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Title: Development of a small animal of cardiac contractility and calcium/calmodulin-dependent protein kinase II
Author: Mooney, Laura
ISNI:       0000 0004 2743 6728
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2012
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Several drugs in development or on the market have adverse effects on cardiac contractility. Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractility with a particularly prominent role in pathophysiological conditions where contractile dysfunction occurs. Therefore, CaMKIIδ may be an intracellular target for drugs that alter cardiac performance. The aim of the work presented in this thesis was to develop a small animal model for the integrated assessment of cardiac contractility and CaMKII. An anaesthetised guinea pig model was developed to assess haemodynamics and cardiac contractility via two indices - left ventricular (LV) dP/dtmax and the QA interval. Acute administration of isoprenaline and ouabain increased contractility whilst verapamil, imatinib and sunitinib decreased contractility. There was a strong inverse correlation between LVdP/dtmax and the QA interval. CaMKIIδ expression and CaMKII activity were not significantly altered by any acute drug treatment. Both LVdP/dtmax and the QA interval were influenced by changes in blood pressure. Additionally, LVdP/dtmax was influenced by changes in heart rate. Measurement of contractility via LV pressure-volume loops was also assessed. Surgical approaches and recordings were optimised and isoprenaline and verapamil had positive and negative inotropic actions, respectively. Several issues were identified which require further attention. Chronic administration of isoprenaline and verapamil decreased cardiac contractility and increased CaMKIIδ expression and CaMKII activity. Chronic imatinib and sunitinib treatments did not alter cardiac contractility significantly. However, both CaMKIIδ expression and CaMKII activity were increased. The work presented in this thesis indicates that the guinea pig is suitable for the integrated assessment of cardiac contractility and CaMKII. Alterations in CaMKIIδ expression and CaMKII activity following chronic drug treatments could be an indication of cellular cardiotoxicity associated with contractile dysfunction at the whole animal level. The circumstances under which increased CaMKII expression and activity translate to compromised contractile performance require more detailed investigation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral