Effect of nitric oxide synthase inhibitors on basal microvessel permeability and endothelial cell [Ca2+]i.
We evaluated the role of basal nitric oxide (NO) release in the regulation of microvessel permeability under resting conditions. We measured changes in microvessel hydraulic conductivity (Lp) and endothelial cytoplasmic calcium concentration ([Ca2+]i) after application of NO synthase (NOS) inhibitors to the lumen of individually perfused frog mesenteric venular microvessels. NOS inhibitors caused a transient increase in Lp. The mean ratios of peak test Lp values relative to control values in the presence of N omega-nitro-L-arginine methyl ester (L-NAME) at concentrations of 1, 10, and 100 microM were 2.5 +/- 0.6, 2.9 +/- 0.7, and 4.8 +/- 0.4, respectively. N omega-monomethyl-L-arginine (L-NMMA) showed a similar effect and a biologically inactive isomer of L-NMMA, D-NMMA, showed no effect. These results demonstrate that basal levels of NO play a role in modulating microvessel permeability different from that due to NO produced in response to inflammatory agents. In the activated state NOS inhibitors attenuated the increased microvessel permeability in response to ionomycin and ATP [P. He, B. Liu, and F. E. Curry. Am. J. Physiol. 272 (Heart Circ. Physiol. 41): H176-H185, 1997]. The transient increase in basal permeability induced by NOS inhibitors was not accompanied by an increase in endothelial cell [Ca2+]i and did not require the presence of extracellular calcium. Application of ketotifen, a mast cell stabilizer, and an iron-chelating reagent, deferoxamine mesylate, attenuated the transient increase in Lp induced by L-NMMA, suggesting that basal NO may have an important antioxidant role in regulating normal permeability.
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Department of Human Physiology, School of Medicine, University of California, Davis 95616, USA.
Zeng
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Curry
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects*; D003676:Deferoxamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D007665:Ketotifen / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009994:Osmolar Concentration; D011894:Rana pipiens; D012680:Sensitivity and Specificity; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D003676:Deferoxamine; D002118:Calcium; D007665:Ketotifen