Defense Date

2005

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Physiology

First Advisor

Dr. Rakesh C. Kukreja

Abstract

Cell damage represents a major pathomechanism in many diseases of high clinical interest, such as myocardial infarction (MI), where it plays an important role in ischemia-reperfusion (I/R) injury. Considerable progress has been made towards identifying physiological and pharmacological agents that play a key role in myocardial preconditioning against I/R injury and also elucidating the molecular changes leading to such protection.Second messengers in cellular signaling pathways, such as cGMP have been well implicated as key players in ischemic and pharmacological preconditioning (PC) of the heart. Phosphodiesterase type 5 (PDE-5) is an enzyme that specifically hydrolyzes cGMP thereby decreasing its tissue concentration. Sildenafil is a potent selective inhibitor of PDE-5 and therefore allows the accumulation of cGMP in several tissues shown to express PDE-5, including pulmonary and coronary arteries. We initially hypothesized that vasodilation induced by sildenafil may release several endogenous mediators including adenosine, bradykinin or nitric oxide (NO), that may trigger a signaling cascade leading to protection against I/R injury. Our results show that sildenafil, at a clinically relevant dose, induced powerful acute and delayed cardioprotection against I/R injury in an in vivo rabbit model via opening of mitoKATP channels. The acute cardioprotective effect of sildenafil was dependent on activation of protein kinase C in rabbits. Moreover, we observed that sildenafil induced delayed PC by NO produced through activation of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in the mouse heart. The expression of iNOS/eNOS was regulated by ERK phosphorylation and the delayed protection against I/R was blocked by PD98059, a selective ERK inhibitor. Furthermore, sildenafil-induced delayed protection was abolished in the intact heart as well as adult myocytes derived from adenosine A1 receptor knock-out mice suggesting an essential role of A1 receptor in protection. Taken together, these studies suggest that sildenafil is a powerful tool to reduce I/R injury in the animal models. Future clinical studies with relatively safe and effective PDE-5 inhibitors may have an enourmous impact on the use of these compounds in reducing I/R injury in the heart and other organs.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

June 2008

Included in

Physiology Commons

Share

COinS