Selective angiotensin-converting enzyme c-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction

Somatic angiotensin-converting enzyme (ACE) contains 2 domains (C-domain and N-domain) capable of hydrolyzing angiotensin I (Ang I) and bradykinin. Here we investigated the effect of the selective C-domain and N-domain inhibitors RXPA380 and RXP407 on Ang I-induced vasoconstriction of porcine femoral arteries (PFAs) and bradykinin-induced vasodilation of preconstricted porcine coronary microarteries (PCMAs). Ang I concentration-dependently constricted PFAs. RXPA380, at concentrations >1 mumol/L, shifted the Ang I concentration-response curve (CRC) 10-fold to the right. This was comparable to the maximal shift observed with the ACE inhibitors (ACEi) quinaprilat and captopril. RXP407 did not affect Ang I at concentrations less than or equal to 0.1 mmol/L. Bradykinin concentration-dependently relaxed PCMAs. RXPA380 (10 mumol/L) and RXP407 (0.1 mmol/L) potentiated bradykinin, both inducing a leftward shift of the bradykinin CRC that equaled approximate to 50% of the maximal shift observed with quinaprilat. Ang I added to blood plasma disappeared with a half life (t(1/2)) of 42 +/- 3 minutes. Quinaprilat increased the t(1/2) approximate to 4-fold, indicating that 71 +/- 6% of Ang I metabolism was attributable to ACE. RXPA380 ( 10 mumol/L) and RXP407 ( 0.1 mmol/L) increased the t(1/2) approximate to 2-fold, thereby suggesting that both domains contribute to conversion in plasma. In conclusion, tissue Ang I-II conversion depends exclusively on the ACE C-domain, whereas both domains contribute to conversion by soluble ACE and to bradykinin degradation at tissue sites. Because tissue ACE ( and not plasma ACE) determines the hypertensive effects of Ang I, these data not only explain why N-domain inhibition does not affect Ang I - induced vasoconstriction in vivo but also why ACEi exert blood pressure - independent effects at low (C-domain - blocking) doses.