Effects of endothelin‐1 on vascular permeability in the conscious rat: interactions with platelet‐activating factor

Abstract

The objectives of the present experiments were to assess the effects of endothelin‐1 on the macrovascular permeability in selected vascular beds, to study the involvement of platelet‐activating factor (PAF) in vascular responses to endothelin‐1 and to examine the vascular effects of combined administration of endothelin‐1 and PAF in conscious rats. Intravenous bolus injection of endothelin‐1 (0.1–2 nmol kg−1) resulted in a dose‐dependent biphasic change in mean arterial blood pressure (MABP) with initial transient hypotension followed by a prolonged pressor action. These changes were accompanied by a dose‐dependent increase in haematocrit values. Endothelin‐1 (0.1 and 1 nmol kg−1) increased dose‐dependently the vascular permeability of the trachea, upper and lower bronchi, stomach, duodenum, spleen and kidney (up to 240%) as measured by the extravasation of Evans blue dye. The permeability of pulmonary parenchyma, liver and pancreas was not affected significantly by endothelin‐1 treatment. Pretreatment of animals with the specific PAF receptor antagonist, WEB 2086 (1 mg kg−1, i.v.) or BN 52021 (10 mg kg−1, i.v.) reduced the endothelin‐1 (1 nmol kg−1)‐induced rise in haematocrit by about 50 and 30%, respectively. Both antagonists were highly effective at inhibiting protein extravasation in the stomach, duodenum and kidney. On the other hand, BN 52021, but not WEB 2086, significantly attenuated the effect of endothelin‐1 on permeability in the lower bronchi and spleen. Neither WEB 2086 nor BN 52021 modified the changes in MABP evoked by endothelin‐1. When low doses of endothelin‐1 (0.1 nmol kg−1) and PAF (0.19 nmol kg−1) were administered simultaneously, enhanced protein extravasation was detected in the upper and lower bronchi, whereas neither endothelin‐1 nor PAF by themselves affected vascular permeability in these tissues. These changes occurred in the absence of significant changes in MABP. Combined administration of higher doses of endothelin‐1 (1 nmol kg−1) and PAF (1.9 nmol kg−1) resulted in marked increases (up to 530%) in protein extravasation in the airways, pancreas, stomach and duodenum. The effect of endothelin‐1 on permeability was not affected by PAF in the spleen, whereas it was completely inhibited by PAF in the kidney. Combined injection of endothelin‐1 and PAF resulted in a slight, but significant increase in MABP. The present findings show that endothelin‐1 is capable of increasing vascular permeability in selected vascular beds including the airways, gastrointestinal tract and kidney, and suggest that PAF may mediate, in part, its action on permeability, but not its hypotensive action. The present data also suggest that endothelin‐1 and PAF can act in concert to increase vascular permeability in rat airways and gastrointestinal tract.

Loss of Mouse P2Y4 Nucleotide Receptor Protects against Myocardial Infarction through Endothelin-1 Downregulation

“…These data suggest an attenuated remodeling in P2Y 4 -null mice that is compatible with the reduction of inflammation, permeability, and fibrosis observed in these mice. ET-1 can also enhance vascular permeability in selected rat vascular beds, including the pulmonary, renal, and mesenteric circulation (37). It appeared that LPS-induced cardiac microvascular hyperpermeability, measured after Evan's blue injection, was reduced in P2Y 4 -null mice compared with wild-type mice.…”

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats

“…Thus, in non-diabetic rats ET causes increased vascular permeability [61], which is greatly exacerbated when NO synthase activity is also blocked [62]. Many treatments that normalise NCV in diabetic rats also improve blood flow, which would reduce nerve hypoxia and, therefore, minimise at least one potential stimulus for local ET production.…”

Acute pro‐inflammatory actions of endothelin‐1 in the guinea‐pig lung: involvement of ETA and ETB receptors

“…Albumin extravasation was estimated by measuring tissue accumulation of Evans blue dye, which binds to plasma albumin (Rawson, 1943) as described previously (Filep et al, 1991). In brief, Evans blue dye (20mg kg-', 25mg ml-' in 0.9% NaCl) was injected i.v.…”