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 permeability in normal dog lungs but not after pacing-induced heart failure. This study investigated how ANG II induces permeability in isolated blood-perfused canine lung lobes and what alterations occur during heart failure. In normal lobes, the protein kinase C (PKC) inhibitors staurosporine (500 nM) or chelerythrine (10 microM) did not modify ANG II-induced increases in the capillary filtration coefficient (Kf,c, ml . min-1 . cmH2O-1 . 100 g-1; an index of microvascular permeability), suggesting that PKC is not involved. Thapsigargin (150 nM) was used to stimulate capacitative Ca2+ entry in lobes from control dogs and dogs paced at 245 beats/min for 4 wk to induce heart failure. In control lobes, Kf,c rose after thapsigargin, from 0.06 +/- 0.01 to 0.17 +/- 0.03 ml . min-1 . cmH2O-1 . 100 g-1 (mean +/- SE, P < 0.05) but did not change in the paced group. A Ca2+ ionophore, A-23187, increased Kf,c in both control (10 microM; 0.05 +/- 0.01 to 0.17 +/- 0.05 ml . min-1 . cmH2O-1 . 100 g-1, P < 0.05) and pace (5 microM; 0.06 +/- 0.01 to 0. 21 +/- 0.07 ml . min-1 . cmH2O-1 . 100 g-1, P < 0.05) lobes, indicating that increasing intracellular Ca2+ is sufficient to induce pulmonary microvascular permeability after pacing. We conclude that during heart failure, Ca2+ signaling within the pulmonary microvascular endothelium is altered.
Ivey
C L
CL
Department of Physiology, University of South Alabama, Mobile, Alabama 36688, USA.
Roy
B J
BJ
Townsley
M I
MI
D000470:Alkaloids; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D053119:Benzophenanthridines; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D002303:Cardiac Output, Low / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
D000470:Alkaloids; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007476:Ionophores; D010617:Phenanthridines; D000804:Angiotensin II; D000001:Calcimycin; D019284:Thapsigargin; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine; D002118:Calcium