ETA receptor blockade attenuates hypertension and decreases reactive oxygen species in ETB receptor-deficient rats.
We hypothesize that endothelin-A receptor stimulation contributes to the elevated blood pressure and superoxide production in endothelin-B receptor-deficient rats on a high salt diet. Experiments were conducted on homozygous endothelin-B-deficient (sl/sl) and wild-type rats (wt) fed a high salt diet (8% NaCl) for 3 weeks. Separate groups were given normal drinking water or water containing the endothelin-A receptor antagonist, ABT-627 (5 mg/kg per day; n = 8-9 in all groups). On a normal salt diet, (sl/sl) rats had a significantly elevated systolic blood pressure compared with wt (138 +/- 3 vs 117 +/- 4 mmHg, respectively; P < 0.05). High salt diet caused a significant increase in systolic blood pressure in (sl/sl) rats compared with wt (158 +/- 2 vs 138 +/- 3 mmHg, respectively; P < 0.05). Endothelin-A receptor blockade decreased systolic blood pressure in (sl/sl) rats on high salt (125 +/- 5 mmHg; P < 0.05 vs without antagonist) without affecting the systolic blood pressure in wt (119 +/- 4 mmHg). Aortic superoxide production (lucigenin chemiluminescence) and plasma 8-isoprostane were elevated in sl/sl rats and were significantly reduced by endothelin-A receptor blockade in sl/sl, but not in wt rats. These findings suggest that endothelin-1, through the endothelin-A receptor, contributes to salt-induced hypertension and vascular superoxide production in endothelin-B-deficient rats.
Elmarakby
Ahmed A
AA
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912-2500, USA.
Dabbs Loomis
E
E
Pollock
Jennifer S
JS
Pollock
David M
DM
D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000652:urine; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017673:Sodium Chloride, Dietary; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D016232:Endothelins; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017673:Sodium Chloride, Dietary; D013481:Superoxides; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D000077868:Atrasentan