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 (Pa(O2)), leukocyte (WBC) count, arterial thromboxane B2 (TxB2), prostaglandin (PG) F(2α), and 6-ketoprostaglandin F(1α) (6-keto-PGF(1α)) concentrations were obtained before and at predetermined intervals after a 10-min infusion of Escherichia coli endotoxin (0.3 μg/kg). On separate occasions, the sheep received a bolus injection of verapamil (150 μg/kg) before endotoxin, followed by a continuous infusion of verapamil [10 μg·kg-1·min-1 (n=5) or 20 μg·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 < 0.05). SVR also showed biphasic increases of 44 and 42% during phase I and II, respectively. Mean Pa(O2) decreased by 16 Torr and WBC count decreased from 6.4 ± 1.5 to 3.3 ± 1.1 thousand/mm3, associated with marker increase in plasma TxB2, PGF(2α), and 6-keto-PGF(1α). Verapamil at the lower dose had no significant effect on endotoxin-induced changes in PVR, WBC, TxB2, PGF(2α), and 6-keto-PGF(1α), whereas changes in RL and Pa(O2) were blunted. The higher dose of verapamil completely blocked the endotoxin-induced increases in PVR and RL during both phases and also attenuated the changes in Pa(O2), WBC count, TxB2, PGF(2α) and 6-keto-PGF(1α). Both doses of verapamil attenuated the biphasic increase of SVR. These data suggest that the calcium antagonist verapamil attenuates endotoxin-induced changes in pulmonary hemodynamics, airway mechanics, blunt leukopenia, and generation of cyclooxygenase metabolites.
ASJC Scopus subject areas
- Physiology (medical)