N-acetylcysteine inhibits angiotensin converting enzyme in vivo.
Nitrate tolerance has been explained by 1) a direct loss of pharmacological effect due to reduced bioconversion and 2) an indirect effect due to activation of the renin/angiotensin system and counter-regulatory vasoconstriction. The sulfhydryl compound N-acetylcysteine (NAC) has been shown to attenuate and partly counteract tolerance to nitrates, and this effect has been attributed to a nitrate/sulfhydryl interaction and increased production of vasoactive intermediates. The effect of NAC on counter-regulatory mechanisms is, however, unknown. This study examined whether NAC modulates the function of the renin/angiotensin system in normal rats and in nitrate-tolerant healthy volunteers. Animal study: Conscious rats received NAC (5 mmol/kg/hr i.v., n = 8) or placebo (N-acetylserine, n = 8). Two hours of NAC infusion significantly reduced the pressor effect of angiotensin I (ANG I) by 39 +/- 14% (mean +/- SEM) and reduced angiotensin converting enzyme activity by 31% in plasma (N-acetylserine: 74 +/- 9 nmol/min/mg, NAC: 51 +/- 7) and 43% in kidney (N-acetylserine: 0.9 +/- 0.3, NAC: 0.5 +/- 0.1 nmol/min/mg protein) (P < .05). Clinical study: Isosorbide dinitrate (5 mg/hr) was infused into six male volunteers for 48 hr. NAC (2 g i.v. followed by 5 mg/kg/hr) was co-infused from 24 to 48 hr. Plasma angiotensin II (ANG II) increased during the first 24 hr of isosorbide dinitrate infusion and decreased from 28 +/- 4 to 14 +/- 2 ng/l after 2 hr of NAC infusion (P < .05). The results suggest that sulfhydryl supplementation modifies the function of the renin/angiotensin system in vivo, an effect probably mediated by inhibition of angiotensin converting enzyme activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Medicine B, Rigshospitalet, University of Copenhagen, Denmark.
S
S
Boesgaard
J
J
Aldershvile
H E
HE
Poulsen
S
S
Christensen
H
H
Dige-Petersen
J
J
Giese
D000111:Acetylcysteine / Q000494:pharmacology*; D000293:Adolescent; D000328:Adult; D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D007548:Isosorbide Dinitrate; D000111:Acetylcysteine