CORONARY VASCULAR HYPERPERMEABILITY AND ANGIOTENSIN-II

Elevations in plasma angiotensin II (AngII) are associated with eviden ce of vascular hyperpermeability expressed as efflux of plasma macromo lecules into the perivascular and interstitial space. This exudative r esponse is followed by a series of fibrogenic events that lead to a pe rivascular fibrosis of involved vessels, Mediators of hyperpermeabilit y and fibrogenesis are unknown, In dogs receiving intravenous AngII, h emodynamic factors (i.e., arterial hypertension or coronary venoconstr iction) were discounted as being responsible for the rise in cardiac l ymph-to-plasma protein ratio. Accordingly, we investigated the relatio nship between AngII-induced coronary hyperpermeability and the release of prostaglandin E(2) (PGE(2)) and activation of the basement membran e degrading matrix metalloproteinase, gelatinase/type IV collagenase, In dogs, cardiac lymph was monitored over the course of a 90-minute in travenous infusion of either AngII (0.2 to 0.3 mu g/kg/min; n = 8) or saline solution (n = 6): Lymph was examined at 30-minute intervals for the following: total protein (Lowry's method), albumin (sodium dodecy l sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)), plasma fibro nectin (SDS-PAGE and enzyme-linked immunosorbent assay); PGE(2) (radio immunoassay) and gelatinase/type IV collagenase (zymography). In compa rison with baseline we found a consistent rise in lymph flow (p = 0.02 ), total protein (p = 0.02), albumin, fibronectin, PGE(2) (p = 0.03), and gelatinase/type IV collagenase (p = 0.019), which began after 30 m inutes of AngII infusion. Similar trends were not observed in dogs rec eiving saline solution alone. We therefore conclude that AngII-induced coronary vascular hyperpermeability is associated with an early relea se of PGE(2) and gelatinase.