Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2

Abstract

Background-Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function and arterial pressure by converting angiotensin II (Ang II) into the vasodilator and antitrophic heptapeptide, angiotensin-(1-7) [Ang-(1-7)]. As the only known human homolog of ACE, the demonstration that ACE2 is insensitive to blockade by ACE inhibitors prompted us to define the effect of ACE inhibition on the ACE2 gene. Methods and Results-Blood pressure, cardiac rate, and plasma and cardiac tissue levels of Ang II and Ang-(1-7), together with cardiac ACE2, neprilysin, Ang II type 1 receptor (AT 1 ), and mas receptor mRNAs, were measured in Lewis rats 12 days after continuous administration of vehicle, lisinopril, losartan, or both drugs combined in their drinking water. Equivalent decreases in blood pressure were obtained in rats given lisinopril or losartan alone or in combination. ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity. Combination therapy duplicated the effects found in rats medicated with lisinopril, except that cardiac ACE2 mRNA fell to values found in vehicle-treated rats. Losartan treatment but not lisinopril increased cardiac tissue levels of Ang II and Ang-(1-7), whereas none of the treatments had an effect on cardiac neprilysin mRNA. Conclusions-Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity but not cardiac ACE2 mRNA. Although the predominant effect of ACE inhibition may result from the combined effect of reduced Ang II formation and Ang-(1-7) metabolism, the antihypertensive action of AT 1 antagonists may in part be due to increased Ang II metabolism by ACE2.

Plasma and tissue concentrations of proangiotensin-12 in rats treated with inhibitors of the renin-angiotensin system

“…For example, proang-12 was recently shown to be digested by ACE2, chymase and neprilysin, in addition to ACE. What's more, proang-12 is reportedly converted to Ang I, Ang II, Ang -(1-9) and Ang-(1-7) ex vivo, 14,15 and losartan, olmesartan and lisinopril all increase rat cardiac ACE2 expression, leading to increases in Ang-(1-7) levels 25,26 and chymase activation. 27 Thus, ACE inhibitors and angiotensin receptor blockers appear to activate endogenous proteases that metabolize proang-12.…”

“…27 Another mechanism that could be involved in the imidapril-induced reduction in blood pressure is ACE inhibitor-mediated activation of ACE2, leading to increases in Ang (1-7) levels. 25 In addition, metabolism of bradykinin is strongly inhibited by ACE inhibitors, and the resultant increases circulating bradykinin levels would lead to increases in nitric oxide and prostaglandin levels, 32 which would in turn reduce blood pressure.…”

Characterization of angiotensin-converting enzymes 1 and 2 in the soleus and plantaris muscles of rats

“…This effect could reduce myocardial blood flow preferentially via coronary vasoconstriction or microcirculatory dysfunction. ACE2 is enhanced by ACE1 inhibitors or angiotensin receptor blockers (12,18).…”

Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker

“…28 Conversely, there is evidence that Ang-(1-7) contributes to the antihypertensive actions of both ACE inhibitors and ARBs. 29,30 Renin inhibition would be expected to reduce formation of Ang-(1-7), and, therefore, the addition of renin inhibition to ACE inhibition or ARB could potentially diminish blood pressure lowering. Indeed, the trend for a rise in pressures in the ARB/aliskiren combination study, when the dosage of aliskiren was increased from 75 to 150 mg daily, and the lack of correlation with changes in blood pressure with changes in PRA, suggests that further studies of this combination of agents are certainly warranted, with both greater patient numbers and a wider range of doses.…”