheter to the peripheral side beyond the bifurcated region of the cystic artery; 40 cases who had undergone TAE in which caerulein was not administered, from the central side of the bifurcated region of the cystic artery; and 34 cases given 20 g caerulein 15–30 min before TAE. A comparison was made using the abdominal pain, pyrexia, rate of leukocytosis and the US findings of the gallbladder as the indices of the gallbladder complications. As a result, it become evident that it was possible to prevent or alleviate gallbladder complications if caerulein were administered before TAE in cases where the embolizing substances were infused in the right hepatic artery from the central side of the bifurcated region of the cystic artery. It was conclusively shown that the gallbladder blood flow decreases if the organ is contracted by caerulein, which in turn causes a decrease in the inflow of the embolizing substances whereby complications are alleviated.     

Bruch''s membrane of the brachymorphic mouse

Bruch's membrane exists between the retinal pigment epithelium and the choriocapillary endothelium. Its structure is very complicated, having five sublayers containing basement membranes of retinal pigment epithelium and choriocapillary endothelium, outer and inner collagenous layers, and a central elastic layer. In the development of Bruch's membrane in normal mice, both basement membranes are created first. Secondarily, collagen fibers are accumulated in the space between these basement membranes and then form a collagenous layer. Finally, the elastic layer elaborated in the collagenous layer separates this into outer and inner collagenous layers. Brachymorphic mice have a disorder in the sulfation pathway, resulting in undersulfation. Consequently, in Bruch's membrane of brachymorphic mice, the expression of decorin, a small proteoglycan containing chondroitin sulfate and an indispensable component in collagen assembly, is at a very low level. It is clear that hypoplasia of the collagenous layer in Bruch's membrane of brachymorphic mice induces a disorder in the following formation of the elastic layer. These findings suggest that the formation of the collagenous layer, regulated with acidic glycoconjugates such as decorin, is important in the development of Bruch's membrane.     

Functional linkage of the cardiac ATP-sensitive K+ channel to the actin cytoskeleton

The role of the cytoskeleton in the rundown and reactivation of adenosine triphosphate (ATP) sensitive K⁺ channels (KATP channels) was examined by perturbing selectively the intracellular surface of inside-out membrane patches excised from guinea-pig ventricular myocytes. Actin filament-depolymerizing agents (cytochalasins and desoxyribonuclease I) accelerated channel rundown, while actin filament stabilizer (phalloidin) or phosphatidylinositol biphosphate (PIP₂; inhibitor of F-actin-severing proteins) inhibited spontaneous and/or Ca²⁺-induced rundown. When rundown was induced by cytochalasin D or by long exposure to high Ca²⁺, channel activity could not be restored by exposure to MgATP, but application of F-actin with MgATP could reinstitute channel activity. The processes of rundown and reactivation of cardiac K_ATP channels may thus be influenced by the assembly and disassembly of the actin cytoskeletal network, which provides a novel regulatory mechanism of this channel.     

Simple,rapid, and accurate determination of deletion mutations by automated dna sequencing of heteroduplex fragments of the adenomatous polyposis coli (APC) gene generated by PCR amplification

Germline mutations in patients with familial adenomatous polyposis were analyzed by polymerase chain reaction (PCR) amplification of the adenomatous polyposis coli gene. PCR products from heterozygous patients for deletions of this gene formed four distinct bands on polyacrylamide gel electrophoresis. The four fragments were subsequently purified and both strands of each fragment were directly sequenced, using an automated DNA sequencer and the same primers as those for PCR amplification. It was found that the two slower migrating fragments were “bulge” heteroduplexes, while the other two were homoduplexes made up of two wild-type strands and two deletion-mutant strands, respectively. The sites of deletions in the adenomatous polyposis coli gene could be exactly determined in four of the five patients. In an attempt to identify deletion-carriers of familial adenomatous polyposis at the presymptomatic stage, a family study was also carried out, and two children were found to have the same mutations as those of their affected parents. The direct sequencing of heteroduplex fragments generated during PCR amplification is a potentially useful method for detecting mutations of not only the adenomatous polyposis coli gene but also many other genes of genetic diseases. © 1993 Wiley-Liss, Inc.     

Relationship between muscle fatigue and oxygen uptake during cycle ergometer exercise with different ramp slope increments

Summary The surface electromyogram (EMG) from active muscle and oxygen uptake ( ) were studied simultaneously to examine changes of motor unit (MU) activity during exercise tests with different ramp increments. Six male subjects performed four exhausting cycle exercises with different ramp slopes of 10, 20, 30 and 40 W · min^–1 on different days. The EMG signals taken from the vastus lateralis muscle were stored on a digital data recorder and converted to obtain the integrated EMG (iEMG). The was measured, with 20-s intervals, by the mixing chamber method. A non-linear increase in iEMG against work load was observed for each exercise in all subjects. The break point of the linear relationship of iEMG was determined by the crossing point of the two regression lines (iEMG_bp). Significant differences were obtained in the exercise intensities corresponding to maximal oxygen uptake ( ) and the iEMG_bp between 10 and 30, and 10 and 40 W · min –1 ramp exercises (P < 0.05). However, no significant differences were obtained in and corresponding to the iEMG_bp during the four ramp exercises. With respect to the relationship between and exercise intensity during the ramp increments, the -exercise intensity slope showed significant differences only for the upper half (i.e. above iEMG_bp). These results demonstrated that the and at which a nonlinear increase in iEMG was observed were not varied by the change of ramp slopes but by the exercise intensity corresponding to and the iEMG_bp was varied by the change of ramp slopes. In addition, the significant differences in the exercise intensity slopes for the upper half of the tests would suggest that the recruitment patterns of MU and/or muscle metabolic state might be considerably altered depending upon the ramp slope increments.     

MCP-1-dependent signaling in CCR2(-/-) aortic smooth muscle cells

Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a mediator of inflammation that has been implicated in the pathogenesis of a wide variety of human diseases. CCR2, a heterotrimeric G-coupled receptor, is the only known receptor that functions at physiologic concentrations of MCP-1. Despite the importance of CCR2 in mediating MCP-1 responses, several recent studies have suggested that there may be another functional MCP-1 receptor. Using arterial smooth muscle cells (SMC) from CCR2(-/-) mice, we demonstrate that MCP-1 induces tissue-factor activity at physiologic concentrations. The induction of tissue factor by MCP-1 is blocked by pertussis toxin and 1,2-bis(O-aminophenyl-ethane-ethan)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, suggesting that signal transduction through the alternative receptor is G(alphai)-coupled and dependent on mobilization of intracellular Ca(2+). MCP-1 induces a time- and concentration-dependent phosphorylation of the mitogen-activated protein kinases p42/44. The induction of tissue factor activity by MCP-1 is blocked by PD98059, an inhibitor of p42/44 activation, but not by SB203580, a selective p38 inhibitor. These data establish that SMC possess an alternative MCP-1 receptor that signals at concentrations of MCP-1 that are similar to those that activate CCR2. This alternative receptor may be important in mediating some of the effects of MCP-1 in atherosclerotic arteries and in other inflammatory processes.     

Cross education of muscular strength during unilateral resistance training and detraining

Abstract. The purpose of the present study was to examine the changes in maximum voluntary isometric contraction (MVC) in the contralateral untrained limb during unilateral resistance training and detraining, and to examine the factors inducing these changes by means of electrophysiological techniques. Nine healthy males trained their plantar flexor muscles unilaterally 4 days·week^–1 for 6 weeks using 3 sets of 10–12 repetitions at 70–75% of one-repetition maximum a day, and detrained for 6 weeks. Progressive unilateral resistance training significantly (P<0.05) increased MVC, integrated electromyogram (iEMG), and voluntary activation in the trained and contralateral untrained limbs. The changes in MVC after training were significantly correlated with the changes in iEMG in both limbs. No significant changes occurred in MVC, voluntary activation, and iEMG in the contralateral limb after detraining. The changes in MVC after detraining did not correlate with the changes in voluntary activation or iEMG in either limb. Training and detraining did not alter twitch and tetanic peak torques in either limb. These results suggest that the mechanisms underlying cross education of muscular strength may be explained by central neural factors during training, but not solely so during detraining. Electronic Publication