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.     

Combined enzyme defect of mitochondrial fatty acid oxidation.

A young girl presented with recurrent episodes of muscle weakness culminating in a severe attack of generalized muscle weakness. In the muscle mitochondria from the patient there was an abnormal pattern of intermediates of beta-oxidation with an accumulation of 3-hydroxyacyl- and 2-enoyl-CoA and carnitine esters, and 3-oxoacylcarnitines. There was low activity of long-chain 3-hydroxyacyl-CoA dehydrogenase in mitochondria from all tissues. The activity of long-chain 2-enoyl-CoA hydratase was low in muscle mitochondria and 3-oxoacyl-CoA thiolase activity measured with 3-oxohexadecanoyl-CoA as substrate was low in fibroblast, muscle, and cardiac mitochondria but only partial deficiency was present when the activity was measured with 3-oxooctanoyl-CoA. The activity of the long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-oxoacyl-CoA thiolase in fibroblasts from the patient's parents was intermediate between those of controls and the patient. The patient has a combined defect of the long-chain 3-hydroxyacyl-CoA dehydrogenase, long-chain 3-oxoacyl-CoA thiolase, and long-chain 2-enoyl-CoA hydratase which appears to be inherited in an autosomal recessive manner. This suggests there is a multifunctional enzyme catalyzing these activities in human mitochondria and that this enzyme is deficient in our patient.