Lung mechanics and pulmonary but not systemic vascular responses to ET-1 are Tx and infusion rate dependent

The role of cyclooxygenase metabolites formation in the systemic and pulmonary vascular and airway responses to different intravenous infusion rates of endothelin-1 (ET-1) was investigated in eight barbiturate-anesthetized mechanically ventilated adult sheep. ET-1 (20, 200, and 400 pmol/kg) was infused into the femoral vein over either 1, 10, or 180 s before and after pretreatment with indomethacin (1.5 mg/kg iv). ET-1 infusion produced a dose-dependent systemic vasoconstriction that was similar with all three infusion rates. In contrast, the pulmonary vascular and airways responses to ET-1 were not only dose dependent but also infusion rate dependent so that consistent effects on the pulmonary vasculature and airways were observed only when the peptide was injected over 1 s. At the highest dosage and at the fastest rate of administration, ET-1 produced a fivefold rise in pulmonary vascular resistance, a twofold rise in airway resistance, and a 45% decrease in dynamic pulmonary compliance, whereas no changes were observed when the peptide was injected over 180 s. Plasma levels of 6-ketoprostaglandin F-1 alpha (6-keto-PGF(1 alpha)) increased 20-fold when ET-1 was administered over 1 s but only 5-fold when it was administered over 180 s. Thromboxane B-2 (TxB(2)) increased 6-fold when ET-1 was administered over 1 s and did not increase when ET-1 was given over 180 s. Plasma TxB(2) levels were linearly correlated with pulmonary vascular or airway resistance during the bolus ET-1 infusion. Pretreatment with indomethacin completely prevented the ET-1-induced rise in TxB(2) and 6-keto-PGF(1 alpha), and blocked pulmonary vaso- and bronchoconstriction observed, whereas it enhanced systemic vasoconstriction. These results demonstrate that in adult sheep intravenous ET-1 produces pulmonary vaso and bronchoconstriction that is infusion rate dependent and is associated with the rate-dependent production of thromboxane. In contrast, the increase in systemic vascular tone elicited by ET-1 is not affected by its rate of infusion and does not depend on the secondary generation of cyclooxygenase metabolites.