The broad and long-term objectives of this proposal are to define the mechanisms of peripheral vascular and microvascular dysfunction in trauma, ischemia, and circulatory shock. The investigator focuses on the role of the potent vasoactive neuropeptide calcitonin gene-related peptide (CGRP) in resistant artery dysfunction in endotoxin-induced circulatory shock. The fundamental hypothesis to be addressed is that in vivo exposure of the vasculature to LPS results in release of CGRP from sensory nerve terminals, enervating the vasculature and that CGRP in combination with enhanced vascular NO production contributes to the observed vasodilatation and diminished resistance vascular responsiveness. This investigation has two principal inter-related objectives: 1) to further define the cellular mechanisms of action of CGRP on resistance artery smooth muscle cell and specifically define interactions between CGRP and NO; 2) to establish whether a cause and effect relationship exists between augmented perivascular CGRP release during septic shock and progressive microvascular dysfunction. These hypotheses and objectives will be subjected to a rigorous examination using a combination of methodologies including systemic hemodynamic recordings in anesthetized rats, in vivo video microscopy of the cremaster muscle microcirculation, assessment of the functional state of isolated cannulated cremaster arterioles, and digital fluorescence ratio imaging of vascular smooth muscle calcium responses in intact cremaster arterioles. These techniques will allow the investigator to determine whether changes in vascular responses correlate with changes in intracellular calcium-mediated directly or indirectly by CGRP and/or NO.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM055737-02
Application #
2796778
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-09-30
Project End
2002-09-29
Budget Start
1998-09-30
Budget End
1999-09-29
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506