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Title page for ETD etd-09202011-205331


Type of Document Dissertation
Author McHugh, Julia
Author's Email Address julia.mchugh@vanderbilt.edu
URN etd-09202011-205331
Title Cardiovascular effects of water ingestion: an osmosensitive pressor response
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Italo Biaggioni Committee Chair
David Robertson Committee Member
Jens Jordan Committee Member
John Oates Committee Member
Kevin Strange Committee Member
Keywords
  • autonomic nervous system
  • blood pressure
  • TRPV4
  • water
  • baroreflex
  • osmopressor
Date of Defense 2010-06-07
Availability unrestricted
Abstract
Human subjects with impaired baroreflex function cannot buffer rises or falls in blood pressure (BP), thus allowing BP effects of endogenous or environmental stimuli that previously escaped detection to emerge dramatically. Studies in these patients led us to discover that water ingestion induces a robust increase in BP and vascular resistance. This project explores the mechanism of water’s cardiovascular effects using a mouse model of baroreflex impairment. We show that the pharynx, esophagus, and stomach are not critical sites for water’s pressor action, and that plasma volume expansion does not contribute significantly to the rise in BP observed after water ingestion. We also show that the increase in BP after water ingestion is mediated through sympathetic nervous system activation, and appears to be independent of the effects of renin and angiontensin. Genetic knockout mouse models were used to investigate the potential role of several candidate molecular mediators. The osmosensitive transient receptor potential vanilloid 4 channel (TRPV4) was found to be an important component of the response. Although portal osmolality decreased after water ingestion in both wild-type and Trpv4-/- mice, only the wild-type animals showed a pressor response. The same volume of physiological saline failed to elicit an increase in BP, suggesting osmolality as the stimulus. The osmopressor response to water, and TRPV4 thus appear to be new factors now implicated in the physiology of BP regulation.

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