Comparative action of carbocyclic thromboxane A(2) stereoisomers on platelets.

Stereospecific requirements for the interaction of the thromboxane A(2) carbocyclic mimetic CTA(2) 1 with the human platelet PGH(2)/TXA(2) receptor have been explored. The two pairs of trans-1,2 and cis-3,4 side chain diastereoisomers were synthesised and evaluated for agonist and antagonist activity in human platelet rich plasma. Interestingly, the natural and unnatural trans diastereoisomers, both possessed potent aggregatory activity and equipotently inhibited platelet responses to subsequent addition of agonists, whereas, the respective unnatural cis isomers proved only weakly active or inert.

Kinetic characteristics of ZENECA ZD5522, a potent inhibitor of human and bovine lens aldose reductase.

Aldose reductase (aldehyde reductase 2) catalyses the conversion of glucose to sorbitol, and methylglyoxal to acetol. Treatment with aldose reductase inhibitors (ARIs) is a potential approach to decrease the development of diabetic complications. The sulphonylnitromethanes are a recently discovered class of aldose reductase inhibitors, first exemplified by ICI215918.

The effect of interleukin-4 on tumour necrosis factor-alpha induced expression of tissue factor and plasminogen activator inhibitor-1 in human umbilical vein endothelial cells.

The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is able to alter the haemostatic balance of human umbilical vein endothelial cells (HUVECs) towards that of a procoagulant and anti-fibrinolytic state. Treatment of HUVECs in culture with human recombinant TNF-alpha (0.5-50 U/ml; 6 h) significantly increased total cell expression of tissue factor (TF) 10-fold from 40 mU/well to 400-500 mU/well.

Inhibition of aldose reductase by (2,6-dimethylphenylsulphonyl)nitromethane: possible implications for the nature of an inhibitor binding site and a cause of biphasic kinetics.

Aldose reductase (aldehyde reductase 2, ALR2) is often isolated as a mixture of two forms which are sensitive (ALR2S), or insensitive (ALR2I), to inhibitors. We show that ICI 215918 ((2-6-dimethylphenylsulphonyl)-nitromethane) follows either noncompetitive, or uncompetitive kinetics with respect to aldehyde for ALR2S, or the closely related enzyme, aldehyde reductase (aldehyde reductase 1, ALR1). Similar behaviour is exhibited by two other structural types of aldose reductase inhibitor (ARI), spirohydantoins and acetic acids, when either aldehyde, or NADPH is varied.