Resistance to the metabolic actions of insulin is thought to play a determining role in the aetiology of a great variety of disorders, including essential hypertension, accelerated atherosclerosis and cardiomyopathies. ACE inhibitors are recognised as being highly effective therapy for hypertension and cardiac insufficiency, and have a more beneficial effect on survival rate than expected on the basis of known mechanisms of action. The mechanism responsible for these extremely positive effects are just beginning to be understood and appear to be linked to the effects these drugs have on metabolism. The relationship between the insulin and angiotensin II (Ang II) signalling pathways needs to be fully clarified in order to prevent or correct the target organ damage resulting from changes in the cross-talk of these two hormonal systems. In recent years, Ang II has been shown to play a central role in cardiovascular and neuroendocrine physiology as well as in cellular cycle control. Moreover, the fact that Ang II utilises the insulin-receptor substrate (IRS)-1 to relay signals towards their intracellular destination, provides the biochemical explanation of how these two systems interact in a healthy organism and in a diseased one. Since it is overactivity of the renin-angiotensin system that seems to impair the intracellular response to insulin signalling, cardiovascular drugs that modulate the cellular transmission of Ang II have attracted particular interest. As well as the already widely-used ACE inhibitors, selective blockers of the Ang II type 1 receptor (AT(1)) have been shown to be clinically effective in the control of haemodynamic parameters, but with perhaps a less striking effect on glucose homeostasis. Many trials have investigated the effect of Ang II blockade on systemic glucose homeostasis. The inhibition of Ang II by ACE-inhibitors frequently showed a positive effect on glycaemia and insulin sensitivity, while information on the effects of AT(1) receptor antagonists on glucose homeostasis is more limited and controversial. An important limitation of these studies has been the short treatment and follow-up periods, even for the 'so called' long-term studies which were only 6 months. Several investigators have focused on the effects of the nuclear factors involved in gene transcriptions, especially with respect to the agonists/antagonists of peroxisome proliferator-activated receptors (PPARs) and their intriguing interconnections with the insulin and Ang II subcellular pathways. In fact, in vitro and in vivo experimental studies have shown that thiazolidinediones (selective PPAR-gamma ligands) are not only powerful insulin sensitisers, but also have anti-hypertensive and anti-atherosclerotic properties. In addition to conventional pharmacological approaches, attempts have been made to use genetic transfer in the treatment of cardiovascular and metabolic disorders. The development of powerful viral vectors carrying target genes has allowed us to restore the expression/function of specific proteins involv...
The effects on active social interaction of acute and chronic dosage with diazepam (1 mg/kg), desmethyldiazepam (2 mg/kg), and chlor-desmethyl-diazepam (0.125 mg/kg) were studied in pairs of mice. The mice were tested under either high or low levels of illumination. In all cases acute drug treatment significantly reduced social interaction, but this was not seen with chronic treatment (9 days). Two of the drugs, diazepam and desmethyldiazepam, showed an anxiolytic action, i.e., these drugs resulted in significantly less variation in social interaction with the change in light levels, compared with vehicle-injected controls.
Available evidence derived from behavioural and clinical studies indicates that antidepressant drugs may be effective as anxiolytic agents. In this connection, the present study was designed to assess the behavioural effects of three antidepressant drugs, i.e. imipramine (IMI), a non selective serotonin (5-HT) and noradrenaline re-uptake (NA) inhibitor, fluoxetine (FLU), a selective 5-HT re-uptake inhibitor (SSRI) and moclobemide (MOC), a reversible inhibitor of type A monoamine-oxidase enzyme (RIMA) on anxiety, exploratory and locomotor activities in mice. The experiments used two animal models which attempt to separate these three factors: the "light-dark aversion" test and the "open-field" test. Naive female CD1 mice were administered intraperitoneally (i.p.) 30 min before testing with IMI (10, 20 and 40 mg/kg) or FLU (5, 10 and 20 mg/kg) or MOC (1, 5 and 10 mg/kg) or vehicle. Results showed that IMI (10 and 20 mg/kg), FLU (10 and 20 mg/kg) and MOC (1, 5 and 10 mg/kg) significantly reduced the aversive behavior of mice for the lit area in the light/dark aversion test, suggesting an anxiolytic-like effect. In fact, vehicle controls preferred the dark box where they spent approximately 70% of their time, indicating that light serves as an anxiogenic stimulus. Importantly, the anxiolytic-like effects of these antidepressant drugs were not associated with any increase in locomotor activity. In summary, these data suggest that FLU and the new generation of RIMA, exemplified by MOC, in terms of probable efficacy and greater safety, are of interest as treatment for a broad spectrum of anxiety disorders.
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