Semester

Fall

Date of Graduation

2011

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

S Jamal Mustafa

Abstract

One out of three individuals suffer from one form of cardiovascular disease, out of which, about 6,000,000 individuals suffer from coronary heart disease. Adenosine has long been known to play a role in coronary flow (CF) regulation; however, the individual role of A2A and A2B adenosine receptors (AR) and their contribution is yet to be fully elucidated. The purpose of this study was to characterize the pharmacology of both A2 ARs in coronary arteries (CAs), in addition, to identifying their role in reactive hyperemia, and their signaling mechanisms. We hypothesized that A2 ARs mediate an increase in CF, in addition, to being involved in metabolic control of CF. Therefore, in this study, we investigated CF changes due to exogenous activation of A2A and A2B ARs, in addition, to their endogenous activation during coronary reactive hyperemia, when metabolic factors, such as adenosine, play a pivotal role. We used the well established Langendorff isolated heart system as well as selective and non-selective AR agonists and antagonists, and A2A and A2B AR single and double knockout mice. We found that activation of both A2A and A2B ARs induces an increase in CF, albeit with different pharmacological profile. Further, in A2BKO mice, A2AARs are up-regulated in order to compensate for deletion of A2BARs. These findings may suggest that both A2ARs are capable of increasing the CF in conditions when a sufficient level of adenosine is available. However, we also found that only A2AARs contribute to CF changes in coronary reactive hyperemia, which may suggest that A2BARs may be activated in more severe conditions such as longer ischemic conditions, where adenosine levels are significantly augmented. We next investigated signaling pathways involved in A2AR-mediated effects. We found that non-mitochondrial K ATP channels are a major end effectors in A2AR-induced increase in CF. What is more interesting is that we illustrated that H2O 2 mediates adenosine's effect on CF and that is coupled to adenosine-mediated effect on KATP channels. From these data, it can be concluded that A2A and A2B ARs may regulate CF in different conditions, albeit, maybe through the same signaling pathway.

Download

Share

COinS