Endothelin-1 induced proinflammatory markers in the myocardium and leukocytes of guinea-pigs: role of glycoprotein IIB/IIIA receptors.

Aim:To assess whether endothelin-1 (ET-1) induces the in vivo expression of inflammatory-related proteins, namely cyclooxygenase-2 (COX-2) and tissue factor, in the myocardium and circulating leukocytes of guinea-pigs. The involvement of platelets was also analyzed. Methods: ET-1 (0.013 mug/min) was infused to male guinea-pigs for 45 min in the presence and absence of tirofiban, a nonpeptidic blocker of the glycoprotein IIb/IIIa receptor (GPIIb/IIIa). Tissue factor and COX-2 expression were determined by Western blot. Results: No changes in mean arterial pressure and heart rate were detected. ET-I-infused guinea-pigs showed a marked increase in the number of platelets expressing activated GPIIb/IIIa receptors (0.8 +/- 0.03% vs. 6.5 +/- 0.2%; P < 0.05). Tirofiban (10 mug/Kg bw/min) blunted ex vivo platelet aggregation in response to ADP, although only partially reduced COX-2 and tissue factor expression in both the myocardium and leukocytes of ET-I-infused guinea-pigs. The myocardium of platelet-depleted guinea-pigs also showed a reduced COX-2 expression after ET-I infusion (57 +/- 3% reduction; P < 0.05). In vitro studies demonstrated that platelets (10(7) and 10(9) platelets/well) enhanced ET-1 (10(-7) mol/l)-induced COX-2 expression in heart slices. Conclusion: ET-1 stimulated in vivo the expression of the pro-inflammatory proteins COX-2 and tissue factor in the myocardium and in leukocytes by a mechanism GPIIb/IIIa platelet receptors. (C) 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.