Τίτλος:
Selective angiotensin-converting enzyme c-domain inhibition is
sufficient to prevent angiotensin I-induced vasoconstriction
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
van Esch, JHM
Tom, B
Dive, V
Batenburg, WW
Georgiadis, D
and Yiotakis, A
van Gool, JMG
de Bruijn, RJA
de Vries, R and
Danser, AHJ
Περιοδικό:
JOURNAL OF HYPERTENSION
Εκδότης:
Lippincott, Williams & Wilkins
Λέξεις-κλειδιά:
angiotensin; bradykinin; angiotensin-converting enzyme
DOI:
10.1161/01.HYP.0000151323.93372.f5
