Pharmacological approaches for myocardial protection In healthy and diseased hearts

In recent years, cardiovascular research has focused on investigating approaches to protect the heart against the severe consequences of ischemia/reperfusion (I/R) injury occurring after myocardial infarction and revascularization. Numerous pharmacological strategies have shown beneficial effects on cardioprotection in different animal species. Employing substances as pharmacological conditioning strategies that are already clinically approved and used in patients, for instance volatile anesthetics, opioids or α2-adrenoreceptor agonists, seems encouraging. However, definite translation of these strategies from experimental studies into the clinical setting improving patient outcome, remains incomplete. The question lingers whether certain substances, conditioning strategies or combination of approaches targeting different mechanisms, can be successful in conferring cardioprotection in patients.
The present thesis focuses on cardioprotective strategies before (preconditioning) and after (postconditioning) myocardial ischemia by different pharmacological agents, investigating their underlying mechanisms in healthy and diseased hearts. Studies included in this thesis demonstrate that Ramelteon-induced preconditioning is mediated via protein kinase B / protein kinase G (Akt/PKG) pathways which trigger activation of mitochondrial large-conductance calcium-sensitive potassium (mBK_Ca) channels. This activation in turn leads to reactive oxygen species (ROS) release and inhibition of mitochondrial permeability transition pore (mPTP) opening. Further, our research shows that a combination of conditioning stimuli and substances, in specific Sildenafil and Milrinone, in sub-protective concentrations leads to a reduction of cardiac damage after I/R injury.
Finally, it is demonstrated that Dexmedetomidine induces early and late postconditioning via activation of different mitochondrial potassium (mK⁺) channels and that postconditioning with Dexmedetomidine is fully abolished under acute hyperglycemia.