Role of endothelin and isoprostanes in slow pressor responses to angiotensin II.
We tested the hypothesis that angiotensin II (Ang II)-induced stimulations of endothelin (ET) and isoprostanes are implicated in the slow pressor responses to Ang II. We infused either vehicle (group 1) or Ang II (groups 2 to 4) intravenously at 5 ng/kg per minute via osmotic pumps for 15 days into Sprague-Dawley rats. Groups 3 and 4 received 30 mg/kg per day of either losartan (Ang II type 1 receptor blocker) or bosentan (ET(A) and ET(B) receptor blocker) in their drinking water. We measured systolic blood pressure (SBP) every 3 days during the infusion. Plasma levels of Ang II, ET, isoprostanes, and urinary nitrites were determined at 15 days. Vehicle infusion did not change SBP (from 138+/-13 to 136+/-2 mm Hg at day 15). Circulating Ang II, ET, and isoprostane levels were 35+/-9, 39+/-3, and 111+/-10 pg/mL, respectively, whereas urinary nitrites were 2.3+/-0.4 microgram/d. Ang II increased SBP (from 133+/-10 to 158+/-8 mm Hg), plasma Ang II (179+/-77 pg/mL), and isoprostanes (156+/-19 pg/mL) without altering ET levels (38+/-5 pg/mL) or urinary nitrites (1.8+/-0.5 microgram/d). Losartan prevented Ang II-induced increases in SBP and isoprostanes (SBP went from 137+/-5 to 120+/-4 mm Hg; isoprostanes were 115+/-15 pg/mL) while increasing urinary nitrite levels (5.2+/-1.1 microgram/d). Losartan did not alter Ang II (141+/-57 pg/mL) or ET (40+/-4 pg/mL) levels. Bosentan also blocked Ang II-induced hypertension (from 135+/-4 to 139+/-3 mm Hg) but did not decrease isoprostanes (146+/-14 pg/mL). Ang II (63+/-11 pg/mL), ET levels (46+/-2 pg/mL), and urinary nitrites (2.8+/-0.4 microgram/d) were not altered. In conclusion, our results suggest that low-dose Ang II increases isoprostanes via its Ang II type 1 receptor and causes an ET-dependent hypertension, without altering circulating ET levels.
Department of Physiology and Biophysics and Division of Nephrology, Mayo School of Medicine and Mayo Clinic, Rochester, Minnesota, USA.
M C
MC
Ortiz
E
E
Sanabria
M C
MC
Manriquez
J C
JC
Romero
L A
LA
Juncos
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D005919:Glomerular Filtration Rate; D007262:Infusions, Intravenous; D019808:Losartan / Q000494:pharmacology; D009573:Nitrites / Q000097:blood / Q000652:urine; D011453:Prostaglandins / Q000097:blood / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D016232:Endothelins; D009573:Nitrites; D011453:Prostaglandins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D000804:Angiotensin II; D019808:Losartan; D000077300:Bosentan