Chronic heart failure (CHF) disproportionally afflicts the aged, impairing the O2 transport system, specifically muscle O2 delivery, thereby crippling exercise tolerance. Despite this fact, CHF research has overwhelmingly utilized young rather than old animals, where CHF (CHF+Aged) is a profoundly different disease. Therefore, the mechanistic bases for dysfunction and therapeutic countermeasures must be addressed specifically in this population. CHF compromises multiple systems (especially sympathetic nervous (SNS), immune, cardiovascular, muscular) with these effects interacting to decrease skeletal muscle micro- circulatory blood-myocyte O2 flux. Our first round of this R15 provided evidence that that both CHF-induced SNS and muscle O2 delivery dysregulation may be ameliorated by strategies that increase nitric oxide (NO) bioavailability i.e., targeting systemic inflammatory mediators (i.e., TNFa) with pentoxifylline therapy and increasing NO directly with beetroot juice. This proposal addresses the mechanistic bases for CHF+Aging- induced dysfunction from a novel vertically-integrated perspective: sympathetic nervous system - cardiovascular - microcirculation - vascular protein control. We propose to address the global hypothesis that, in CHF+Aged rats, SNS and cardiac dysfunction coalesce within the skeletal muscle microcirculation to impair muscle O2 transport and exercise tolerance. Thus, multi-targeted therapeutic interventions (PTX, SNS activation, cardiac function; sildenafil or nitrat supplementation, NO bioavailability + O2 requirements) will restore muscle capillary function, O2 delivery/utilization balance and exercise tolerance. Strengths of our approach include: 1) Resolving the mechanisms responsible for impaired muscle O2 delivery and exercise intolerance among systems in a highly relevant CHF model (i.e., CHF+Aged); 2) our unique intravital micro- scopy model (rat spinotrapezius) facilitates direct and rapid observation of muscle microcirculation and blood- myocyte O2 flux using phosphorescence quenching during contractions. 3) Quantitating how NO bioavailability facilitates capillary hemodynamics using NO synthase blockade. 4) Provision of novel empirical evidence supporting optimal treatment strategies for CHF patients; and 5) interrogation of the latest principles of capillary function an blood-myocyte O2 flux to construct a novel model of contracting muscle capillary hemodynamics. The proposed studies will provide original data addressing muscle and exercise dysfunction in CHF+Aging, defining their mechanistic bases and assessing the efficacy of treatment strategies for CHF patients whilst fulfilling the AREA award mandate to integrate authentic science with student research experience.
The exercise intolerance of patients suffering from chronic heart failure (CHF) is thought to be based substantially in skeletal muscle and, irrespective of left-ventricular function per se, results from a mismatching of oxygen delivery to oxygen demands in contracting muscles. However, recent evidence indicates that this mismatching is the consequence of centrally (i.e., brainstem) enhanced sympathetic vasoconstriction combined with locally impaired muscle capillary blood flow secondary to decreased nitric oxide bioavailability at both sites. This proposal assesses the efficacy of strategies to increase nitric oxide bioavailability to improve capillary hemodynamics, oxygen delivery/utilization matching and muscle function in CHF. One key aspect is determination of the mechanistic bases for the efficacy of pentoxifylline and nitrate supplementation (beetroot juice) to treat CHF patients. Under these auspices and the AREA Award mission this proposal integrates meritorious science with opportunities for development of undergraduate and graduate student scientists.
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