Pharmacological Research, Vol. 38, No. 5, 1998 Article Number: fr980377 CALCIUM DOBESILATE INCREASES ENDOTHELIUM-DEPENDENT RELAXATION IN ENDOTHELIUM-INJURED RABBIT AORTA EMILIO RUIZ and TERESA TEJERINA Department of Pharmacology, School of Medicine, Complutense Uni ersity, 28040 Madrid, Spain Accepted 22 July 1998 Ž . Calcium dobesilate DOBE is an orally administered angioprotective agent which is used in some vascular diseases such as diabetic retinopathy, although its mechanism of action is not yet fully understood. The aim of this work was to correlate previous ‘ in itro ’ findings carried out in our laboratory with an ‘ ex i o ’ model of endothelium-injury by overdose of vitamin D . Male New Zealand White rabbits were used. The study was divided into two 2 protocols. Protocol 1: 10 days of treatment; and Protocol 2: 30 days of treatment. Rabbits in Ž 1 . each group were treated with vitamin D 200 000 IU day for the first 2 days and two 2 Ž 1 groups were subsequently treated with DOBE at different doses 50 mg kg per day or 1 . Ž 8 4 . 500 mg kg per day . The concentration response curve induced by NA 10 10 M in Ž aorta arteries was shifted downwards in the groups treated with DOBE in both Protocol 1 . Ž . and 2 , whereas only in Protocol 2 30 days of treatment was this curve affected in the Ž 8 5 hypervitaminic group. The endothelium-dependent relaxation induced by ACh 10 10 . Ž . M decreased in the hypervitaminic groups in both Protocol 1 and 2 but only in Protocol 2 Ž . 30 days of treatment was the endothelium-dependent relaxation restored to normal Ž . control, untreated group in both DOBE-treated groups. The endothelium-independent Ž .Ž 8 4 . relaxation induced by sodium nitroprusside SNP 10 10 M decreased in the hypervi- taminic groups only in Protocol 1. We did not find differences in the DOBE-treated groups Ž . in any protocol compared with the control untreated group. These findings show evidence that DOBE restored endothelial functionality in endothelium-injured rabbit aorta only after 30 days of treatment. 1998 The Italian Pharmacological Society KEY WORDS: calcium dobesilate, endothelium-injured arteries, rabbit, hypervitaminosis. INTRODUCTION Ž .Ž Calcium dobesilate DOBE calcium 2,5-dihydroxy- . benzene sulphonate is an orally administered an- gioprotective agent which, in addition to lowering blood, plasma and aqueous humor hyperviscosity 1, 2 reduces microvascular hyperpermeability 3 , pos- sesses platelet antiaggregatory activity 4 , and has been successfully used in the treatment of chronic venous insufficiency 5 and diabetic retinopathy 6. It has been described in previous reports 7, 8 that DOBE increased endothelium-dependent relaxation in isolated rabbit aorta, in an ‘ in itro ’ model and that this increase was due to an increase in synthe- sisrelease of EDRF and to an additional mecha- nism such as a scavenging effect of DOBE on super- oxide anion radicals. In order to correlate these actions of DOBE ‘ in itro ’ with those ‘ ex i o ’, we have tested the effects of DOBE on endothelium- Corresponding author. dependent relaxation in endothelium-injured rabbit aorta. Endothelium-injury was induced by adding an overdose of vitamin D in the animal chow. It is 2 well-known that hypervitaminosis with D causes 2 degeneration of both endothelial and vascular smooth muscle cells followed by smooth muscle cell proliferation 9 . MATERIALS AND METHODS General procedure Eighty male New Zealand white rabbits weighing Ž 2.5 3.0 kg, obtained from Biocentre S.A. Barcelona, . Spain , were used in this study. The study was di- vided into two protocols as shown in Table I. Administration of itamin D and calcium 2 dobesilate Animals were fed a standard diet 7 days before the start of the experiment. 104366189811036106$30.000 1998 The Italian Pharmacological Society