Published Online
on September 8, 2003

A more recent version of this article appeared on September 30, 2003

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Submitted on June 19, 2002
Revised on May 15, 2003
Accepted on May 19, 2003

Emergence of Smooth Muscle Cell Endothelin B-Mediated Vasoconstriction in Lambs With Experimental Congenital Heart Disease and Increased Pulmonary Blood Flow

Stephen M. Black PhD, Eugenia Mata-Greenwood PhD, Robert W. Dettman PhD, Boaz Ovadia MD, Robert K. Fitzgerald MD, Olaf Reinhartz MD, Stefan Thelitz MD, Robin H. Steinhorn MD, Rene Gerrets PhD, Karen Hendricks-Munoz MD, Gregory A. Ross MD, Janine M. Bekker BS, Michael J. Johengen BS, and Jeffrey R. Fineman MD^*

From the Department of Pediatrics (S.M.B, E.M.-G., R.W.D., R.H.S), Northwestern University, Chicago, Ill; Departments of Pediatrics (B.O., R.K.F., G.A.R., J.M.B., S.T., M.J.J., J.R.F.) and Cardiothoracic Surgery (O.R.), University of California San Francisco, San Francisco, Calif; Department of Pediatrics (R.G., K.H.-M.), New York University, New York, NY; and the Cardiovascular Research Institute (J.R.F.), University of California, San Francisco.

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 ET_A 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 ET_B receptor agonist, and was blocked by the ET_B 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 ET_B 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 ET_B receptors on smooth muscle cells. These data suggest an important role for ET_B receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

Key words: endothelin • pulmonary heart disease • heart defects, congenital

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