N-ACETYLCYSTEINE INHIBITS ANGIOTENSIN-CONVERTING ENZYME INVIVO

Nitrate tolerance has been explained by 1) a direct loss of pharmacolo gical effect due to reduced bioconversion and 2) an indirect effect du e 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, a nd this effect has been attributed to a nitrate/sulfhydryl interaction and increased production of vasoactive intermediates. The effect of N AC on counter-regulatory mechanisms is, however, unknown. This study e xamined whether NAC modulates the function of the renin/angiotensin sy stem in normal rats and in nitrate-tolerant healthy volunteers. Animal study: Conscious rats received NAC (5 mmol/kg/hr i.v., n = 8) or plac ebo (N-acetylserine, n = 8) Two hours of NAC infusion significantly re duced 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% i n kidney (N-acetylserine: 0.9 +/- 0.3, NAC: 0.5 +/- 0.1 nmol/min/mg pr otein) (P < .05). Clinical study: Isosorbide dinitrate (5 mg/hr) was i nfused 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/I after 2 hr of NAC infusi on (P < .05). The results suggest that sulfhydryl supplementation modi fies the function of the renin/angiotensin system in vivo, an effect p robably mediated by inhibition of angiotensin converting enzyme activi ty. Thus, it is possible that sulfhydryl supplementation, in addition to its likely effect on nitrate metabolism, may attenuate nitrate-indu ced counter-regulatory mechanisms.