Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

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Abstract
We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET‐mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ETAand ETBreceptor subtypes. Chronically instrumented swine with (MI swine;n= 25) or without (normal swine;n= 19) MI were studied at rest and during treadmill exercise (up to 4 km h−1), in the absence and presence of the ETAantagonist EMD 122946 or the mixed ETA/ETBantagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ETAblockade had no effect on PVR at rest or during exercise. Conversely, ETA/ETBblockade decreased PVR but only during exercise (at 4 km h−1, from 3.0 ± 0.1 to 2.3 ± 0.1 mmHg min l−1;P≤ 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (bothP≤ 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r= 0.71;P≤ 0.01). Furthermore, the pulmonary vasoconstrictor response to ET‐1 infusion was enhanced after MI (P≤ 0.05). ETA/ETBblockade decreased PVR in MI swine from 3.6 ± 0.3 to 3.1 ± 0.5 mmHg min l−1at rest and from 3.4 ± 0.3 to 2.4 ± 0.2 mmHg min l−1during exercise at 4 km h−1(bothP≤ 0.05). This increased response to mixed ETA/ETBblockade in MI compared to normal swine appeared to be the result of an increased ETA‐mediated vasoconstriction, as ETAblockade decreased PVR in MI swine from 3.4 ± 0.4 to 2.8 ± 0.2 mmHg min l−1at rest and from 3.1 ± 0.3 to 2.6 ± 0.2 mmHg min l−1at 4 km h−1(bothP≤ 0.05). In conclusion, increased plasma ET levels together with increased pulmonary resistance vessel responsiveness to ET result in an exaggerated pulmonary vasoconstrictor influence of ET in swine with a recent MI. This vasoconstrictor influence is the result of an emergent tonic ETA‐mediated vasoconstriction in addition to the exercise‐induced ETB‐mediated vasoconstriction that is already present in normal swine.

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