Pharmacological Research, Vol. 40, No. 1, 1999 Article No. phrs.1998.0485, available online at http:www.idealibrary.com on EFFECT OF VERAPAMIL ON RESPONSES TO ENDOTHELIN-1 IN AORTIC RINGS FROM STREPTOZOTOCIN-INDUCED DIABETIC RATS NERGIS MURAT, SULE KALKAN and SEDEF GIDENER Dokuz Eylul Uni ersity Medical Faculty, Department of Pharmacology, 35340 Balco a Izmir, ¨ Turkey Accepted 18 December 1998 Ž In this study, we investigated the constrictor responsiveness to endothelin-1 ET-1, 10 30 . Ž . nM of aortic rings under 1 g resting tension in Krebs-Bicarbonate solution from 8-weeks Ž 1 . streptozotocin STZ, 65 mg kg , i.p -induced diabetic rats and vehicle-treated control rats. The maximum ET-1-induced contraction of the aorta in diabetic rats was increased by 150%, but the EC of ET-1 remained unchanged. Although in both groups, verapamil 50 Ž reduced the constrictor responses to ET-1 diabetic group P 0.001, control group P . 0.05 , there were not any significant differences between PD values. These results suggest 2 that verapamil inhibits ET-1-induced Ca 2 entry through the L-type channel and this effect did not change in diabetes mellitus. 1999 Academic Press KEY WORDS: diabetes mellitus, endothelin-1, verapamil, rat, aorta. INTRODUCTION The endothelium is involved in both the physiologi- cal regulation of vascular tone and the structural transformation of the vessel under pathological con- ditions. Under physiological conditions, endothelial cells continuously secrete nitric oxide which relaxes smooth muscle cells and ensures vessel potency 1. Damaged or excessively activated endothelial cells can also secrete vasoconstrictor factors, the best Ž . known of which is endothelin-1 ET-1 2 . Electron microscopy studies have shown that endothelial cells have few secretory granules, in which the peptide can be stored and rapidly released in response to appropriate stimuli 3 . ET-1 is a vasoconstrictor peptide 2 that is shown to be a potent mitogen for vascular smooth muscle cells 4 , suggesting its possi- ble role in the development of atherosclerotic vascu- lar diseases. Vascular disorders are common complications of diabetes mellitus, but its exact mechanism which is responsible for angiopathy in diabetic patients re- mains elusive 4, 5 . Isolated vascular tissue from diabetic patients shows impaired endothelial cell function. Glucose causes concentration and time dependent endothelial cell dysfunction 5 . It has Corresponding author. also been suggested that the high blood glucose- stimulated ET-1 release may be involved in the development of vascular complications in diabetes 6. In vascular smooth muscle, the ET-1 interaction 2 at the ET receptor elevates Ca due to both an A i initial release of Ca 2 from the intracellular stores and a prolonged entry of extracellular Ca 2 through L-type channels 7 . The mechanisms involved in Ca 2 influx are largely unknown, although Ca 2 can enter the cell through both L-type Ca 2 channels 2 and receptor-operated Ca channels 8 . The L-type Ca channel is inhibited by phenylalkylamines, such as verapamil. The aim of the present study was to investigate the effect of verapamil on contractile responses of Ž . aortic rings to ET-1 in streptozotocin STZ treated rats. MATERIALS AND METHODS Animal model Wistar rats weighting 150 250 g were used in all experiments. They were housed under controlled Ž . conditions of temperature 20 2°C . While Group Ž 1 served as a control received citrate buffer alone, . Ž . n 6 , Group 2 had diabetes mellitus n 8 . Dia- betes mellitus was induced by a single i.p. injection 104366189907003704$30.000 1999 Academic Press