The reversible oral P2Y 12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature

Abstract

Objectives The platelet ADP P2Y 12 receptor which is a target for the antithrombotic drug clopidogrel is also distributed on vascular smooth muscle cells and stimulate contraction. This study investigates whether AZD6140, in contrast to clopidogrel, can inhibit ADP-mediated arterial contractions. Methods Mice were treated with clopidogrel, 50 mg/kg, 24 and 2 h before experiment. Thoracic aorta ring segments from both clopidogrel-treated ( n = 5) and untreated ( n = 4) mice were mounted in myograph baths. Contractions of human left internal mammary arteries (IMA) and small arteries were studied in an identical manner. Results Clopidogrel treatment per os did not inhibit contractions by the stable ADP analogue 2-MeSADP (10 µM). However, addition of 1 µM AZD6140 in vitro inhibited ADP contraction (% of maximal contraction by 60 mM K +) both in the clopidogrel-treated, from 64% to 32% ( P = 0.002) and in the untreated group, from 59% to 33% ( P = 0.015). 2-MeSADP contractions in human IMA and small arteries were inhibited by AZD6140. Conclusions The antiplatelet drug AZD6140 blocks the contractile effects of ADP in both murine and human vasculature. These effects of AZD6140 could be beneficial in the management of conditions in which vasospasm may play a role.