MYOCARDIAL PRESERVATION DURING ISCHEMIC ARREST

University Of Connecticut Sch Of Med/Dnt, Farmington CT

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Provided by Applicant): Endogenous factors generated from myocardial endothelium are released into the circulation during and following ischemia. Factors such as nitric oxide and prostacyclin function as vasodilators while endothelin and angiotensin II are potent vasoconstrictors. Inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibition and/or AT1 receptor antagonism has been found to be cardioprotective. During the current grant funding, our laboratory demonstrated that available ACE AT1 receptor blockers only partially inhibit the formation of angiotensin II, because angiotensin II car be formed by more than a single pathway. We also documented that AT1 receptor blockers function by two ways: one by blocking AT1 receptors, and the other by increasing cardioprotective bradykinin formation. We plan to expand these important findings by examining 1) whether angiotensin II about formation can be blocked by AT1 antisense therapy, and if so, how such intervention would manipulate myocardial preservation; ii) whether angiotensin II antagonism leads to the formation of other intercellular mediators such as nitric oxide and prostaglandins, and if so, their contribution to cardioprotection; iii) whether detrimental compotents such as inflammatory adhesion molecules and arachidonic acid are formed by angiotensin II due to its incomplete inhibition by ACE/AT1 receptor antagonism; and finally, iv) if angiotensin II by itself provides cardioprotection by preconditioning the heart. Myocardial preconditioning with angiotensin II has recently been documented; however, the mechanism of action remains unknown. The grant proposes to examine as yet unknown intracellula signaling pathways for angiotensin II during ischemia and reperfusion. This will include phospholipase signaling, protein kinase C, and newly discovered JAK/STAT pathway. The approach will consist of a combination of molecular and cellular biological techniques, genetically engineered animals and gene therapy.