Abstract

): The proposed research aims to answer the question: """"""""What are the cellular mechanisms responsible for the alterations in contractility associated with hypertensive heart disease?"""""""" The prevailing view of cardiac hypertrophy and heart failure describes the observed abnormalities in [Ca]i handling in terms of decreased contractility and progressive uncoupling of Ca entry and sarcoplasmic reticulum (SR) Ca release. Preliminary and literature data support the alternative view that mild to moderate hypertrophy is associated with enhanced contractility which end stage hypertrophy and failure is associated with decreased contractility. The overall hypothesis is that abnormalities in [Ca]i handling are a consequence of alterations in the gain between Ca entry and Ca release.
Aim 1 will test the hypothesis that mild to moderate hypertrophy is associated with enhanced contractility and increased gain between Ca entry and SR Ca release whereas severe hypertrophy and failure are associated with decreased contractility and decreased gain. The hypothesis that reversal of hypertrophy and prevention of failure is dependent on correction of systemic hypertension only during the stage of the disease characterized by increased gain also will be tested.
Aim 2 tests at the whole cell and single channel level whether ICa, the trigger for SR Ca release, is unaltered in hypertrophy and failure. Gain will be determined from the [Ca]i transients (whole cell and local) and L-type Ca currents (whole cell and single channel) in voltage clamped ventricular cells and by measuring force, [Ca]i transients in intact trabeculae. This proposal will provide insights regarding the cellular mechanisms of altered contractility in hypertensive heart disease by combining (1) the new concept of local control, (2) new experimental methodologies (1 and 2 photon laser scanning confocal microscopy), and (3) the longitudinal study of the development of hypertrophy and its progression to failure in a relevant experimental model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL050435-05
Application #
2703931
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1994-04-01
Project End
2001-06-30
Budget Start
1998-07-27
Budget End
1999-06-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201

  Publications

Armoundas, Antonis A; Rose, Jochen; Aggarwal, Rajesh et al. (2007) Cellular and molecular determinants of altered Ca2+ handling in the failing rabbit heart: primary defects in SR Ca2+ uptake and release mechanisms. Am J Physiol Heart Circ Physiol 292:H1607-18
Izu, Leighton T; Means, Shawn A; Shadid, John N et al. (2006) Interplay of ryanodine receptor distribution and calcium dynamics. Biophys J 91:95-112
Chen-Izu, Ye; McCulle, Stacey L; Ward, Chris W et al. (2006) Three-dimensional distribution of ryanodine receptor clusters in cardiac myocytes. Biophys J 91:1-13
Kirk, Malcolm M; Izu, Leighton T; Chen-Izu, Ye et al. (2003) Role of the transverse-axial tubule system in generating calcium sparks and calcium transients in rat atrial myocytes. J Physiol 547:441-51
Sha, Qun; Robinson, Shawn W; McCulle, Stacey L et al. (2003) An antisense oligonucleotide against H1 inhibits the classical sodium current but not ICa(TTX) in rat ventricular cells. J Physiol 547:435-40
Goldman, L; Balke, C W (2002) Do defects in the late sodium current in human ventricular cells cause heart failure? J Mol Cell Cardiol 34:1473-6
Chen-Izu, Y; Sha, Q; Shorofsky, S R et al. (2001) I(Ca(TTX)) channels are distinct from those generating the classical cardiac Na(+) current. Biophys J 81:2647-59
Shorofsky, S R; Aggarwal, R; Corretti, M et al. (1999) Cellular mechanisms of altered contractility in the hypertrophied heart: big hearts, big sparks. Circ Res 84:424-34
Aggarwal, R; Shorofsky, S R; Goldman, L et al. (1997) Tetrodotoxin-blockable calcium currents in rat ventricular myocytes; a third type of cardiac cell sodium current. J Physiol 505 ( Pt 2):353-69
Wier, W G; ter Keurs, H E; Marban, E et al. (1997) Ca2+ 'sparks' and waves in intact ventricular muscle resolved by confocal imaging. Circ Res 81:462-9

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