ABLATION OF LUNG ENDOTHELIAL INJURY AFTER PACING-INDUCED HEART-FAILURE IS RELATED TO ALTERATIONS IN CA2+ SIGNALING

We have previously shown that ANG II increases microvascular permeabil ity in normal dog lungs but not after pacing-induced heart failure. Th is study investigated how ANG II induces permeability in isolated bloo d-perfused canine lung lobes and what alterations occur during heart f ailure. In normal lobes, the protein kinase C (PKC) inhibitors stauros porine (500 nM) or chelerythrine (10 mu M) did not modify ANG II-induc ed increases in the capillary filtration coefficient (K-f,K-c, ml.min( -1).cmH(2)O(-1).100 g(-1); an index of microvascular permeability), su ggesting that PKC is not involved. Thapsigargin (150 nM) was used to s timulate capacitative Ca2+ entry in lobes from control dogs and dogs p aced at 245 beats/min for 4 wk to induce heart failure. In control lob es, K-f,K-c rose after thapsigargin, from 0.06 +/- 0.01 to 0.17 +/- 0. 03 ml.min(-1).cmH(2)O(-1).100 g(-1) (mean +/- SE, P < 0.05) but did no t change in the paced group. A Ca2+ ionophore, A-23187, increased K-f, K-c in both control (10 mu M; 0.05 +/- 0.01 to 0.17 +/- 0.05 ml.min-1. cmH(2)O(-1).100 g(-1), P < 0.05) and pace (5 mu M; 0.06 +/- 0.01 to 0. 21 +/- 0.07 ml.min(-1).cmH(2)O(-1).100 g(-1), P < 0.05) lobes, indicat ing that increasing intracellular Ca2+ is sufficient to induce pulmona ry microvascular permeability after pacing. We conclude that during he art failure, Ca2+ signaling within the pulmonary microvascular endothe lium is altered.