title: Nitric oxide synthase inhibition accelerates the pressor response to low-dose angiotensin II, exacerbates target organ damage, and induces renin escape.
abstract: Because nitric oxide may attenuate both the pressor and cytotoxic effects of angiotensin II (Ang II), we investigated whether nitric oxide synthase (NOS) inhibition might accelerate the slow pressor effect of Ang II, and augment target organ damage. Using conscious, chronically catheterized rats, we previously observed that low-dose Ang II (10 ng/kg/min) rapidly increased mean arterial pressure (MAP) by approximately 25 mm Hg. The MAP then remained at this level for 2 to 4 days, and then increased again during the next 5 days by a further 25 mm Hg to a second plateau. In the present study, 7 days of N(omega)-nitro-l-arginine methyl ester (L-NAME; 10 microg/kg/min) alone increased MAP by 16 mm Hg. When Ang II was added to L-NAME, MAP increased as much as with Ang II alone, but then continued to increase until day 4, reaching a plateau as high as that reached only on day 9 of Ang II alone. In approximately half the rats infused with L-NAME + Ang II, plasma renin escaped from Ang II-induced suppression after day 4 of Ang II, and continued to increase for the duration of the study. On the first day that Ang II was added to L-NAME, urinary protein excretion and plasma cardiac troponin T increased, indicating early target organ damage. By the end of the study, all rats treated with L-NAME + Ang II developed tubulointerstitial and glomerular injuries, fibrosis of the renal and cardiac arteries, and cardiac interstitial fibrosis. Target organ damage was greater in rats that developed renin escape than in those in which plasma renin remained suppressed, but was minimal in rats infused with Ang II or L-NAME alone. Taken together, these findings suggest that endogenous NO normally attenuates the pressor response to low-dose Ang II for several days, and protects from Ang II-induced target organ damage. Under conditions of reduced NO bioavailability, which may result from endothelial insufficiency, relatively small changes in circulating Ang II levels may damage target organs. Moreover, renal damage leading to renin escape may initiate a vicious cycle of elevated Ang II production, leading to higher blood pressure and greater target organ damage.
authors.affiliation: Cardiovascular Center, Department of Cardiothoracic Surgery, Weill Medical College, Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Lufei
authors.initials: L
authors.lastname: Hu
authors.forename: Jean E
authors.initials: JE
authors.lastname: Sealey
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Carmen
authors.initials: C
authors.lastname: Merali
authors.forename: Yuexian
authors.initials: Y
authors.lastname: Shi
authors.forename: John H
authors.initials: JH
authors.lastname: Laragh
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Catanzaro
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005355:Fibrosis; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D011507:Proteinuria / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood* / Q000187:drug effects*; D013997:Time Factors; D020107:Troponin T / Q000097:blood / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage*
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D020107:Troponin T; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D012083:Renin; D019331:NG-Nitroarginine Methyl Ester