Inhibition of nitric oxide synthesis increases venular permeability and alters endothelial actin cytoskeleton.
Inhibition of nitric oxide (NO) synthesis using NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) increases venular permeability in the rat mesentery (I. Kurose, R. Wolf, M. B. Grisham, T. Y. Aw, R. D. Specian, and D. N. Granger. Circ. Res. 76: 30-39, 1995), but the cellular mechanisms of this response are not known. This study was performed to determine whether such venular leaks are associated with changes in the endothelial actin cytoskeleton. In anesthetized Sprague-Dawley rats, the microvasculature of a mesenteric window was perfused with buffered saline, with or without 10(-5) M L-NAME, L-NMMA, or the inactive enantiomer NG-nitro-D-arginine methyl ester for 3 or 30 min. FITC-albumin was added to the perfusate for the last 3 min. The vasculature was perfusion fixed, stained for filamentous actin and for mast cells, and viewed microscopically. In control preparations, venules showed few FITC-albumin leaks and the endothelial actin cytoskeleton consisted of a peripheral rim along the cell-cell junctions. Preparations treated with L-NAME or L-NMMA showed significantly more leakage, the actin rims in leaky venules were discontinuous, and short, randomly oriented fibers appeared within the cells. In nonleaky venules, the peripheral actin rims sometimes contained small, equally spaced discontinuities not seen in control preparations. Although a mast cell stabilizer was used, 27-70% of the mast cells were degranulated in the presence of L-NMMA. Thus inhibition of NO synthesis alters the endothelial cytoskeleton and increases albumin leakage from mesenteric venules, either directly or indirectly via the involvement of mast cells.
Baldwin
A L
AL
Department of Physiology, College of Medicine, University of Arizona, Tucson 85724-5051, USA.
Thurston
G
G
al Naemi
H
H
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008643:Mesentery / Q000098:blood supply*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014699:Venules / Q000473:pathology* / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester