Cardiovascular dysfunction is a potentially lethal complication of hypothermia. Due to a knowledge gap, pharmacological interventions are not recommended at core temperatures below 30°C. Yet, further cooling is induced in surgical procedures and survival of accidental hypothermia is reported after rewarming from below 15°C, advocating a need for evidence-based treatment guidelines. In vivo studies proposed a combination of positive inotropic effects through intracellular cAMP-elevation and afterload reduction through arteriole smooth muscle cAMP and/or cGMP-elevation as a favorable strategy to prevent cardiovascular dysfunction in hypothermia. Further development of treatment guidelines demand information about temperature-dependent changes in pharmacological effects of clinically relevant vasodilators.
In our recent papers, we found PDE3- and PDE5-inhibitors were able to inhibit elimination of cGMP and cAMP down to 20°C. As the cellular effects of these drugs can provide increased inotropy and afterload reduction, they show potential in treating cardiovascular dysfunction during hypothermia.
Different in vitro models for studying the temperature-dependent effects of phosphodiesterase-enzymes and transporter proteins were utilized to evaluate how PDE-inhibitors sildenafil, vardenafil, milrinone, amrinone, levosimendan and pentoxifylline affected cellular efflux and enzymatic breakdown of cAMP and cGMP at 37°C-20°C. We also assessed the electrophysiological effects of levosimendan, milrinone and isoprenaline in hiPSC-derived cardiomyocytes. Recordings of cellular action potential waveforms and contraction were recorded from monolayers of cultured cells during cooling to 26°C and after rewarming.