Enhancement by endothelin-1 of microvascular permeability via the activation of ETA receptors.
1. The objective of the present experiments was to assess the involvement of endothelin-A (ETA) receptors in mediating the effects of endothelin-1 on microvascular permeability in conscious rats. 2. Bolus injection of endothelin-1 (0.1 and 1 nmol kg-1, i.v.) resulted in a dose-dependent prolonged pressor effect preceded by a transient depressor response. These changes were accompanied by a dose-dependent loss of plasma volume. Endothelin-1 (1 nmol kg-1) enhanced the vascular permeability of the upper and lower bronchi, kidney, stomach, duodenum and spleen (up to 270%) as measured by the extravasation of Evans blue dye. 3. Pretreatment of the animals with the selective ETA receptor antagonist, BQ-123 (1 mg kg-1, i.v.) significantly blunted the pressor response to endothelin-1 without affecting the depressor response. BQ-123 inhibited by 87% the endothelin-1 (1 nmol kg-1)-induced plasma volume loss. BQ-123 markedly attenuated protein extravasation elicited by endothelin-1 in the upper and lower bronchi and kidney, whereas it completely inhibited the permeability effect of endothelin-1 in the stomach and duodenum. BQ-123 by itself had no significant effect on the parameters studied. 4. The endothelin-1 analogue, [Trp(For)21]-endothelin-1, in which Trp21 is formylated, was as potent a pressor agent as endothelin-1, but had no depressor action. Bolus injection of [Trp(For)21]-endothelin-1 (0.1 and 1 nmol kg-1, i.v.) evoked similar plasma volume losses to those observed following administration of equimolar doses of endothelin-1. Furthermore, 1 nmol kg-1 [Trp(For)21]-endothelin-l evoked increases in protein extravasation similar to endothelin-l, 1 nmol kg-1.5. The present findings suggest that endothelin- 1 enhances microvascular permeability, in part, via the activation of ETA receptors.
Filep
J G
JG
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, P.Q., Canada.
Sirois
M G
MG
Földes-Filep
E
E
Rousseau
A
A
Plante
G E
GE
Fournier
A
A
Yano
M
M
Sirois
P
P
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D019332:Endothelin-1 / Q000031:analogs & derivatives; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005070:Evans Blue; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology; D010953:Plasma Volume / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects
D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C082875:endothelin-1, formylTrp(21)-; D005070:Evans Blue; C072247:cyclo(Trp-Asp-Pro-Val-Leu)