A comparison of the effects of renin inhibition and angiotensin converting enzyme inhibition upon bradykinin potentiation.
OBJECTIVE
The goal of the present study was to show that, in contrast to an angiotensin converting enzyme (ACE) inhibitor, Ro 42-5892, a new renin inhibitor, can block the renin-angiotensin system without potentiating skin reactions induced by bradykinin.


METHODS
Potentiation of skin reaction to i.d. injections of bradykinin and histamine was evaluated in guinea pigs in the presence and absence of the drug (placebo, Ro 42-5892 or cilazapril). The elimination rate of radioactive bradykinin in blood was measured in other groups of guinea pigs treated with the same drugs. Maximal effective doses of each drug were used.


METHODS
Measurements of erythema area induced by bradykinin and histamine injection were performed using a digital planimeter. Radioactive bradykinin was measured in blood by high-performance liquid chromatography and followed over 40 min.


RESULTS
The ACE inhibitor cilazapril increased the area of erythema induced by bradykinin but not that induced by histamine. In contrast, Ro 42-5892 did not potentiate the effect of bradykinin. In addition, cilazapril did not change the elimination rate of i.v. radioactive bradykinin in blood.


CONCLUSIONS
These results suggest that potentiation of bradykinin-induced skin reaction by cilazapril is due to a tissular (and not systemic) inhibition of ACE and does not occur with Ro 42-5892. Thus, side effects such as rash, angioneurotic edema or cough, which have been attributed to bradykinin accumulation by ACE inhibitors, may not occur with the use of specific renin inhibitors such as Ro 42-5892.
Véniant
M
M
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Clozel
J P
JP
Fischli
W
W
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001920:Bradykinin / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D017315:Cilazapril; D003875:Drug Eruptions / Q000209:etiology; D004357:Drug Synergism; D004890:Erythema / Q000139:chemically induced; D006168:Guinea Pigs; D007093:Imidazoles; D011724:Pyridazines / Q000009:adverse effects / Q000494:pharmacology*; D012083:Renin / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000092502:Renin Inhibitors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001920:Bradykinin; D017315:Cilazapril; D007093:Imidazoles; D011724:Pyridazines; D012083:Renin; D000092502:Renin Inhibitors; C065581:remikiren