ISOLATED DIASTOLIC DYSFUNCTION

Project: Research project

Project Details

Description

The objective of this revised application is to investigate the integrative pathophysiology of isolated diastolic dysfunction (IDD) and to translate this knowledge into novel therapeutic strategies for this common condition that is often the consequence of renal hypertension (RH). The focus is on the role of neurohumoral activation in the pathogenesis and therapeutics of IDD in experimental RH. The rationale for the study of IDD stems from epidemiological studies which established that IDD is common and that the morbidity and mortality associated with CHF due to IDD is equal to that associated with reduced systolic function. The importance of this clinical problem is further underscored by the absence of proven therapies for IDD. The role of neurohumoral activation in the pathophysiology and therapeutics of systolic dysfunction is established. The role of neurohumoral activation in the pathophysiology and therapeutics of IDD remains unclear. Endothelin (ET) and the natriuretic peptide system (NPS) are activated in systolic dysfunction where a unique cross-talk between these systems exists. In vitro studies indicate that the NPS may be lusitropic and that ET may be anti-lusitropic. The importance of these factors in the regulation of diastolic function in vivo in IDD remains unclear. The hypotheses to be tested are that there is myocardial activation of the ET system in IDD due to RH, that ET activation contributes to the diastolic dysfunction via myocardial effects mediated by the myocardial ET-A receptor and that selective antagonism of the ET system represents a novel therapeutic strategy to ameliorate IDD. The applicant further hypothesize that the deleterious effects of endogenous ET are attenuated by co-activation of the NPS which preserves diastolic function via particulate guanylate cyclase linked myocardial receptors and the NPS second messenger cGMP and that chronic augmentation of the NPS in RH will improve diastolic function. The specific aims are 1) to determine the temporal activation of circulating and local myocardial ET and the NPS and their relation to pressure overload, hypertrophy, and diastolic function during the development of IDD in experimental RH; 2) to determine if ET and the NPS modulate diastolic function via receptor mediated myocardial effects in experimental RH; and 3) to determine if chronic neurohumoral modulation, specifically ET antagonism or NPS augmentation, attenuates diastolic dysfunction in IDD associated with experimental RH.
StatusFinished
Effective start/end date4/10/003/31/10

Funding

  • National Institutes of Health: $353,197.00
  • National Institutes of Health: $372,500.00
  • National Institutes of Health: $317,475.00
  • National Institutes of Health: $353,197.00
  • National Institutes of Health: $317,475.00
  • National Institutes of Health: $363,746.00
  • National Institutes of Health: $317,475.00
  • National Institutes of Health: $317,475.00

ASJC

  • Medicine(all)

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