Abstract 134 Pulmonary Vascular Biology Platform, Monday, 5/3

Endothelin-1 (ET-1) is a potent vasoconstrictor and co-mitogenic peptide that contributes to hypoxic pulmonary hypertension (PH) by activation of ET-A or ET-B receptors. Although the ET-A receptor mediates vasoconstriction, controversy exists regarding the physiologic roles of the ET-B receptor. Stimulation of endothelial ET-B receptors causes vasodilation and clears circulating ET-1 levels, but ET-B receptors on smooth muscle cause vasoconstriction in the rat lung. To examine the role of the ET-B receptor in the pathogenesis of PH, we studied the effect of acute hypoxia in an animal model of ET-B receptor deficiency. The spotting lethal rat (sl/sl) is a naturally occurring model of Hirschprung disease and carries a deletion in the ET-B receptor gene (EDNRB). Rescue of the sl/sl rat by transgenic expression of the EDNRB prevents intestinal aganglionosis and death (transgenic sl/sl ET-B deficient). We hypothesized that deficiency of the ET-B receptor would predispose the transgenic sl/sl ET-B deficient animals to exaggerated hypoxic pressor responses. Forty-two rats born at 5,280 feet were studied (wild type, transgenic +/+, transgenic sl/+, and transgenic sl/sl). After 3 months, aortic and pulmonary artery (PAP, mmHg) catheters were placed, and the hemodynamic response to acute hypoxia was studied on the next day. TPR (total pulmonary resistance, mmHg/L/min) was calculated as PAP/cardiac output. Although basal PAP was not different between groups, brief exposure to hypoxia (FiO2, 0.10 for 10 min) caused a more marked elevation of mean PAP and TPR in the transgenic sl/sl ET-B deficient rats (*p<0.05 Baseline vs. Hypoxia). (Table) We conclude that transgenic sl/sl ET-B deficient rats have exaggerated pulmonary vasoconstriction to acute hypoxia. This finding suggests that the ET-B receptor plays a significant role in modulating the pressor response to acute hypoxia, and may predispose this strain to the development of severe pulmonary hypertension.

Table 1 No caption available
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