title: Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats.
abstract: The cellular signaling pathways responsible for the transition from compensated left ventricular hypertrophy (LVH) to LV dilatation (remodeling) and heart failure are unclear. As chronic administration of a beta-adrenoreceptor (beta-AR) agonist mediates the premature onset of cardiac remodeling without myocyte necrosis or myocardial dysfunction in LVH, we suggest that beta-AR activation is critical in promoting the transition from compensated LVH to cardiac dilatation. However, beta-AR mediated effects in the heart can occur via either the cyclic adenosine monophosphate (cAMP) system or via cAMP independent signaling pathways. To determine the role of cAMP in promoting adverse cardiac chamber remodeling, we evaluated whether phosphodiesterase inhibition (PDEI) promotes LV dilatation in rats with compensated LVH. The impact of chronic administration of the PDEI, pentoxifylline, on LV remodeling and function was assessed in spontaneously hypertensive rats (SHR) with compensated LVH. The PDEI mediated inotropic effects and increased cAMP concentrations in SHR. This dose of the PDEI administered for 4 months to SHR did not modify LV weight or influence intrinsic myocardial systolic function (as assessed in the absence of the PDEI) in SHR. However, the PDEI mediated the development of a right shift in LV end diastolic (LVED) pressure-internal dimension and LVED pressure-volume relations, LV wall thinning, and increments in myocardial soluble (non-cross-linked) collagen concentrations. In conclusion, chronic PDEI administration induces adverse geometric and interstitial cardiac remodeling in SHR, a finding that supports the notion that the beta-AR-cAMP system is important in mediating the progression to heart failure by promoting interstitial remodeling and LV dilatation in LVH.
authors.affiliation: Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand Medical School, Parktown, Johannesburg, South Africa.
authors.forename: Christopher
authors.initials: C
authors.lastname: Anamourlis
authors.forename: Danelle
authors.initials: D
authors.lastname: Badenhorst
authors.forename: Mark
authors.initials: M
authors.lastname: Gibbs
authors.forename: Raul
authors.initials: R
authors.lastname: Correia
authors.forename: Demetri
authors.initials: D
authors.lastname: Veliotes
authors.forename: Oleg
authors.initials: O
authors.lastname: Osadchii
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Norton
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Woodiwiss
mesh_terms: D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006321:Heart; D009200:Myocardial Contraction / Q000187:drug effects; D009929:Organ Size; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D010726:Phosphodiesterase Inhibitors; D003094:Collagen; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D010431:Pentoxifylline