Neuromechanical basis of baroreceptor function

Indiana University Indianapolis, Indianapolis IN

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Abstract

DESCRIPTION (provided by applicant): Arterial baroreceptors (BR) are essential for reliable neural control of heart rate and blood pressure. The data quantifying the properties of these pressoreceptors and the reflexogenic consequences of BR function and dysfunction are extensive. Experimental interpretations of baroreflex dysfunction and cardiovascular pathologies such as neurally mediated syncope, dysrhythmias and hypertension are of significant clinical importance. Age related changes in arterial wall properties strongly correlate with cardiovagal baroreflex impairment, increased levels of blood pressure variability, an impaired ability to respond to acute hemodynamic challenges and increased risk of sudden cardiac death (Monahan, 2007). The BR sensor itself represents an essential functional intersection across these diverse pathologies and yet a clarifying explanation of the transduction machinery is lacking. Our working hypothesis is that the microanatomy, extracellular tissue matrix, excitable neural membrane of the BR terminal complex and regional arterial wall tissues all make functionally distinct contributions to the spatial integration and transduction of localized micromechanical forces arising from arterial pressure dynamics. Our specific aims center upon the neuromechanical properties of myelinated and unmyelinated rat aortic BR as these are accessible for both micro- and macroscopic study using three complementary methodologies: 1) confocal, electron and fluorescent microscopy in conjunction with immunohistochemical labeling of protein expression within, and the tissue constructs that circumscribe, the BR terminal ending, 2) extracellular recording of aortic BR fiber discharge in response to computer controlled pressure loading of the arterial wall and 3) synthesis of these disparate microscopy and biophysical data into comprehensive computational models of the neural and micromechanical mechanisms of mechanosensory transduction that are inaccessible for direct testing and measurement. Our preliminary results illustrate: 1) essential differences between the topological distribution of molecularly identified ion channels along the ultrastructure of BR terminals with myelinated and unmyelinated fibers, 2) a minimum complement of the ion channels expressed at the cell body of BR neurons may underlie the neurogenic mechanisms of mechanotransduction and 3) that these ionic mechanisms contribute to, but cannot entirely account for, such dynamic properties as adaptation, hysteresis and resetting of discharge threshold. This combined experimental and computational strategy is producing a more biophysical understanding of the structure-function relationships associated with BR afferents relative to the basement membrane about the terminal ending, the elastin and collagen fibers within the surrounding tissue matrix as well as the neuro-integrative processes of mechanotransduction. As we recently demonstrated (Feng et al., 2007), this integrative approach can lead to new insights concerning acute cardiovascular pathologies that are well known to invoke autonomic reflexes through activation of arterial mechanoreceptors. PUBLIC HEALTH RELEVANCE: In order for the brain to properly control the heart it must continually receive information concerning blood pressure and heart rate. This application involves experimental bioengineering research related to the arterial pressure sensors (baroreceptors) that provide this critically important information to the brain. A more detailed understanding of how these sensors normally work and adapt to short and long term changes in blood pressure, heart rate and the condition of the arteries (e.g. with aging) will help physicians better manage heart function under conditions of health and disease.