Effect of verapamil on pulmonary and eicosanoid responses to endotoxin in awake sheep

Leukotrienes have been suggested to play a role in the endotoxin-induced changes of the pulmonary hemodynamics and airway mechanics. Since Ca2+ is necessary for contraction of airway and vascular smooth muscle as well as for activation of phospholipase A2 and 5-lipoxygenase enzymes, we wondered whether the calcium antagonist verapamil would modify the endotoxin-mediated pulmonary effects as well as the generation of circulating eicosanoids. In twelve conscious sheep, measurements of pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), lung resistance (RL), arterial PO2 (PaO2), leukocyte (WBC) count, arterial thromboxane B2 (TxB2), prostaglandin (PG) F2 alpha, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentrations were obtained before and at predetermined intervals after a 10-min infusion of Escherichia coli endotoxin (0.3 microgram/kg). On separate occasions, the sheep received a bolus injection of verapamil (150 micrograms/kg) before endotoxin, followed by a continuous infusion of verapamil [10 micrograms.kg-1.min-1 (n = 5) or 20 micrograms.kg-1.min-1 (n = 7)] for up to 4 h post-endotoxin. Endotoxin caused a biphasic response with an increase in mean PVR and RL to 326 and 276% of base line during phase I (0-1 h) and lesser increases to 177 and 157% of base line during phase II (1.5-4 h), respectively (P less than 0.05). SVR also showed biphasic increases of 44 and 42% during phase I and II, respectively. Mean PaO2 decreased by 16 Torr and WBC count decreased from 6.4 +/- 1.5 to 3.3 +/- 1.1 thousand/mm3, associated with marked increases in plasma TxB2, PGF2 alpha, and 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)