Enhancement of hypertension and renal injury by salt-loading during chronic nitric oxide inhibition. Effects of TCV-116, a novel angiotensin II receptor antagonist.
Endothelium-derived nitric oxide (EDNO) and angiotensin II play a role in the regulation of vascular tone and sodium handling. The objective of this study was to determine the role played by angiotensin II in mediating the arterial pressure and renal response to increments in sodium intake during chronic EDNO inhibition. Six groups of Wistar rats were studied; they were fed either a normal sodium diet (groups I, II, and III) or a high sodium diet (groups IV, V and VI). Rats in groups II, III, V and VI were placed on oral L-N-nitroarginine-methyl ester (L-NAME) for 4 weeks. In groups III and VI, the angiotensin II receptor antagonist, TCV-116, was administered. A significant increase in blood pressure was observed in group V compared with group II at the end of the experimental period. TCV-116 attenuated the L-NAME-induced hypertension in both group III and group VI. Urinary protein excretion and the glomerular sclerotic injury score in group V were greater than in group II. TCV-116 attenuated the proteinuria and glomerular injury induced by chronic EDNO inhibition in the groups with normal (group III) and high sodium intake (group IV). Systemic hypertension and glomerular injury were enhanced by salt loading during EDNO inhibition, and the angiotensin II receptor antagonist, TCV-116, attenuated this salt-induced increase in blood pressure and renal injury, suggesting that EDNO may counteract the renal effects of angiotensin II.
Okamura
M
M
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Konishi
Y
Y
Nishimura
M
M
Umetani
N
N
Iwai
J
J
Negoro
N
N
Inoue
T
T
Takeda
T
T
Kanayama
Y
Y
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000633:toxicity; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005069:Evaluation Studies as Topic; D006977:Hypertension, Renal / Q000139:chemically induced* / Q000188:drug therapy*; D007674:Kidney Diseases / Q000139:chemically induced; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012982:Sodium, Dietary / Q000008:administration & dosage* / Q000633:toxicity*; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D012982:Sodium, Dietary; D013777:Tetrazoles; D009569:Nitric Oxide; D001120:Arginine; C077793:candesartan cilexetil; D019331:NG-Nitroarginine Methyl Ester