Alterations in endothelial control of the pulmonary circulation in exercising swine with secondary pulmonary hypertension after myocardial infarction

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 ETA/ETBreceptor blockade (tezosentan) was performed in the absence and presence of single or combined inhibition of endothelial NO synthase (eNOS, with Nω-nitro-L-arginine) and cyclo-oxygenase (COX, with indometacin). In normal swine, mixed ETA/ETBblockade 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 ETA/ ETBreceptor blockade. Inhibition of eNOS enhanced the vasodilator response to ETA/ETBblockade, 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. © 2007 The Authors. Journal compilation

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