EFFECT OF FLUORIDE ON CARDIOPULMONARY FUNCTION AND RELEASE OF EICOSANOIDS IN PIGS

Fluoroaluminates are believed to stimulate guanine nucleotide-binding (G) proteins, leading to activation of effector enzymes and release of vasoactive mediators. As a model for G protein-induced cardiopulmonary dysfunction, we infused NaF (0.9 M in 0.9% NaCl at 15 mu l.kg(-1).min(-1) for 3 h iv) in the presence (n = 8) and absence (n = 4) of AlCl3 (0.6 mu g.kg(-1).min(-1)) into pigs anesthetized with pentobarbital sodium. NaF, with or without AlCl3, induced progressive deterioration of cardiopulmonary function after 1 h of infusion. At 3 h, mean pulmonary arterial pressure, pulmonary vascular resistance (PVR), tracheal pressure, and plasma concentrations of thromboxane B-2 (TxB(2)), 6-ketoprostaglandin F-1 alpha, and prostaglandin F-2, were significantly (P < 0.05) increased to similar to 200, 520, 175, 759, 402, and 336%, respectively, of baseline values (0 h). At 3 h, cardiac index and arterial Pot decreased 38% and 28 Torr, respectively, from baseline values. Although indomethacin blocked the NaF-induced increase in plasma TxB(2) concentration, the cyclooxygenase inhibitor did not modify any cardiopulmonary parameter measured or calculated, except for a transient reduction in PVR at 2.5 h. In porcine whole blood treated with AlF4- (30 mM NaF + 10 mu M AlCl3) in vitro for 0.5 h, TxB(2) concentration increased to 649% of the control value. In porcine alveolar macrophages labeled with [H-3]arachidonic acid, AlF4- (30 mM NaF + 10 mu M AlCl3) induced release of radioactivity to 165, 539, and 573% of control values after 0.5, 1, and 2 h of incubation, respectively. These results indicate that NaF activates G proteins and phospholipase A(2) in vivo and in vitro, leading to release of eicosanoids; however, the cardiopulmonary dysfunction was largely independent of cyclooxygenase products.