TY - JOUR
T1 - Emergence of smooth muscle cell endothelin B-mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow
AU - Black, Stephen M.
AU - Mata-Greenwood, Eugenia
AU - Dettman, Robert W.
AU - Ovadia, Boaz
AU - Fitzgerald, Robert K.
AU - Reinhartz, Olaf
AU - Thelitz, Stefan
AU - Steinhorn, Robin H.
AU - Gerrets, Rene
AU - Hendricks-Munoz, Karen
AU - Ross, Gregory A.
AU - Bekker, Janine M.
AU - Johengen, Michael J.
AU - Fineman, Jeffrey R.
PY - 2003/9/30
Y1 - 2003/9/30
N2 - Background - Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results - Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2 ± 113.8, versus 209.8 ± 61.8 pg/g, P<0.05). In shunt lambs (n = 9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n = 3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n = 3). However, in control lambs (n = 7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions - Over time, increased pulmonary blood flow and/or pressure results in the emergence of ET B-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.
AB - Background - Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow. Methods and Results - Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2 ± 113.8, versus 209.8 ± 61.8 pg/g, P<0.05). In shunt lambs (n = 9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n = 3). This pulmonary vasoconstriction was mimicked by exogenous Ala 1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n = 3). However, in control lambs (n = 7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs. Conclusions - Over time, increased pulmonary blood flow and/or pressure results in the emergence of ET B-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.
KW - Endothelin
KW - Heart defects, congenital
KW - Pulmonary heart disease
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U2 - 10.1161/01.CIR.0000087596.01416.2F
DO - 10.1161/01.CIR.0000087596.01416.2F
M3 - Article
C2 - 12963646
AN - SCOPUS:0141730234
SN - 0009-7322
VL - 108
SP - 1646
EP - 1654
JO - Circulation
JF - Circulation
IS - 13
ER -