title: 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.
  
  
  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 (AT1), 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 AT1 antagonists may in part be due to increased Ang II metabolism by ACE2.
authors.affiliation: Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. cferrari@wfubmc.edu
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.forename: Jewell
authors.initials: J
authors.lastname: Jessup
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: David B
authors.initials: DB
authors.lastname: Averill
authors.forename: K Bridget
authors.initials: KB
authors.lastname: Brosnihan
authors.forename: E Ann
authors.initials: EA
authors.lastname: Tallant
authors.forename: Debra I
authors.initials: DI
authors.lastname: Diz
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Gallagher
mesh_terms: D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017706:Lisinopril / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood; D007703:Peptidyl-Dipeptidase A; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; D000804:Angiotensin II; D000803:Angiotensin I; D017706:Lisinopril; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D019808:Losartan