Clinical Relevance of Endothelin B–Mediated Vasoconstriction in Lambs With Increased Pulmonary Blood Flow
To the Editor:
Black et al1 present an elegant study that suggests the presence of endothelin-B receptor–mediated vasoconstriction in a model of increased pulmonary blood flow in lambs. They identify this vasoconstriction by administration of exogenous endothelin-1 and use of selective receptor agonists and blockers. The authors propose an important pathophysiological role for the ETB receptor in the vasoconstriction seen in this model.
Although any study of the evolution of changes in receptor expression and density in a disease model is of great interest, the conclusions derived from the use of exogenous vasoconstrictors must always be made with great caution. The natural state for these lambs with high blood flow is one of having a certain level of endogenous endothelin-1. Administration of exogenous endothelin-1 or an agonist does not represent their state in nature. The most telling evidence for this is provided in the Results section of the above-mentioned article,1 where the authors state clearly that in the shunted lambs, without exogenous administration of endothelin-1 or agonists (baseline), administration of the ETA antagonist PD 156707 caused a statistically significant and clinically relevant reduction in pulmonary vascular resistance, whereas administration of the ETB antagonist BQ 788 did not change the baseline hemodynamic variables. This suggests strongly that it is the ETA receptor that is predominantly relevant to the disease state.
Although the authors do comment that ETB receptor activation “makes a minimal contribution to basal tone,” it is in fact that “basal” tone that represents the state of the animal in vivo. The increased presence of ETB receptors may be clinically irrelevant, at least as far as their role in vasoconstriction, particularly given that the effect is only apparent in the presence of pharmacological doses of exogenous vasoconstrictors. The conclusions of the article as presented might be reconsidered.
Black SM, Mata-Greenwood E, Dettman RW, et al. Emergence of smooth muscle cell endothelin B–mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow. Circulation. 2003; 108: 1646–1654.
We respectfully acknowledge and appreciate the comment of Dr Langleben. The use of pharmacological agonists and antagonists certainly has its limitations but remains extremely useful as a pharmacological tool and provides important information. In our recent study,1 we demonstrated an upregulation of ETB receptor protein levels over the second month of life in lambs with increased pulmonary blood flow and showed that these receptors are now localized to the vascular smooth muscle cells. With the use of both ETA and ETB receptor antagonists, we determined that the ETA receptors have the predominant effect on basal vasoconstricting tone, whereas the newly characterized ETB receptors have minimal contribution to basal tone. We agree with Dr Langleben that these data are telling and clinically relevant. However, we respectfully disagree with the interpretation that these data suggest that the ETB receptor may be clinically irrelevant. With the use of pharmacological agonists, we demonstrated that the ETB receptors are able to induce potent pulmonary vasoconstriction. Although this was pharmacological stimulation, there are several clinical situations in which ET-1 production and/or release is increased, such as inflammation, hypoxia, and cardiopulmonary bypass.2–3 Under these conditions of increased ET-1, ETB-mediated pulmonary vasoconstriction may become clinically relevant. In addition, the lambs in our study were only 8 weeks old and had only modest pulmonary vascular disease. In addition, smooth muscle cell–localized ETB receptors were not appreciated in these lambs when studied at 4 weeks of age. It is unknown whether with increasing time, these receptors will continue to be upregulated and begin to significantly contribute to basal pulmonary vasoconstriction. Further studies are clearly warranted to answer these important questions.