Role of endothelin in the pathogenesis of acute laminitis in horses

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

Pulmonary hypertension in the dog

Canine pulmonary hypertension is a clinical condition that needs to be adequately investigated and recognised because of the lack of specific clinical signs, the potential for rapid and irreversible deterioration of pulmonary vascular function and the development of right-sided heart failure. In recent years, many studies have been published on pulmonary hypertension, improving the understanding of its pathophysiology, the accuracy of diagnostic tests and the management of affected patients. This article provides updated information on pulmonary hypertension and serves as a resource for veterinarians regarding the interpretation of diagnostic tests and the clinical management of affected dogs

A Novel Preclinical Model for Chronic Thrombo-Embolic Pulmonary Hypertension development, validation and characterization

Since the disease chronic thrombo-embolic pulmonary hypertension (CTEPH), which is caused by an abnormal increase in blood pressure in the lungs due to obstructions, is still incompletely understood, therapeutic interventions are limited, and a curative medicine is still not available for CTEPH, we aim to unravel some mechanisms of this disease in this dissertation. To establish this, we developed a large animal model for CTEPH in which chronic catheters in and around the heart enable serial and awake measurements of blood pressures, cardiac output and oxygen metabolism both at rest and during exercise. The research in this thesis provides an insight in some of the underlying mechanisms which cause remodeling of the pulmonary vasculature and the heart in this disease. Our results indicate that specific research in global signaling pathways such as the vasodilator nitric oxide, the vasoconstrictor endothelin and Rho-kinase are very important for the development of more effective CTEPH treatment. In addition, we show the importance of exercise testing in PH, especially in the early stages to provide earlier diagnosis. All together we provided a lot of information on the pathophysiology of CTEPH with the help of a novel large animal model. Although we gathered all this information, future studies need to be conducted before the ideal, curative therapy will reach the patient

The effects of bradykinin and angiotensin II on the thoracic aorta vasa sasorum microcirculation system

Vasa vasorum forms a network of microvessels within and around the walls of large blood vessels and is thought to be necessary to deliver oxygenated blood to the outer parts of the vessel wall that are inadequately nourished by diffusion from luminal blood. Vasa vasorum flow, therefore, may play an important role for aortic wall structure and function. Angiotensin II and bradykinin are two important vasoactive peptides, which produce vasoconstriction and vasodilatation, respectively. They can also change the permeability of microcirculation. In the present study, we documented the effect of different concentrations of ANG II and bradykinin on the vasa vasorum of isolated rabbit throcic aorta in vitro. Using a camera system, we observed changes in the number of leakages and diameter of vasa vasorum in response to perfusion of ANG II and BK, their antagonists (AT 2 receptor antagonist PD 123319, AT1 receptor antagonist EXP3174, B2 receptor antagonist HOE 140, B1 receptor antagonist (Leu9 ) Des Arg 10- KD (1 ?M), and nitric oxide synthase inhibitor L-NAME."--Résumé abrégé par UM