ARTERIAL-WALL RATHER THAN PLATELETS IS RESPONSIBLE FOR DIMINISHED THROMBOGENICITY DURING ISRADIPINE THERAPY

We investigated whether the vessel wall or platelets are primarily res ponsible for the decreased thrombogenicity induced by the calcium chan nel blocker isradipine after endothelium removal. In a cross-perfusion model, rabbit aorta and iliac artery endothelium of receiver animals were removed by balloon catheter before being perfused with the blood of the blood donor rabbits. Donor and/or receiver animals were treated with 0.3 mg/kg isradipine intravenously (i.v.) daily for 1 week or wi th 10 mg acetylsalicylic acid (ASA) in addition. The other animals rec eived vehicle only or ASA. The animals were divided into four groups ( I-IV, total n = 24) consisting of four subgroups of 6 animals each. In all, 96 rabbits were examined. Immediately after the last administrat ion of the respective drug, native blood from a donor rabbit was circu lated (30 ml/min) through a deendothelialized segment of a receiver ra bbit. The contract (C) and spread (S) platelets as well as the denuded surface covered with platelet aggregates (>5 mu m high) were quantifi ed by morphometry. Deposition of [In-111]oxine-labeled platelets was q uantitatively determined per surface unit. In addition, prostaglandin I-2 (PGI(2)) formation by the denuded aortic and iliac artery segment was determined. In group I, receiver rabbit pretreatment with isradipi ne exhibited decreased adhesion and aggregation of platelets, even whe n the donor rabbit was treated with solvent or ASA, In group II, conco mitant treatment of donor animals with ASA and isradipine had no signi ficant effect, whereas ASA isradipine treatment of receiver animals en hanced thrombogenicity. In group III, an untreated receiver rabbit, in contrast, showed platelet deposition comparable to that of untreated controls, even when the donor rabbit was pretreated with isradipine. I n group IV, ASA-pretreated receiver animals showed enhanced thrombogen icity as compared with respective controls. Although donor animals pre treated with isradipine generally exhibited less thrombogenicity, no s ignificant differences were noted in either groups. In contrast, recei ver animals showed significantly enhanced thromboresistance induced by isradipine that was completely abolished by ASA pretreatment. Isradip ine has beneficial effect on vascular wall rather than on circulating platelets, thus decreasing in vivo arterial thrombogenicity.