Effect of chronic estradiol and haloperidol treatment on striatal dopamine receptors

The intravenous injection of 10 μg of a lipopolysaccharide extracted from E. Coli to rabbits leads to the appearance of a hypotensive effect for des-Arg⁹-BK and increases significantly the vasodilator effect of this peptide in isolated hearts and its contractile effects in strips of large arteries and veins. LPS elicits these responses when administered 5 or 20 h before anaesthesia; the hypotensive response of animals receiving LPS just before anaesthesia is similar to that of untreated rabbits. All actions of des-Arg⁹-BK in vivo, in isolated hearts and in isolated tissues are blocked by des-Arg¹⁰,[Leu⁹]-kallidin (KD), a specific inhibitor of kinins B₁-receptor. These data are taken as evidence of the appearance of B₁-response to kinins in the few hours following LPS injection. The response of the animals, perfused organs and isolated tissues to other agonists, such as substance P or [Tyr(Me)⁸]-BK (an activator of B₂-receptors for kinins) are not affected by the treatment with LPS nor are they modified by the antagonist des-Arg¹⁰,[Leu⁹]-KD. The present data, together with previous studies on the sensitization mechanism of B₁-receptor containing preparations, suggest that LPS induces the formation of B₁-receptors in the rabbit, within a few hours. The activation of B₁-receptors by des-Arg⁹-BK produces hypotension, coronary vasodilation and stimulation of large arteries and veins isolated and suspended in vitro. Some large arteries and veins (e.g. the aorta and the anterior mesenteric vein) as well as some peripheral vascular beds (e.g. the coronary vessels) have the ability of generating B₁-receptors, while other organs (e.g. the external jugular vein) have not or very little. The reason for this phenomenon as well as the intimate mechanism by which LPS induces the formation of B₁-receptors remain to be elucidated.     

3Beta-alkyl-androsterones as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: inhibitory potency in intact cells, selectivity towards isoforms 1, 2, 5 and 7, binding affinity for steroid receptors, and proliferative/antiproliferative activities on AR+ and ER+ cell lines

Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of the potent androgen testosterone (T), which plays an important role in androgen-sensitive diseases. In an attempt to design compounds to lower the level of T, we designed androsterone (ADT) derivatives substituted at the position 3beta as inhibitors of type 3 17beta-HSD, and then selected the eight most potent ones (compounds 1-8) for additional studies. In an intact cell assay, they inhibited efficiently the conversion of natural substrate 4-androstene-3,17-dione into T, although they were less active in intact cells (IC50 approximately 1 microM) than in homogenated cells (IC50=57-100 nM). A study of the inhibitory potency with four other 17beta-HSDs revealed they were selective, since they do not inhibit reductive types 1, 5 and 7, nor oxidative type 2. Interestingly, they did not show any binding affinity for steroid receptors (androgen, estrogen, glucocorticoid and progestin). Only two inhibitors, 3beta-phenyl-ADT (5) and 3beta-phenylmethyl-ADT (6) showed some proliferative activities on an AR+ cell line and on an ER+ cell line, but their effects were not mediated through the androgen or estrogen receptors. This study identified selective inhibitors of type 3 17beta-HSD acting through a mixed-type inhibition, and devoid of non-suitable androgenic and estrogenic proliferative activities. The more potent inhibitors were 3beta-hexyl-ADT (2), 3beta-cyclohexylethyl-ADT (4) and 3beta-phenylethyl-ADT (7).     

A newly recognized autosomal recessive syndrome with short stature and oculo-skeletal involvement

This report describes a young girl and her cousin presenting with postnatal short stature, strabismus, photophobia, retinitis pigmentosa, short neck, rhizomelic shortening of the long bones, short and slightly bowed humeri with prominent deltoid tuberosities, short and wide ribs and clavicles, dorso-lumbar scoliosis, biconcave vertebral bodies of the thoraco-lumbar spine, and narrowed lumbar canal. In addition, in the girl there were amelogenesis imperfecta of the hypomaturation type, and the radiographs showed short distal ulnae, sloping epiphyses of the radii, short femoral necks, and slightly flat uncovered femoral heads. The children's parents are first cousins. Differential diagnoses are discussed and the possibility of a newly recognized oculo-skeletal syndrome is raised.     

Impact of kinins in the treatment of cardiovascular diseases

In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikrein-kinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs.