Mechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats
2003
Abstract Our in vivo assay for thrombolysis consisted of recording the weight of platelet-rich thrombi adhering to a collagen strip that was superfused with arterial blood in extracorporal circulation of anaesthetised Wistar rats. Immediate thrombolysis occurred in response to intravenously administrated angiotensin-converting enzyme inhibitor (ACE-I) at non-hypotensive doses of 3–30 μg kg −1 (captopril −1 , SC 560 and acetaminophen, 0.3–3 mg kg −1 ) slightly augmented thrombolysis by ACE-I, while COX-2 inhibitors (nimesulide and coxibs at doses −1 and aspirin at a high dose of 50 mg kg −1 ) or a kinin B 2 receptor antagonist (icatibant) abolished it. NOS inhibition by l -NAME blunted and delayed thrombolysis by ACE-I. In parallel to maximum thrombolysis by quinapril (30 μg kg −1 ), plasma levels of 6-keto-PGF 1α rose significantly from 40±7 to 554±91 pg ml −1 ( n =5, mean±S.D.), while basal levels of PGE 2 (12±3 pg ml −1 ) and TXB 2 (47±11 pg ml −1 ) remained essentially unchanged. Pretreatment with celecoxib (0.1–1.0 mg kg −1 ) abolished not only thrombolysis by quinapril but also the quinapril-induced rise in plasma 6-keto-PGF 1α . In cultured bovine aortic endothelial cells, perindoprilate (30 μM) increased cytosolic free calcium [Ca 2+ ]i, but this effect was by three to four orders of magnitude weaker than that of bradykinin (Bk). In aortas of Wistar rats, the transcripts of COX-2 and PGI-S were overexpressed as compared to COX-1. Thus, in blood vessels of Wistar rats, the preferable route of the PGI 2 generation might lead through the COX-2 pathway. We conclude that in Wistar rats, ACE-I induces thrombolysis via accumulation of endogenous kinins over the endothelium and a subsequent activation of B 2 receptors followed by the release of prostacyclin and nitric oxide. Thrombolysis by ACE-I seems to be mediated mainly through prostacyclin that is made by COX-2. It may well be that an increase in endothelial [Ca 2+ ]i by ACE-I activates phospholipase A 2 , which supplies COX-2 with the substrate for making thrombolytic prostacyclin.
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