Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats.
1. Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats. 2. Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 mumol kg-1, for 20 min) induced a very small fall in blood pressure. Similarly, a non-selective ETA/ETB receptor antagonist, TAK-044 (12.5 mumol kg-1, for 20 min) slightly decreased blood pressure. A selective ETB receptor antagonist, BQ-788 (0.5 mumol kg-1, for 20 min) had no effect of blood pressure. 3. FR139317 and TAK-044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ-788 significantly reduced renal blood flow by 18.2 +/- 2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ-788 was not observed when combined with FR139317. 4. Pretreatment with a nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 37 mumol kg-1, i.v.) and a cyclo-oxygenase inhibitor ibuprofen (44 mumol kg-1, i.v.) completely abolished the BQ-788-mediated renal vasoconstriction. 5. These results indicate that activation of ETB receptors by endogenous ET acts as a physiological brake for the ETA-mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.
Matsuura
T
T
Department of Pharmacology, Osaka City University Medical School, Japan.
Miura
K
K
Ebara
T
T
Yukimura
T
T
Yamanaka
S
S
Kim
S
S
Iwao
H
H
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
D001381:Azepines; D016861:Cyclooxygenase Inhibitors; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D007211:Indoles; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C079574:FR 139317; C088196:TAK 044; D009569:Nitric Oxide; C086539:BQ 788; D019331:NG-Nitroarginine Methyl Ester; D007052:Ibuprofen