DRUGS UPON MYOCARDIAL HYPOXIA

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DESCRIPTION: This application for Dr. Gross and his research team is concerned with the determination of the mechanism of myocardial preconditioning. More specifically, the investigators will determine the role of KATP in mediating preconditioning and its interaction with other signaling pathways. Their first aim is to determine if preconditioning (PC) produced by ischemia, hypoxia, KATP openers or adenosine share common hemodynamic or electrophysiologic (EP) mechanisms. They will determine the effect of a nonselective blocker (glyburide), an ischemia selective blocker (5-HD), or a vascular selective blocker on preconditioning. They will also determine the effect of a putative pancreatic selective KATP blocker on preconditioning. They will determine the importance of APD shortening in mediating preconditioning. This will be done by determining the effect of adenosine or PCO or APD before and after preconditioning. They will also determine the effect of IKr blockers which will abolish the APD shortening effects of preconditioning, etc., on preconditioning. In aim II, they will determine the receptor or signal transduction pathways for PC produced by regional hypoxia. They will determine the role of PKC-alpha-1 interactions, cAMP (via catecholamines), adenosine, and finally if KATP is the end effector produced by PKC activation. This will be done using hypoxic buffer (4X5 min) in dogs. They will use a variety of agonists and antagonists of KATP, adenosine, PKA, PKC to determine their importance. In aim III, they will determine if increased adenosine release is responsible for triggering PC and if KATP openers work through enhancing adenosine release. This will be done using hypoxia or ischemia as described in other aims. Adenosine will be measured using a microdialysis technique. In aim IV the applicant will determine if KATP openers or adenosine agonists lower PC threshold and if adenosine or PKC or KATP mediate memory (how long after PC can protection be seen?). They will also determine the role of Ito in cardiac memory. They will use PKC inhibitors, KATP blockers, adenosine antagonists, 4-aminopyridine.