title: Modulation of cardiac L-type Ca2+ current by angiotensin-(1-7): normal versus heart failure.
abstract: OBJECTIVE
  Recent evidence has shown that, in heart failure (HF), clinically relevant concentrations of angiotensin-(1-7) [Ang-(1-7)] counteracts angiotensin II induced cardiac depression and produces positive inotropic effects in both left ventricle (LV) and myocytes. However, the underlying electrophysiological mechanism is unclear. We investigated the role and mechanism of Ang-(1-7) on LV myocyte L-type calcium current (ICa,L) responses in normal state and in HF.
  
  
  METHODS
  We compared the effect of Ang-(1-7) (10(-5) M) on ICa,L responses in isolated LV myocytes obtained from 11 rats with isoproterenol (ISO) induced HF (3 months after 170 mg/kg subcutaneous for 2 days) and from 8 age-matched normal control rats by patch clamp technique.
  
  
  RESULTS
  In normal myocytes, compared with baseline, superfusion of Ang-(1-7) caused no significant changes in ICa,L (8.2 ± 0.2 versus 8.0 ± 0.3 pA/pF, p= not significant). In HF myocytes, the baseline ICa,L was significantly reduced (5.3 ± 0.1 versus 8.0 ± 0.3 pA/pF, p < 0.01). Ang-(1-7) produced a 21% increase in ICa,L (6.4±0.1 versus 5.3±0.1 pA/pF, p < 0.01). Pretreatment of HF myocytes with a nitric oxide (NO) synthase inhibitor (L-NAME, 10(-5) M) resulted in a significantly greater increase in ICa,L (28%, 8.4 ± 0.1 versus 6.5 ± 0.1 pA/pF, p < 0.01) during Ang-(1-7) superfusion. In contrast, during incubation with the bradykinin (BK) inhibitor HOE 140 (10(-6) M), Ang-(1-7) induced increase in ICa,L was significantly decreased. The Ang-(1-7) induced increase in ICa,L was abolished by [D-Ala(7)]-Ang-(1-7) (A-779, 10(-5) M).
  
  
  CONCLUSIONS
  HF alters the response of ICa,L to Ang-(1-7). In normal myocytes, Ang-(1-7) has no significant effect on ICa,L. However, in HF myocytes, Ang-(1-7) increases ICa,L. These effects are mediated by the Ang-(1-7) Mas receptors and involve activation of NO/BK pathways.
authors.affiliation: Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Che Ping
authors.initials: CP
authors.lastname: Cheng
authors.affiliation: Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USADepartment of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Tiankai
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Surgery, Internal Medicine-Nephrology, and Physiology-Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
authors.affiliation: Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157-1045, USAInstitute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA hcheng@wakehealth.edu.
authors.forename: Heng-Jie
authors.initials: HJ
authors.lastname: Cheng
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007545:Isoproterenol; D008297:Male; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000819:agonists / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D009569:Nitric Oxide; D000803:Angiotensin I; C118790:angiotensin I (1-7); D007545:Isoproterenol; D001920:Bradykinin
keywords: calcium; heart failure; ion currents; receptors; vasodilator agents