Stimulation of angiotensin AT2 receptors by the non-peptide agonist,Compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Background and purpose:

Angiotensin type 2 receptor (AT₂ receptor) stimulation evokes vasodilator effects in vitro and in vivo that oppose the vasoconstrictor effects of angiotensin type 1 receptors (AT₁ receptors). Recently, a novel non-peptide AT₂ receptor agonist, Compound 21, was described, which exhibited high AT₂ receptor selectivity.

Experimental approach:

Functional cardiovascular effects of the drug candidate Compound 21 were assessed, using mouse isolated aorta and rat mesenteric arteries in vitro and in conscious spontaneously hypertensive rats (SHR).

Key results:

Compound 21 evoked dose-dependent vasorelaxations in aortic and mesenteric vessels, abolished by the AT₂ receptor antagonist, PD123319. In vivo, Compound 21 administered alone, at doses ranging from 50 to 1000 ng·kg⁻¹·min⁻¹ over 4 h did not decrease blood pressure in conscious normotensive Wistar-Kyoto rats or SHR. However, when given in combination with the AT₁ receptor antagonist, candesartan, Compound 21 (300 ng·kg⁻¹·min⁻¹) lowered blood pressure in SHR only. Further analysis in separate groups of conscious SHR revealed that, at a sixfold lower dose, Compound 21 (50 ng·kg⁻¹·min⁻¹) still evoked a significant depressor response in adult SHR (∼30 mmHg) when combined with different doses of candesartan (0.01 or 0.1 mg·kg⁻¹). Moreover, the Compound 21-evoked depressor effect was abolished when co-infused (50 µg·kg⁻¹·min⁻¹ for 2 h) with the AT₂ receptor antagonist PD123319.

Conclusion and implications:

Collectively, our results indicate that acute administration of Compound 21 evoked blood pressure reductions via AT₂ receptor stimulation. Thus Compound 21 can be considered an excellent drug candidate for further study of AT₂ receptor function in cardiovascular disease.     

Changing infant feeding practices and declining incidence of coeliac disease in West Somerset

An association was investigated between changing infant feeding practices and a declining incidence of childhood coeliac disease and transient gluten intolerance (TGI) in West Somerset, England during 1971-92. Dietary histories of 18 patients with coeliac disease were compared with 23 controls during 1971-80 and eight patients with coeliac disease and 39 controls during 1981-92. Our findings showed that the declining incidence of coeliac disease and TGI were associated with changing infant feeding practices, characterised by the later introduction of dietary gluten, an increased use of baby rice and gluten free foods for weaning, and an increased incidence of initial breast feeding.     

Ultrasound prediction of fetal lung maturity

Amniocentesis for determination of fetal lung maturity and ultrasonographic (US) evaluation of the biparietal diameter (BPD) and placental grade were performed simultaneously in 261 nondiabetic pregnant women. A BPD of at least 9.3 cm and a grade 3 placenta were evaluated as predictors of fetal lung maturity using amniotic fluid phospholipids as indicators of a mature lung profile. The ability of the sonographic parameters to predict fetal lung maturity was closely related to menstrual age. Before 37 weeks, the false-positive prediction rate using a grade 3 placenta was 100%, and the false-positive prediction using the BPD was 85.6%. After 37 weeks, the false-positive rate using a grade 3 placenta was 5.9%, and the false-positive rate using the BPD was 9.5%. Thus menstrual age, and not these two US parameters, dictated fetal lung maturity. The authors conclude that the best use of US for predicting fetal lung maturity is in establishing menstrual age early in pregnancy.     

Anaesthetists' and surgeons' attitudes towards informed consent in the UK: an observational study

Background  

The attitudes of patients' to consent have changed over the years, but there has been little systematic study of the attitudes of anaesthetists and surgeons in this process. We aimed to describe observations made on the attitudes of medical professionals working in the UK to issues surrounding informed consent.     

Detection of a human CFC with a high proliferative potential

Colony forming cells (CFC) with high proliferative potential have been detected in nutrient agar cultures of human bone marrow cells containing recombinant human interleukin-3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF). These CFC were detected by the formation of large colonies with diameters greater than 0.5 mm and containing approximately 50,000 cells after 28 days incubation. The incidence of these CFC was only two in 100,000 normal bone marrow cells; however, bone marrow from patients treated with 5-fluorouracil contained up to sevenfold higher numbers of these CFC. The characteristics of these CFC, multifactor-responsive progenitors with high proliferative potential, requiring a prolonged growth period in culture and showing a relative preservation in marrow from individuals pretreated with 5-fluorouracil, are consistent with a human cell type equivalent to the primitive murine progenitor termed HPP-CFC.     

Case report: Recurrent hyperammonaemic encephalopathy due to citrullinaemia in a 52 year old man

The present report describes a Chinese male who presented for the first time with recurrent encephalopathy and hyperammonaemia at the age of 52 years. He was found to have citrullinaemia. To our knowledge, this is the first Chinese with citrullinaemia and the first non-Japanese who has the variant form of presentation. The patient also has the longest asymptomatic period for citruliinaemia so far described. The patient's biochemical derangement, clinical features and the postulation of his late presentation are discussed. It is noteworthy that simple therapeutic measures, such as lactulose and dietary protein restriction, controlled his symptoms well.     

5-Hydroxy-3-indole acetic acid levels in infantile colic: Is serotoninergic tonus responsible for this problem?

Abstract Levels of 5-hydroxy-3-indole acetic acid (5-OHIAA), a metabolite of serotonin, were studied in infants with infantile colic in order to investigate the aetiology of infantile colic pathogenesis. The study included 16 patients with infantile colic and 10 control subjects. Random urinary 5-OH IAA levels of colicky infants were found to be higher than those in the control group. This finding suggested that high serotonin levels may be responsible for infantile colic.     

Megakaryocyte growth and development factor accelerates platelet recovery in peripheral blood progenitor cell transplant recipients

We have investigated the potential of PEGylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a molecule related to thrombopoietin (mpl ligand or TPO) in minimizing the thrombocytopenia associated with hematopoietic ablation and peripheral blood progenitor cell (PBPC) transplant. Irradiated mice that received PBPC mobilized by PEG-rHuMGDF or granulocyte colony-stimulating factor (G-CSF) had a reduced number of thrombocytopenic days with platelets below 100 x 10(6) per mL of blood. Recipients of unmobilized PBPC had a 9 day thrombocytopenic phase which was shortened to 7 days if they were given granulocyte-macrophage colony-stimulating factor (GM-CSF)- mobilized PBPC. This was further reduced to 2 or 3 days of thrombocytopenia in recipients of G-CSF- or PEG-MGDF-mobilized PBPC. Despite our observation that PEG-rHuMGDF is a relatively modest stimulator of the mobilization of myeloid progenitors to the blood, MGDF-mobilized PBPC do effect accelerated recovery of platelets after transplantation. However, the most effective use of PEG-rHuMGDF is when it is given during the recovery phase after PBPC transplantation to hematopoietically ablated mice. Posttransplant treatment with PEG- rHuMGDF reduces thrombocytopenia to a single day or less, in recipients of most types of PBPC. Mice that were treated during the first 2 weeks after PBPC transplant with PEG-rHuMGDF had 1 thrombocytopenic day compared to 9 days in carrier-treated recipients of unmobilized PBPC and 2 to 3 days in carrier-treated recipients of the optimally mobilized PBPC from G-CSF or G-CSF/PEG-rHuMGDF treated donors. In groups where PEG-rHuMGDF was included in the mobilization protocol and used to treat recipients as well thrombocytopenia was effectively eliminated. These data show that PEG-rHuMGDF is a highly effective agent in eliminating the thrombocytopenia associated with PBPC transplantation.