Our long term objectives are to provide new insight into the cellular signaling pathways that underlie the regulation of peripheral vascular resistance. The interaction between skeletal muscle contractions and sympathetic nerve activity (SNA) determines muscle blood flow and arterial pressure during exercise through governing the diameter of resistance vessels. The resistance network is comprised of arterioles embedded within the muscle and their feed arteries (FA) located extemal to the tissue. As motor unit recruitment and contractile activity increase, vasodilation is initiated on arterioles and """"""""ascends"""""""" into FA via cell-to-cell conduction of a signal (hyperpolarization) along the endothelium that relaxes surrounding smooth muscle cells. Resistance vessels are invested with sympathetic nerves; thus, arterioles and FA constrict progressively as SNA increases. With SNA during exercise, dilation prevails in downstream arterioles while constriction prevails in upstream FA, which thereby restricts muscle blood flow. Our working hypothesis is that ascending (conducted) vasodilation is modulated by SNA to govem muscle blood flow while maintaining arterial pressure.
Our Specific Aims are to: (1) Determine the signaling pathway(s) that initiate(s) ascending vasodUation; (2) Determine which ion channels underlie the initiation and the conduction of vasodUation; and (3) Determine how SNA modulates conducted vasodilation. Using the retractor muscle preparation in anesthetized hamsters, muscle fibers are stimulated to contract and vasomotor responses are observed using video microscopy. Individual FA are isolated and pressurized to record vasomotor and electrophysiological responses during conducted vasodilation and SNA. Underlying signaling pathways are investigated using specific pharmacological interventions, intracellular recording, and selective disruption of endothelium or smooth muscle function. Findings from these experiments will provide new, mechanistic insight into vascular determinants of physical performance and strengthen the foundation for understanding decrements in physical work capacity that occur with disease, inactivity, and aging. This insight will promote the development of novel strategies for the maintenance of an active lifestyle as well as rehabilitation and recovery from impaired physical work capacity. ? ?
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