Angiotensin-Converting Enzyme Inhibition Modifies Angiotensin but Not Kinin Peptide Levels in Human Atrial Tissue

Abstract

Abstract-Angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) to angiotensin II (Ang II) and metabolizes bradykinin and kallidin peptides. Decreased Ang II levels and increased kinin peptide levels are implicated in the mediation of the therapeutic effects of ACE inhibition. However, alternative non-ACE pathways of Ang II formation have been proposed to predominate in human heart. We investigated the effects of ACE inhibition on cardiac tissue levels of angiotensin and kinin peptides. High-performance liquid chromatography-based radioimmunoassays were used to measure angiotensin peptides and hydroxylated and nonhydroxylated bradykinin and kallidin peptides in right atrial appendages of subjects who had been prepared for cardiopulmonary bypass. Peptide levels in subjects who received ACE inhibitor therapy were compared with those who did not receive ACE inhibitor therapy. ACE inhibition reduced Ang II levels, which was associated with an 80% reduction in the Ang II/Ang I ratio. ACE inhibition did not modify either bradykinin or kallidin peptide levels or the bradykinin-(1-7)/bradykinin-(1-9) ratio. The 80% reduction in the Ang II/Ang I ratio by ACE inhibition indicated a primary role for ACE in the conversion of Ang I to Ang II in atrial tissue. These data support a role for reduced Ang II levels but do not support a role for increased kinin peptide levels in mediating the direct cardiac effects of ACE inhibition. (Hypertension. 1999;34:171-175.)

Right atrial function in hypertensive patients: effects of antihypertensive therapy

“…Another mechanism leading to this difference in the effects of drugs may be the specific modification of angiotensin from the angiotensin-converting enzyme inhibition in human atrial tissue. 24 Animal studies also suggested that angiotensin-converting enzyme inhibition improved haemodynamic parameters and decreased left and RV weight in hypertensive rats. Moreover, angiotensin-II causes pulmonary vasoconstriction in man and in animals, and angiotensin-converting enzyme inhibition has prevented the development of chronic pulmonary hypertension in animal models.…”

Does the Angiotensin-Converting Enzyme (ACE)/ACE2 Balance Contribute to the Fate of Angiotensin Peptides in Programmed Hypertension?

“…Although ACE2 was first shown to hydrolyze Ang I to release Ang (1-9) with subsequent hydrolysis by ACE to Ang (1-7) in cardiomyocytes, the kinetic data by Vickers et al 11 with recombinant ACE2 revealed a relatively low catalytic constant (kcat) for Ang (1-9) formation. In contrast, the hydrolysis of Ang II to Ang (1-7) by ACE2 exhibited a very high catalytic efficiency (kcat/Km), Ϸ400-fold greater than that for Ang I to Ang (1)(2)(3)(4)(5)(6)(7)(8)(9). In this scheme, the formation of the vasodilator peptide Ang (1-7) occurs at the expense of the vasoconstrictor hormone Ang II.…”

“…Indeed, ACE inhibitors attenuate Ang II formation and augment the levels of the heptapeptide Ang (1-7), a peptide that counterbalances the actions of Ang II on blood pressure and cellular growth through a unique receptor system. Ang II mediates the majority of its actions at the Ang II type 1 (AT 1 ) receptor, including the stimulation of vasoconstriction, sodium retention, cellular growth, and oxidative stress, whereas recent studies show that Ang (1-7) at the AT [1][2][3][4][5][6][7] or mas receptor and Ang II via the AT 2 receptor subtype counterregulate the actions of Ang II at the AT 1 receptor.…”

“…The germinal form, which is found exclusively in the testes, has 1 catalytic site and is involved in fertility. Recently, it has been shown that ACE hydrolyzes Ang (1-7) to Ang (1)(2)(3)(4)(5), thus facilitating the breakdown of Ang (1-7). 1,2 Under conditions of ACE inhibition, not only is there an increase in the substrate Ang I, which can be converted to Ang (1-7) through the action of endopeptidases such as neprilysin and prolylendopeptidase, but there is also prevention of the breakdown of Ang (1-7).…”

“…Acting at multiple sites in the processing scheme, ACE inhibition results in increased plasma, tissue, and urine levels of Ang (1-7). [3][4][5][6] Blockade of Ang (1-7) by its specific receptor antagonist D-alanine 7 -Ang (1-7) reverses the blood pressure-lowering actions of ACE inhibitor lisinopril, 7 illustrating that the increased levels of Ang (1-7) account for a part of the antihypertensive actions of ACE inhibition.…”