Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction.
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 ET(A) and ET(B) receptor 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 ET(A) antagonist EMD 122946 or the mixed ET(A)/ET(B) antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET(A) blockade had no effect on PVR at rest or during exercise. Conversely, ET(A)/ET(B) blockade 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 <or= 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (both P <or= 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r = 0.71; P <or= 0.01). Furthermore, the pulmonary vasoconstrictor response to ET-1 infusion was enhanced after MI (P <or= 0.05). ET(A)/ET(B) blockade decreased PVR in MI swine from 3.6 +/- 0.3 to 3.1 +/- 0.5 mmHg min l(-1) at rest and from 3.4 +/- 0.3 to 2.4 +/- 0.2 mmHg min l(-1) during exercise at 4 km h(-1) (both P <or= 0.05). This increased response to mixed ET(A)/ET(B) blockade in MI compared to normal swine appeared to be the result of an increased ET(A)-mediated vasoconstriction, as ET(A) blockade decreased PVR in MI swine from 3.4 +/- 0.4 to 2.8 +/- 0.2 mmHg min l(-1) at rest and from 3.1 +/- 0.3 to 2.6 +/- 0.2 mmHg min l(-1) at 4 km h(-1) (both P <or= 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 ET(A)-mediated vasoconstriction in addition to the exercise-induced ET(B)-mediated vasoconstriction that is already present in normal swine.
Houweling
Birgit
B
Experimental Cardiology, Thoraxcentre, Erasmus MC, University Medical Centre Rotterdam, PO Box 1738, 3000 DR Rotterdam, the Netherlands.
Merkus
Daphne
D
Sorop
Oana
O
Boomsma
Frans
F
Duncker
Dirk J
DJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003243:Consciousness / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology* / Q000503:physiopathology*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications* / Q000503:physiopathology*; D010805:Physical Conditioning, Animal / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000097:blood / Q000502:physiology*; D012146:Rest / Q000502:physiology; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D017466:Receptors, Endothelin; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan