ANGIOTENSIN-II-INDUCED INCREASE IN TRANSCORONARY PROTEIN CLEARANCE - ROLE OF HYPERTENSION VS NITRIC-OXIDE OR CYCLOOXYGENASE PRODUCTS

Elevations in plasma angiotensin II (AngII) are associated with an eff lux of plasma macromolecules into the perivascular and contiguous inte rstitial space. Whether this exudative response is related to associat ed hypertension or another effect of AngII is uncertain. We therefore monitored plasma and cardiac lymph total protein, albumin and fibronec tin and calculated transvascular clearances for total protein (TVPC) a nd albumin (TVAC) and lymph fibronectin transport (LFT) every 30 min i n open-chested, instrumented dogs. After baseline observations were ob tained over 30 min, presser (250 ng . kg . min(-1)) or nonpressor (11 ng . kg . min(-1)) doses of AngII were given intravenously for 90 min. Saline-treated, instrumented dogs served as controls. To address a po tential. secondary effect of AngII on vascular protein clearance, we m onitored lymph prostaglandin E(2) and cGMP (a marker of released nitri c oxide, NO). At greater than or equal to 30 min, each dose of AngII w as associated with a significant (P less than or equal to 0.05) and co mparable increase in TVPC, TVAC and LFT over baseline, indicating that increase in protein clearance was not related to elevated arterial pr essure. Lymph cGMP rose significantly (P I 0.05) at 30 min for each do se of AngII and remained elevated thereafter. Lymph PGE(2) was increas ed at greater than or equal to 60 min (P less than or equal to 0.05) b ut only with the presser dose. To determine the contribution of NO and PGE(2) on AngII-induced transcoronary protein clearance, each dose of AngII was accompanied by co-administration of either the NO synthase inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME), or the cyclo-ox ygenase inhibitor, indomethacin. L-NAME completely inhibited the relea se of cGMP and the increase in protein clearance was not seen. Indomet hacin suppressed the release of PGE,, but did not prevent the increase in protein clearance. Thus, AngII-induced increase in transcoronary p rotein clearance is not related to arterial hypertension or the releas e of PGE(2), but instead appears to be mediated by NO release.