title: Release of preformed Ang II from myocytes mediates angiotensinogen and ET-1 gene overexpression in vivo via AT1 receptor.
abstract: The role of angiotensin II in pressure overload is still debated because notwithstanding its effects on myocyte contractility angiotensin II is not an obligatory factor for the development of hypertrophy. To define the role of angiotensin II in acute pressure overload we studied the effects of AT1 blockade (valsartan 80mg per day) on myocardial contractility, cardiac growth factor gene expression, and myocardial hypertrophy in aortic banded (60mmHg) pigs. Acute pressure overload caused an abrupt reduction of myocardial contractility, measured by the end-systolic stiffness constant, and a sharp increase in end-systolic stress which rapidly normalized (within 12h) in the placebo group. In AT1-blocked animals end-systolic stiffness constant remained significantly depressed up to 24h and end-systolic stress was still elevated up to 48h (both P<0.05 vs placebo). In both groups confocal microscopy revealed that granular staining of angiotensin II in cardiomyocyte cytoplasm disappeared after 30min of pressure overload. AT1 blockade abolished following cardiac overexpression of angiotensinogen and endothelin-1 genes as shown in RT-PCR studies and the consequent angiotensin II and endothelin-1 release in the coronary circulation. Conversely, insulin-like growth factor-I and ACE mRNA overexpression, as well as the onset of left ventricular mass increase, were not significantly affected by AT1 blockade.
  
  
  CONCLUSIONS
  (1) mechanical stress releases preformed angiotensin II from myocyte in vivo; (2) the AT1 blockade abolishes cardiac angiotensin II and endothelin-1 production with delayed recovery of myocardial contractility; whereas (3) the overexpression of insulin-like growth factor-I gene and the development of myocardial hypertrophy are not angiotensin II-mediated effects.
authors.affiliation: Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134, Florence, Italy. pa.modesti@dfc.unifi.it
authors.forename: Pietro
authors.initials: P
authors.lastname: Amedeo Modesti
authors.forename: Sra
authors.initials: S
authors.lastname: Zecchi-Orlandini
authors.forename: Simone
authors.initials: S
authors.lastname: Vanni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Polidori
authors.forename: Iacopo
authors.initials: I
authors.lastname: Bertolozzi
authors.forename: Avio Maria
authors.initials: AM
authors.lastname: Perna
authors.forename: Lucia
authors.initials: L
authors.lastname: Formigli
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cecioni
authors.forename: Mirella
authors.initials: M
authors.lastname: Coppo
authors.forename: Maria
authors.initials: M
authors.lastname: Boddi
authors.forename: Gian Gastone Neri
authors.initials: GG
authors.lastname: Serneri
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001024:Aortic Valve Stenosis / Q000503:physiopathology; D006328:Cardiac Catheterization; D003593:Cytoplasm / Q000737:chemistry; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006321:Heart / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D018613:Microscopy, Confocal; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology; D013314:Stress, Mechanical; D013552:Swine; D013599:Systole; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D057911:Angiotensin Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; D007334:Insulin-Like Growth Factor I; D000068756:Valsartan; D014633:Valine