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UBC Theses and Dissertations

Myogenic and endothelial properties of the mouse septal artery in health and disease Lui, Amy Hoi-Mel

Abstract

In this thesis I examined vascular responses of the mouse ventricular septal artery to increases in intravascular pressure and pertinent vasoactive mediators in two contrasting models: health and cardiac disease. This work is pertinent because the mouse has been extensively used as a cardiovascular and genetically modified animal model, with the differences between human and mouse genetics not as great as one would expect. Thus it is important to understand murine pharmacology in the context of its use as a tool to understand human pathology. In our first study, responses in the "normal", "healthy" mouse coronary artery were characterized and quantified. Pressure-constriction and concentration-response curves were constructed and compared to published human coronary pharmacology. It was found that myogenic tone was higher in mice than in humans and rats, greatly contributed to by endothelin. Noradrenaline produced concentration-dependent vasodilation, mediated by endothelium- located α2- adrenoceptors and smooth muscle-located β-adrenoceptors. Acetylcholine also produced vasorelaxation, which was abolished with L-NAME. Interestingly, the endothelium-dependent vasodilators bradykinin and substance P produced no vasomotor effect on the coronary arteries, possibly indicating the absence of specific corresponding receptors. In the second study, a murine coxsackie B3-induced myocarditis was used as a representative model of cardiac disease. Again, myogenic and endothelial function was evaluated in this pathological condition. Although hemotoxylin and eosin immunostaining confirmed extensive myocyte damage due to infection, immunohistological methods did not reveal increased endothelin-1 levels near the coronary vasculature. Our study found no difference in coronary arterial pressure-induced vasoconstriction between infected and uninfected/sham-infected mice in the physiological pressure range, as well as between time points in the infected group. However, at a lower pressure range (10-60 mmHg), data from the early time points (1,3 and 7 days post-infection) indicated enhanced vessel tone which could be the result of increased release of vasocontrictor factors. Endothelial dysfunction manifested as a diminished response to acetylcholine occurred at 28 days post-infection, which was recovered with pre-treatment using the mixed endothelin A/B receptor antagonist bosentan. The results in this thesis have allowed a further insight into the use of the mouse as a relevant human model of disease. In addition, information with regards to coronary microvascular function in myocarditis has been obtained and contributes to the overall understanding of the mechanism of pathogenesis.

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