A new series of imidazolones: highly specific and potent nonpeptide AT1 angiotensin II receptor antagonists

Starting from the structure of the novel nonpeptide AT1 receptor antagonist DuP 753 (losartan), a new series of potent antagonists was designed. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5. Like the imidazole series, the best substituents were the linear butyl chain in position 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively inhibit [125I]AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings. The most active compounds had IC50 values in the nanomolar range. In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.     

Effect of constant administration of a gonadotropin-releasing hormone agonist on reproductive activity in mares: induction of ovulation during seasonal anestrus

The potential of a gonadotropin-releasing hormone (GnRH) agonist (goserelin acetate), delivered constantly for 28 days via a subcutaneous depot, to induce ovulation in seasonally anestrous mares, was investigated. Two experiments were conducted, in which a range of doses (30 to 240 micrograms/mare/d) was examined. Mares were selected on the basis of lack of substantial follicular development (follicle diameter < 20 mm determined ultrasonically) and low serum concentrations of luteinizing hormone (LH) and progesterone. Constant administration of the GnRH agonist-induced ovulation in anestrous mares, but a dose-response relation was not observed. Furthermore, with identical doses tested in consecutive or alternate years, considerable variation was observed in the ovulatory response. In general, ovulation in all treated mares was accompanied by increased circulating concentrations of LH and a decrease in follicle-stimulating hormone values. Ovulation was preceded by an increase in estradiol and LH concentrations. In mares in which ovulation did not occur, concentration of LH increased during agonist treatment, whereas that of follicle-stimulating hormone either increased or did not change. It was concluded that constant administration of GnRH agonists may induce ovulation in mares during seasonal anestrus; however, percentage of mares ovulating and the lack of reproducibility of effect indicate that this approach is inappropriate for use as a reliable method to manipulate breeding activity in commercial broodmares.     

Radiological case of the month. Reflex sympathetic dystrophy

The authors report a case of pregnancy in a rudimentary horn diagnosed by laparotomy. The location could not be suspected by any clinical sign. This pregnancy stopped at 19 weeks of amenorrhoea. Any attempts of induction of labour failed. Laparotomy was necessary to assess the diagnosis and to allow the resection of the uterine horn. The authors present a review of literature.     

Impaired pancreatic polypeptide release to insulin hypoglycaemia in chronic autonomic failure with postural hypotension: evidence for parasympathetic dysfunction

1. Release of pancreatic polypeptide (PP) is largely under vagal control and measurement of change in PP after insulin hypoglycaemia offers a non-invasive method of assessing vagal activity. 2. Changes in blood sugar and PP after intravenous insulin (0.2 unit/kg) were examined in six patients with idiopathic chronic autonomic failure (AF) and 12 control subjects. Six of the controls were studied before and after atropine treatment. 3. The PP levels in controls rose from 32 +/- 9 (mean +/- SEM) to 236 +/- 54 pmol/l after 45 min. Patients had similar baseline values (23 +/- 5 pmol/l) but a markedly reduced and delayed PP response to hypoglycaemia (49 +/- 19 pmol/l at 90 min). This impaired PP response was similar to that seen in controls after atropine. 4. The impaired PP response to insulin hypoglycaemia in patients with AF strongly suggests a dysfunction of vagal activity which is often clinically inapparent.     

On the many faces of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.     

Osteosarcoma and other bone cancers

Streptokinase (SK), an extracellular protein from Streptococcus equisimilis, is secreted post-translationally by Escherichia coli using both its native and E. coli-derived transport signals. In this communication we report that cleavage specificity of signal peptidase I, and thus efficiency of secretion, varies in E. coli when SK export is directed by different transport signals. The native (+1) N-terminus of mature SK was retained when it was transported under the control of its own, PelB or LamB signal peptide. However, when translocation of SK was controlled by the OmpA or MalE signal peptide, Ala2 of mature SK was preferred as a cleavage site for the pre-SK processing. Our results indicate that compatibility of the leader peptide with the mature sequences of SK, which fulfills the requirement for a given secondary structure within the cleavage region, is essential for maintaining the correct processing of pre-SK. An OmpA-SK fusion, which results in the deletion of two N-terminal amino acid residues of mature SK, was further studied with respect to the recognition of alternative cleavage site in E. coli. The alanine at +2 in mature SK was changed to glycine or its relative position was changed to +3 by introducing a methionine residue at the +1 position. Both alterations resulted in the correct cleavage of pre-SK at the original OmpA fusion site. In contrast, introduction of an additional alanine at +4, creating three probable cleavage sites (Ala-x-Ala-x-Ala-x-Ala), resulted in the recognition of all three target sites for cleavage, with varying efficiency. The results indicate that the nature of the secondary structure generated at the cleavage junction of pre-SK, resulting from the fusion of different signal peptides, modulates the cleavage specificity of signal peptidase I during extracellular processing of SK. Based on these findings it is proposed that flexibility in the interaction of the active site of signal peptidase I with the cleavage sites of signal peptides may occur when it encounters two or more juxtaposed cleavage sites. Preference for one cleavage site over another, then, may depend on fulfillment of secondary structure requirements in the vicinity of the pre-protein cleavage junction.     

Does arterial revascularization decrease the risk of infarction after coronary artery bypass grafting?

BACKGROUND: This study sought to determine whether extensive arterial grafting reduces the prevalence and consequences of infarct after coronary artery bypass grafting. METHODS: Post-primary coronary artery bypass grafting infarcts and time-related events thereafter were identified by 99.9% complete follow-up of 9,600 patients (1971 to 1992). The contribution of arterial grafting to freedom from infarct was assessed by multivariable hazard function analysis to adjust for other risk factors. RESULTS: Unadjusted 1-month and 10-year freedom from infarction was 97% and 86%. By multivariable analysis, arterial grafting lowered the prevalence of periprocedural (p = 0.005), intermediate term (p = 0.007 and 0.006), and late infarction (arterial grafting to the left anterior descending coronary artery, p = 0.0006). Unadjusted survival after first infarct after coronary artery bypass grafting was 74% and 52% at 1 and 10 years; arterial grafting improved 10-year survival from 48% to 59% (p = 0.002). An additional benefit or cost of extending arterial grafting (n = 1,727) beyond a single one could not be identified (p > 0.1). CONCLUSIONS: Arterial conduits, particularly to the left anterior descending coronary artery, should be used for coronary artery bypass grafting to reduce early and late myocardial infarction and its consequences. However, use of more than a single arterial graft appears to confer no additional benefit.     

Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo

Catestatin (bovine chromogranin A(344-364); RSMRLSFRARGYGFRGPGLQL), reduces catecholamine secretion from chromaffin cells in vitro. We investigated the effects of this peptide on catecholamine release and blood pressure in vivo. Intravenous catestatin reduced pressor responses to activation of sympathetic outflow by electrical stimulation in rats, and the catestatin effect persisted even after adrenergic (alpha plus beta) blockade. Catestatin did not alter plasma norepinephrine levels, but increased plasma epinephrine 11-fold. Catestatin also blunted pressor responses to exogenous neuropeptide Y agonists. A control peptide (chromogranin A(141-160)) did not alter pressor or catecholamine responses to electrical stimulation. Pretreatment with a histamine H1 receptor antagonist blocked both the vasodepressor response to catestatin and the elevation in plasma epinephrine. Catestatin elevated endogenous circulating histamine 21-fold, and exogenous histamine mimicked both the epinephrine elevation and the vasodepressor actions of catestatin. We conclude that catestatin is a potent vasodilator in vivo whose actions appear to be mediated, at least in part, by histamine release and action at H1 receptors.