Journal of Applied Physiology, Vol 65, Issue 5 2138-2143, Copyright © 1988 by American Physiological Society
Verapamil attenuates lung vascular responses to endotoxin in sheep
R. E. Parker, J. R. Hardin and K. L. Brigham
Pulmonary Circulation Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Experiments were conducted on five chronically instrumented unanesthetized
sheep to determine the effects of verapamil, a calcium channel inhibitor,
on the pulmonary hemodynamic and microvascular permeability responses to
endotoxemia. Paired control endotoxemia experiments (E) and endotoxemia
with verapamil treatment (30-60 micrograms.kg-1.min-1) experiments (V + E)
were conducted on each sheep in random order. In the V + E experiments
sheep were pretreated with a continuous intravenous infusion of verapamil
1.5-2.0 h before endotoxin infusion (1.0 microgram/kg, given over 15 min).
Verapamil significantly increased base-line pulmonary arterial pressure,
left atrial pressure, lung lymph flow rate, and circulating blood leukocyte
levels and significantly decreased base-line cardiac output. During the
endotoxin response, verapamil significantly attenuated both phase I
pulmonary arterial hypertension and phase II lung lymph flow rate compared
with control endotoxin experiments. The results indicate that verapamil
attenuates both the pulmonary hemodynamic and increased lung microvascular
permeability response to endotoxin in sheep. In a series of in vitro
experiments, verapamil was found to be a potent inhibitor of phorbol
myristate acetate-induced superoxide production in isolated sheep
granulocytes. These data suggest that the beneficial in vivo effects of
verapamil during endotoxemia may in part be due to its inhibition of
increased free cytosol calcium concentration and/or inhibition of toxic O2
metabolite production.
