Angiotensin II formation by an alternative pathway during exercise in humans.
OBJECTIVE
We postulated a 'kinin-tensin system' in which angiotensin II (Ang II) is cleaved by one or more serine protease independent of renin or angiotensin converting enzyme (ACE). The aim was to determine whether this alternative Ang II-forming pathway by serine proteases participates in the rise in plasma levels of Ang II during exercise in humans.


METHODS
The study consisted of two double-blind crossover experiments. in experiment 1 six healthy volunteers who had been taking either placebo (group P) or the ACE inhibitor captopril (150 mg/day for 3 days; group C) performed a cycle ergometer graded exercise test at four different exercise intensities: stage 1, half of the intensity at the blood lactate threshold (WLT); stage 2, the intensity at WLT; stage 3, the intensity at 4 mmol/l blood lactate; and stage 4, an intensity between stage 3 and maximum intensity. In experiment 2 the same volunteers took captopril (150 mg/day for 3 days) and performed exercise at an intensity corresponding to 90% of the 4 mmol/l blood lactate intensity for 30 min during intravenous drip injection of a serine protease inhibitor, nafamostat [NAF; 0.2 mg/kg per h; NAF(+) group] or saline [NAF(-) group].


RESULTS
In experiment 1 plasma Ang II levels increased from at rest to after exercise in both groups P and C. Although there was a significant treatment effect, captopril did not significantly alter the exercise-induced changes in Ang II level. In experiment 2 the increase in Ang II level after 30 min exercise in the NAF(+) group was significantly lower than in the NAF(-) group.


CONCLUSIONS
These results suggest the presence of an alternative Ang II-forming pathway independent of ACE, and that one or more NAF-sensitive serine protease is responsible, at least partly, for generating Ang II during exercise.
Department of Internal Medicine, School of Medicine, Fukuoka University, Japan.
S
S
Miura
M
M
Ideishi
T
T
Sakai
M
M
Motoyama
A
A
Kinoshita
M
M
Sasaguri
H
H
Tanaka
M
M
Shindo
K
K
Arakawa
D000328:Adult; D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood*; D001550:Benzamidines; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001920:Bradykinin / Q000097:blood; D002216:Captopril / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015444:Exercise / Q000502:physiology*; D006146:Guanidines / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D012083:Renin / Q000097:blood; D015842:Serine Proteinase Inhibitors / Q000097:blood / Q000494:pharmacology
D001550:Benzamidines; D006146:Guanidines; D007773:Lactates; D015842:Serine Proteinase Inhibitors; D000804:Angiotensin II; D019344:Lactic Acid; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D001920:Bradykinin; C032855:nafamostat