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This Article Full Text Full Text (PDF) All Versions of this Article: 580/3/907    most recent jphysiol.2006.127118v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Merkus, D. Articles by Duncker, D. J. Search for Related Content PubMed PubMed Citation Articles by Merkus, D. Articles by Duncker, D. J. Related Collections Cardiovascular

¹ Experimental Cardiology, Thoraxcentre, Cardiovascular Research School COEUR, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands

Secondary pulmonary hypertension after myocardial infarction (MI) has been associated with endothelial dysfunction and activation of the endothelin (ET) system. Here, we investigated whether an increased ET-mediated pulmonary vasoconstrictor influence contributes to pulmonary hypertension after MI, and whether this increased ET vasoconstriction is caused by impaired nitric oxide (NO) and prostanoid production. For this purpose, chronically instrumented swine with and without MI ran on a treadmill at 0–4 km h^–1. Mixed ET_A/ET_B receptor blockade (tezosentan) was performed in the absence and presence of single or combined inhibition of endothelial NO synthase (eNOS, with N-nitro-L-arginine) and cyclo-oxygenase (COX, with indometacin). In normal swine, mixed ET_A/ET_B blockade decreased pulmonary vascular resistance, but only during exercise. In MI swine, an increased ET-mediated vasoconstrictor influence was observed in the pulmonary circulation both at rest and during exercise. Inhibition of COX resulted in pulmonary vasoconstriction at rest in MI, but not in normal swine; this vasoconstriction in MI swine was normalized by ET_A/ET_B receptor blockade. Inhibition of eNOS enhanced the vasodilator response to ET_A/ET_B blockade, indicating that NO blunts the pulmonary vasoconstrictor influence of ET. However, this vasodilator response was enhanced to a similar degree in MI and normal swine. In summary, swine with a recent MI are characterized by an exaggerated pulmonary vasoconstrictor influence of ET. This increased ET-mediated pulmonary vasoconstrictor influence is not caused by a loss of NO bioavailability, and is blunted by an increased prostanoid-mediated vasodilatation. In conclusion, an increased ET-mediated vasoconstriction, which does not appear to be the result of loss of endothelial vasodilators, contributes to pulmonary hypertension after MI.

(Received 20 December 2006; accepted after revision 2 February 2007; first published online 8 February 2007)
Corresponding author D. Merkus: Experimental Cardiology, Thoraxcentre, Erasmus MC, University Medical Centre Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Email: d.merkus{at}erasmusmc.nl

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