Ion Transport Pharmacology in Heart Disease and Type-2 Diabetes

The cardiac sodium-calcium exchanger (NCX) is an important membrane protein which regulates cellular calcium necessary for the optimal contractile function of the heart. NCX has become a focal point in ischemic heart disease (IHD) research as evidence strongly suggests that reactive oxygen species (ROS) produced during IHD aids in causing NCX to malfunction resulting in an intracellular calcium overload in cardiac muscle leading to cardiac contractile abnormalities. Therefore, I hypothesized that NCX function is mediated by ROS increasing NCX1 activity during cardiac ischemia-reperfusion. To research this hypothesis, I investigated cellular mechanisms which may play a role in NCX dysfunction and also examined methods to correct NCX function. My studies were conducted with the use of patch clamping studies, fluorescence imaging, and whole heart studies in experimental models of IHD.;Furthermore, many IHD patients are also co-morbid for type-2 diabetes. These patients are prescribed sulfonylurea (SU) agents which act at the ATP-sensitive K+ channel (KATP). One agent such as glibenclamide is known to have cardiotoxic side effects. Therefore, SUs which are devoid of any cardiac side effects would be more beneficial. Interestingly, patients possessing the newly discovered genetic variant E23K-S1369A KATP channel have improved blood glucose levels with the use of the SU gliclazide. Therefore, I determined the functional mechanism by which gliclazide has increased inhibition at the KATP channel, observing that gliclazide is more potent than glibenclamide in the variant KATP channels. These findings have implications for type-2 diabetes therapy, in which 20% of the type-2 diabetic population carries the KATP channel variant. Furthermore, these findings highlight the cardiac effects of SUs and the potential use of gliclazide in the treatment of cardiac arrhythmias.;In summary, the findings presented in this thesis have implications on treatment strategies in the clinical setting, as a NCX inhibitor can be beneficial in ischemic heart disease, and also in heart failure, cardiac arrhythmias and possibly type-2 diabetes. Moreover, a pharmacogenomic approach in treating type-2 diabetes may also similarly provide a positive outcome when considering co-morbid cardiac complications such as atrial fibrillation and heart failure.;I found that reactive oxygen species directly and irreversibly modify NCX protein, increasing its activity thereby worsening the calcium overload that is deleterious to cardiac function. I also elucidated the molecular means by which NCX protein modification occurs, as ROS target a region of NCX involved in calcium binding which augments the ability of NCX to transport calcium. I also explored pharmacological means by which to decrease NCX function to relieve the calcium overload and reduce the damage to the heart. I discovered that ranolazine (Ranexa(TM)), which is indicated for the treatment of angina pectoris in the United States inhibits NCX activity directly, thereby further reducing the calcium overload-induced injury to the heart.