Exploring novel applications for ursodeoxycholic acid in the treatment of cardiovascular conditions

Abstract

As a bile acid, ursodeoxycholic acid (UDCA) is found endogenously formed in humans and other mammals where it is primarily involved in lipid metabolism. It is approved under a number of different brand names for the treatment of gallstones and Primary Billiary Cholangitis (PBC). Previous studies in cardiac cell models of Intrahepatic Cholestasis of Pregnancy (ICP) have demonstrated that UDCA can also be protective against the conduction slowing effects of the bile acid, taurocholic acid (TC). Therefore, this thesis aimed to identify novel applications for UDCA in the treatment of fetal arrhythmiasin ICP. It describes the development of a novel isolated-perfused neonatal rat heart model as a model of the fetal heart (FH) and an adult female rat heart model as a model of the maternal heart (MH) for evaluating the mechanism of bile acid induced arrhythmias. Using optical mapping and electrocardiogram (ECG) recording techniques, it separately evaluated TC effects in the atria and ventricles of the FH and compared them to effects in the MH model. It also evaluated the effects of UDCA in ischemia in a pilot study. It was observed that TC treatment induced significant conduction slowing in both the atria (ECG PR interval prolongation) and ventricles of the FH, but as occurs in ICP, these effects were absent or less pronounced in the MH model. Interestingly, co-administration of UDCA with TC was protective as it inhibited the observed conduction slowing effects. Using selective cardiac calcium channel blockers, it demonstrated that the conduction slowing effects of TC were mediated by blockade of the T-type calcium channel subtype. This was confirmed using the patch clamp technique that demonstrated that TC reduces the calcium current amplitude in neonatal rat and adult human fetal cardiomyocytes and this effect was inhibited with UDCA treatment. No beneficial effects were identified for UDCA in the treatment of acute global ischemia.