Canine Vasculature: A Study of alpha1- Adrenoceptors and Heart Failure

Argyle, Sally Anne (1998) Canine Vasculature: A Study of alpha1- Adrenoceptors and Heart Failure. PhD thesis, University of Glasgow.

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Heart disease is an important cause of morbidity and mortality in the canine population, with the two most common causes of acquired heart disease being dilated cardiomyopathy and endocardiosis. In human patients with heart disease, it has been noted that the clinical signs and symptoms are often of greater severity than expected from the degree of left ventricular dysfunction, suggesting that additional factors contribute to the syndrome. It has now been shown in several human and experimental animal studies, that blood flow to exercising skeletal muscle is reduced in heart failure and that this is not due to an inability to increase cardiac output. This suggests an inability of the vasculature to accommodate the increased blood flow required by the exercising muscle, leading to an early switch over to anaerobic metabolism and premature fatigue. While the neurohumoral aspects of cardiac failure have been well characterised at a systemic level, the local vascular effects have not. To gain further knowledge of the local effects and their role in the pathophysiology of cardiac disease, it is necessary to characterise normal vessels, in addition to examining vessels from heart failure animals. With these goals in mind, the primary aim of this project was to characterise both the dog saphenous vein and the dog subcutaneous resistance arteries, in relation to their functional alpha1-adrenoceptor population. Findings are discussed in detail in Chapter 3 and Chapter 4. The functional effects of five competitive reversible antagonists and the irreversible alkylating agent CEC, on noradrenaline mediated contractions of dog saphenous vein and dog subcutaneous resistance arteries, were analyzed. In both vessels the alpha1-adrenoceptors appeared to have a low affinity for the alpha1-adrenergic antagonist prazosin, necessitating their classification as alpha1L-adrenoceptors. In addition, in both vessels, there was evidence for the involvement of another subtype in the noradrenaline response. This receptor, despite a low affinity for prazosin had some characteristics of the alpha1B-adrenoceptor. Chapter 5 describes the cloning and sequencing of an 891 bp fragment of the canine alpha1a-adrenergic receptor cDNA. This subtype was chosen because of the mounting evidence that it is responsible for the alpha1L-pharmacology. The fragment was initially isolated using reverse-transcription polymerase chain reaction (RT-PCR) and primers designed from areas of high homology in the alpha1a-adrenoceptor of the human and bovine alpha1a-adrenergic sequence. This fragment, together with a canine partial alpha1b-sequence was used to probe cell lines expressing the human alpha1a- and alpha1b-adrenergic receptors, as well as canine prostate and brain RNA. The canine alpha1a-probe failed to detect message in any of the samples and while the alpha1b-probe hybridized to the alpha1b-expressing cell line RNA, there was evidence for a lack of subtype specificity of this probe. Finally, Chapter 6 describes experiments comparing isolated femoral artery, saphenous vein and subcutaneous resistance arteries from dogs with naturally occurring heart failure, and controls. The findings suggest that in heart failure there is a decrease in sensitivity to exogenous noradrenaline in both the saphenous vein and the femoral artery, but not in the resistance arteries. In addition, vasorelaxations to acetylcholine were examined in all vessels and no significant differences were found between vessels from control and heart failure dogs. Interestingly, on examination of the case details from the heart failure dogs used, it was found that in the cohort of patients used for the large vessel studies, the majority of animals had received no treatment, (seven out of eight animals were not treated). This was in contrast to the cohort used in the resistance artery group, where four out of five animals had received treatment for their cardiac disease. The relevance of this and possible effects are discussed in this chapter.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Ian McGrath
Keywords: Veterinary science
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-75402
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 20:14
Last Modified: 19 Nov 2019 20:14

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