A role for endothelin ETA receptors in regulation of renal function in spontaneously hypertensive rats.
While there is evidence to suggest that endothelin-1 is involved in regulation of kidney function and blood pressure, the importance of endothelin ETA receptors in this area has not been clearly defined. The novel, non-peptide endothelin ETA receptor antagonist, BMS-182874, (5-(dimethylamino)-N-(3,4- dimethyl-5-isoxazolyl)-1-naphthalene sulfonamide) was used to examine effects of endothelin ETA receptor blockade on renal function in spontaneously hypertensive rats. Preliminary studies were conducted to determine an effective dose of BMS-182874. Infusion of BMS-182874 (10 mumol/kg/min, i.v.) inhibited effects of exogenous endothelin-1 on glomerular filtration rate, renal blood flow, and mean arterial pressure in Sprague-Dawley rats. Administration of BMS-182874 (10 mumol/kg/min, i.v.) to anesthetized, male, spontaneously hypertensive rats decreased renal blood flow by approximately 50% (1.2 +/- 0.11 ml/min/100 g body weight) compared to vehicle (2.7 +/- 0.23). There was no effect of BMS-182874 on glomerular filtration rate (0.5 +/- 0.05 ml/min/100 g body weight; vehicle: 0.7 +/- 0.06). Mean arterial pressure decreased significantly after BMS-182874 (123 +/- 3.8 mm Hg; vehicle: 162 +/- 4.8). Urine flow and renal vascular resistance were unchanged by BMS-182874. Endothelin ETA receptor density was increased approximately 50% in spontaneously hypertensive rat kidneys compared to normotensive kidneys, with no change in equilibrium dissociation constant. Endothelin ETB receptor density and equilibrium dissociation constant were similar in the two rat strains. Plasma immunoreactive endothelin was higher in hypertensive (5.9 +/- 0.31 fmol/ml) than normotensive rats (2.8 +/- 0.15). The results suggest endothelin ETA receptors may play a role in the regulation of renal function in this model of hypertension.
Bird
J E
JE
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Webb
M L
ML
Giancarli
M R
MR
Chao
C
C
Dorso
C R
CR
Asaad
M M
MM
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003619:Dansyl Compounds / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007700:Kinetics; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects
D000959:Antihypertensive Agents; D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide