Positive end-expiratory pressure-induced, calcium-channel-mediated increases in pulmonary vascular resistance in neonatal lambs

Abstract

a) To study the dose response of the calcium-channel-mediated increases in pulmonary vascular resistance with different levels of positive end-expiratory pressure; b) to study the reversibility of the calcium-channel mediated increases in pulmonary vascular resistance after discontinuation of positive end-expiratory pressure; and c) to study the effect of cyclooxygenase and lipoxygenase inhibition on the calcium-channel mediated increases in pulmonary vascular resistance. A prospective, multiexperimental, dose response study. Laboratory setting in a university hospital. Twenty-three 4- to 10-day-old neonatal lambs. Lungs of neonatal lambs were isolated in situ, and perfused at a constant flow rate, and ventilated at a fixed tidal volume and rate. Mean pulmonary arterial pressure responses to the application and discontinuation of four levels (3.7, 7.4, 11, and 14.7 mm Hg) of positive end-expiratory pressure were studied before and after calcium-channel blockade with verapamil (5 mg) (n = 12). In addition, the mean pulmonary arterial pressure response to 11 mm Hg of positive end-expiratory pressure was studied before and after inhibition of cyclooxygenase with indomethacin (10 mg/kg) (n = 6) and lipoxygenase with diethylcarbamazine (100 mg/kg) (n = 5). The magnitude of the calcium-channel-dependent mean pulmonary arterial pressure response 4 mins after the application of positive end-expiratory pressure was dose related (2.1, 3.0, 4.1, and 5.5 mm Hg with 3.7, 7.4, 11.0, and 14.7 mmHg positive end-expiratory pressure, respectively) and entirely reversible on discontinuation of positive end-expiratory pressure with a time course of 2 to 4 mins. Neither indomethacin nor diethylcarbamazine affected the pulmonary arterial pressure responses to positive end-expiratory pressure. Airway pressure changes with positive end-expiratory pressure were not affected by verapamil, indomethacin, or diethylcarbamazine. The calcium-channel-mediated pulmonary arterial pressure responses with positive end-expiratory pressure, applied during continuous positive pressure breathing, occur even at low levels of positive end-expiratory pressure, are dose dependent, and are not abolished by treatment with indomethacin or diethylcarbamazine.