Type of Document Dissertation Author Stokes, Ashley Michelle Author's Email Address email@example.com URN etd-0409103-145414 Title Role of Endothelin in the Pathogenesis of Acute Laminitis in Horses Degree Doctor of Philosophy (Ph.D.) Department Veterinary Physiology, Pharmacology, and Toxicology (Veterinary Medical Sciences) Advisory Committee
Advisor Name Title Rustin Moore Committee Chair C. S. Venugopal Committee Member Charles Short Committee Member Leonard Kappel Committee Member Susan Eades Committee Member Ronald Del Vecchio Dean's Representative Keywords
- veterinary physiology
- black walnut extract
- vascular physiology
Date of Defense 2003-03-20 Availability unrestricted Abstract
Acute laminitis is a severely debilitating disease of the laminae of the equine digit; however, the mechanism(s) of pathogenesis have yet to be fully elucidated. In physiologic states, the endothelium synthesizes substances, such as nitric oxide (NO; vasodilator) and endothelin-1 (ET-1; profound vasoconstrictor), which play a crucial role in vasomotor regulation. The overall hypothesis is that the initiating factor in the onset of acute laminitis is a disruption in the balance between NO and ET-1, which leads to digital vasoconstriction and subsequent laminar ischemic necrosis.
In vitro studies with digital vessels from healthy horses and horses with naturally-acquired laminitis determined that ET-1 caused concentration-dependent, sustained contraction of arteries and more profound contraction of veins, and incubation with the nonselective ET receptor antagonist (PD145065) at a 10-5 M concentration abolished these contractile effects. ET-1 was then administered into the digit of healthy conscious horses, which resulted in reduced blood flow and the ET antagonist, especially in combination with a NO donor, reversed these reductions.
Naturally-acquired laminitic horses had a trend for increased jugular and cephalic venous plasma ET-like immunoreactivity, and horses during the development of black walnut extract (BWE)-induced laminitis developed increased digital venous plasma ET-like immunoreactivity. After validation for equine tissues, ET-1 immunohistochemical staining was conducted on digital vascular and laminar tissues, but no notable differences were found between healthy and naturally-acquired or experimentally-induced laminitic horses.
During the developmental stages of BWE-induced laminitis, digital blood flow initially decreased followed by hyperemia, corresponding with demonstration of clinical signs of laminitis. Administration of the ET antagonist, and the antagonist combined with a NO donor, improved Starling force alterations by improving digital vascular resistances and blood flow. Utilizing digital vessel rings from BWE-treated horses, ET-1 caused a concentration-dependent contraction in vitro that was abolished by the ET antagonist. Endothelium-dependent vasodilation was decreased in these vessels, demonstrating possible altered endothelial function due to BWE administration.
Based on the results of these studies, ET-1 appears to play a role in the pathophysiology of acute laminitis in horses and continued investigations evaluating ET antagonists as preventative and therapeutic agents for this devastating disease are warranted.
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