CAPILLARY HYDRAULIC CONDUCTIVITY IS DECREASED BY NITRIC-OXIDE SYNTHASE INHIBITION

Nitric oxide (NO) has been reported to modulate microvascular permeability to solutes in whole organs, venules, and cultured endothelial cell monolayers. NO derived from L-arginine via NO synthase activates soluble guanylate cyclase in vascular smooth muscle and endothelial cells. While the effects of NO on capillary water permeability have not been characterized, other activators of guanylate cyclase, such as sodium nitroprusside and atrial natriuretic peptide, increase capillary hydraulic conductivity (L(p)). We hypothesized that inhibition of NO synthase with the arginine analogue, N-G-monomethyl-L-arginine (L-NMMA), would decrease L(p) from control levels. L(p) was assessed in situ in single perfused frog mesenteric capillaries, first during control conditions (L(p)(control)) and then during superfusion (L(p)(test)) with either L-NMMA, N-G-monomethyl-D-arginine D-NMMA), a biologically inert enantiomer, or L-NMMA and L-arginine. Superfusion with 1 mu M L-NMMA caused a decrease in L(p) (L(p)(test)/L(p)(control) = 0.6 +/- 0.1, P < 0.001), whereas 1 mu M D-NMMA was without effect on L(p) (L(p)(test)/L(p)(control) = 1.0 +/- 0.2). The decrease in L(p) by 1 mu M L-NMMA was not only prevented by the presence of excess L-arginine (100 mu M), but L(p) increased from control (L(p)(test)/L(p)(control) = 1.4 +/- 0.2, P < 0.05). Furthermore, superfusion orf L-arginine (100 mu M) caused an increase in capillary L(p) (L(p)(test)/L(p)(control) = 2.4 +/- 0.9, P < 0.05), whereas D-arginine had no effect on L(p) (L(p)(test)/L(p)(control) = 1.2 +/- 0.3). The results of this study support our hypothesis that inhibition of NO synthase decreases capillary L(p) in the intact circulation. In addition, L-arginine increases capillary L(p) in our model. These results support a role for NO in the modulation of capillary permeability.