Aortic Wall Substance P and Permeability

Markle, Ronald

Abstract

The long-term objective of this line of study is to elucidate the role(s) of neuropeptide tachykinins in vascular wall physiology, beginning with substance P (SP).
The specific aim of this application is based upon preliminary studies and will test the WORKING HYPOTHESIS that endogenous SP can enhance aortic transmural permeability to circulating plasma albumin. Since the nourishment and will-being of any vessel wall (and in turn the tissue served by the vessel) is dependent upon transmural permeability, it is absolutely critical to identify and characterize endogenous substances which influence vascular wall permeability. To date SP is postulated to serve in nociceptive neural transmission and has pronounced effects upon the permeability of the microcirculation of inflammed tissue sites. However, there have been no studies of SP's effects upon physiology of the macrocirculation, e.g., the aorta, under normal or abnormal states. The studies outlined in this proposal will examine in vivo aortic albumin permeablility after manipulations designed to both trigger or inhibit SP interaction with the aorta. The working hypothesis will be tested with three series of in vivo electrical field stimulation experiments: 1) in the absence of any SP antagonism, 2) with the SP-antagonist spantide bathing the aorta before and during field stimulation, and 3) after pretreatment with capsaicin, an agent which causes prolonged depletion of SP- containing nerves. Each experimental protocol will be accompanied by in vitro determinations of aortic SP content and plasma albumin flux by use of radioimmunoassay and fluorometric tracer techniques, respectively. These procedures will be performed to obtain evidence for changes of both the endogenous SP pool and albumin flux in the aorta. If the results support the hypothesis this would demonstrate that endogenous SP can alter aortic permeability. If true, this would be the first evidence that an endogenous, neurally-sequestered peptide (reported to prompt inflammatory events) can exert alterations upon permeability of the macrocirculation. The implications of this finding for control of normal aortic permeability, as well as mechanisms of vascular inflammatory injury per atherosclerosis or hypertensive vessel disease, would be novel as well as significant.