Angiotensin blockade reverses hypertension during long-term nitric oxide synthase inhibition.
Blockade of the renin-angiotensin system was studied in male Sprague-Dawley rats during long-term inhibition of nitric oxide synthase. Nitro-L-arginine-methyl ester (L-NAME) was placed in the drinking water for 4 weeks (approximately 100 mg/kg per day). Separate groups of rats were coadministered the angiotensin II antagonist A-81988 in the drinking water ranging from approximately 0.001 to 1 mg/kg per day. Control groups received only tap water or A-81988 alone. Each week, rats were placed in metabolic cages, and tail-cuff blood pressures and blood samples were taken. L-NAME produced a sustained elevation in tail-cuff pressure that was completely prevented by A-81988. No changes in creatinine clearance, sodium excretion, plasma creatinine concentration, or blood urea nitrogen were observed. Food and water intakes were identical in all groups. Water excretion was significantly increased in L-NAME-treated animals regardless of additional inhibitor treatment, suggesting a possible role for nitric oxide synthase in the control of water excretion; this effect was independent of blood pressure. Although less potent than A-81988, the angiotensin II antagonist losartan and the angiotensin converting enzyme inhibitor enalapril also blocked L-NAME-induced hypertension. In a separate series of experiments, rats were not given A-81988 until 2 weeks after hypertension had fully developed in L-NAME-treated rats. Within 1 week of treatment with the angiotensin II antagonist, tail-cuff pressure returned to normal. We conclude from these studies that long-term inhibition of endogenous nitric oxide production produces an angiotensin II-dependent form of hypertension.
Pollock
D M
DM
Abbott Laboratories, Abbott Park, IL 60064.
Polakowski
J S
JS
Divish
B J
BJ
Opgenorth
T J
TJ
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009539:Nicotinic Acids; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D011507:Proteinuria / Q000652:urine; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors
D009539:Nicotinic Acids; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C081174:A 81988; D019335:Nitroarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D012083:Renin