This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cardiovascular disease is the leading cause of death and disability in older Americans. Results of studies in experimental animals have shown that with senescence there is a decline in myocardial fatty acid utilizaion (MFAU) and oxidation (MFAO) and a relative increase in function. We recently confirmed these observations in humans. It has also been shown in experimental animals that inhibition of nitric oxide (NO) likely produced by endothelial isoform of nitric oxide synthase (eNOS) stimulates myocardial MGU and inhibits MFAO and possibly MFAU via a cGMP-dependent mechanism. Given that eNOS decreases with age, we hypothesize that chnages in substrate utilization in the aging heart are mediated, at least in part, by a decline NO production and that these changes are paralleled changes in systolic function. To this end, we will address the following specific aims:1. To determine, in young healthy volunteers, the extent to which acute inhibition of NO production will effect a shift in myocardial substrate utilization to a pattern similar to what is seen in the aging population and whether these changes are associated with a decline in left ventricular systolic.2. To determine, in aged healthy volunteers, whether acute stimulation of NO production shifts myocardial substrate utilization to a pattern similar to what is seen in the younger subjects and whether these changes are associated with an increase in left ventricular systolic function.The significance of this age-related shift in myocardial substrate utilization may be manifold. The inability to increase MFAU and MFAO in response to stress may decrease the yocardial mechanical response to an increase in demand for cardiac work. The age-related shift in substrate metabolism could either exacerbate the decline in fatty acid use as observed in left ventricular hypertrophy and dilated cardiomyopathy of impair the adaptive metabolic response that occurs in diabetes mellitus. These observations would provide at least partial explanation as to why the incidence and manifestations of these cardiac disorders increase with age. Understanding the role NO in this metabolic shift would provide a potential target for novel therapeutics designed to treat these disorders and potentially slow the impact of aging on hte human heart.
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