ETA receptor-mediated responses to endothelin-1 and big endothelin-1 in the rat kidney.
1. Renal clearance experiments were conducted in anaesthetized Sprague-Dawley rats to determine the effect of the ETA receptor antagonist, BQ-123, on the renal haemodynamic response to endothelin-1 (ET-1) and its precursor, big endothelin-1 (big ET-1) at doses that produce an equivalent degree of renal vasoconstriction. 2. Infusion of either big ET-1 at 100 pmol kg-1 min-1 or ET-1 at 12 pmol kg-1 min-1 for 60 min produced almost identical decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Big ET-1 produced an increase in mean arterial pressure (MAP) that was significantly larger than the increase produced by ET-1. 3. Co-infusion with BQ-123 (0.1 mg kg-1 min-1) prevented the rise in MAP produced by big ET-1 and completely blocked the renal response. Similarly, BQ-123 inhibited both the increase in MAP and the decrease in RPF and GFR produced by ET-1. 4. Big ET-1 but not ET-1, produced a significant increase in water and sodium excretion. BQ-123 had no effect on the diuretic and natriuretic response to big ET-1 consistent with possible ETB-mediated inhibition of tubular reabsorption. 5. We have previously shown that at higher doses of ET-1, BQ-123 was unable to inhibit the renal vasoconstrictor response despite blockade of the pressor response. Taken together, these results indicate that ET-1 activates primarily ETA receptors at moderately low doses to produce renal vasoconstriction while higher doses also involve non-ETA receptors. 6. Since ET-l has a similar binding affinity for both ETA and ETB receptors, we suggest that there maybe a third type of ET-1 receptor in the rat kidney with lower affinity for ET-1 that is coupled to a vasoconstrictor mechanism.
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, IL 60064.
D M
DM
Pollock
T J
TJ
Opgenorth
D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000648:ultrastructure*; D008297:Male; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects; D012964:Sodium / Q000652:urine; D014655:Vascular Resistance / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D011498:Protein Precursors; D017466:Receptors, Endothelin; D012964:Sodium; C072247:cyclo(Trp-Asp-Pro-Val-Leu)