ZD-1611

Animal experiment:

The precursor of ET-1, big ET-1, is used for in vivo analysis of the effects of ZD1611. Exogenously administered big ET-1 is converted to the biologically active peptide ET-1 in vivo via a phosphoramidon-sensitive ET-converting enzyme. In the present study, the use of big ET-1 in vivo is preferred because this compound fails to elicit the initial depressor response associated with i.v. administered ET-1 and yields a greater maximum response than that to ET-1 itself. A partial cumulative dose-response curve to i.v. big ET-1 starting at 0.3 nmol/kg) is constructed until pressor responses >30 mm Hg are achieved. After a 55-min recovery period, ZD1611 (0.03-0.3 mg/kg) or vehicle is administered, and the big ET-1-response curve is repeated 5 min later. The activity of ZD1611 is calculated as a ratio of the dose of big ET-1 required to give a 30-mm Hg rise in MAP in the absence and then the presence of the compound.

References:

[1]. Wilson C, et al. Pharmacological profile of ZD1611, a novel, orally active endothelin ETA receptor antagonist. J Pharmacol Exp Ther. 1999 Sep;290(3):1085-91.
[2]. Stenman E, et al. Cooperative effect of angiotensin AT(1) and endothelin ET(A) receptor antagonism limits the brain damage after ischemic stroke in rat. Eur J Pharmacol. 2007 Sep 10;570(1-3):142-8. Epub 2007 Jun 9.