Acute and Chronic Afferent Engagement: Sympathetic and End Organ Responses

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This is a resubmission of a program project grant to the NHLBI by {four} investigators located within the College of Medicine of the Pennsylvania State University in Hershey, Pennsylvania. All investigators are highly productive scientists. All project leaders are collaborative and all will greatly benefit from this program. We believe this application fulfills the criteria for a PPG because: 1) there is a unifying theme namely that {peripheral arterial disease (PAD) accentuates autonomic reflex responses. Two models of limb ischemia will be employed: a) PAD in human subjects (Projects 1 and 4); and b) hindlimb arterial occlusion in rats (Projects 2 and 3)}; 2) conceptual synergy exists between the projects that will lead to important advances in cardiovascular physiology and pathophysiology; 3) this PPG has broadly defined goals that can be accomplished within the first 5 year funding period; and 4) many of the ideas and concepts proposed are a direct result of previous collaborations between the project leaders. Dr. Sinoway will be the PPG Program Director (PD). He has substantial scientific and administrative experience, serving as the PD of the Penn State General Clinical Research Center (GCRC) since 1996, and PD of a PPG since 2004. In Project 1, Dr. Sinoway will examine the role the exercise pressor reflex (EPR) {plays in regulating blood pressure during muscular activity in patients with PAD.} He will examine the role oxidative stress plays in altering reflex effects in PAD patients. In Project 2, Dr. Li will determine if hindlimb arterial occlusion (rat model) leads to upregulation of P2X, TRPV1 and ASIC channels in dorsal root ganglion (DRG) neurons. Dr. Li will also examine the role nerve growth factor (NGF) plays in this response. In Project 3, Dr. Kaufman will examine group III and IV muscle afferent discharge {during contraction in rats with the hindlimb arterial occlusion model.} In Project 4, Dr. Leuenberger will examine the role intermittent hypoxia, a potent oxidative stress, plays in altering sympathetic reflexes and vasodilator responsiveness in {normal humans and those with diseases characterized by oxidative stress including PAD. Two cores are proposed: 1) Core A will be administrative; and 2) Core B will be a human physiology core.