Project: Research project

Project Details


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.
Effective start/end date4/10/003/31/10


  • Medicine(all)