Cryobiology · 2014
Negative inotropic effects of epinephrine in the presence of increased β-adrenoceptor sensitivity during hypothermia in a rat model.
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Dietrichs Erik Sveberg, Schanche Torstein, Kondratiev Timofei, Gaustad Svein Erik, Sager Georg, Tveita Torkjel
Аннотация
BACKGROUND: Animal studies show reduced inotropic effects of cardiac β-adrenoceptor agonists like epinephrine (Epi) during hypothermia and rewarming, while drugs targeting other pharmacological mechanisms have positive effects. This study therefore aimed to determine β-adrenoceptor sensitivity in isolated cardiomyocytes and investigate hemodynamic effects of Epi and its ability to stimulate cardiac β-adrenoceptors at different temperatures in vivo.
METHODS: Isolated rat myocardial cells were incubated with the radioactive β-adrenoceptor ligand [(3)H]-CGP12177 and propranolol, used as a displacer. Cells were subjected to normothermia (37 °C) or hypothermia (15 °C). After incubation, radioactivity was measured to estimate β-adrenoceptor affinity for propranolol (IC50), as a measure of β-adrenoceptor sensitivity. In separate in vivo experiments, Epi (1.25 μg/min) was administered the last 5min of experiments in normothermic (37 °C, 5h), hypothermic (4h at 15 °C) and rewarmed rats (4h at 15 °C, and subsequently rewarmed to 37 °C). Hemodynamic parameters were monitored during infusion. Hearts were thereafter freeze-clamped and tissue cAMP was measured.
RESULTS: In vitro measurements of IC50 for propranolol showed a hypothermia-induced increase in β-adrenoceptor sensitivity at 15 °C. Corresponding in vivo experiments at 15 °C showed decreased cardiac output and stroke volume, whereas total peripheral resistance (TPR) increased during Epi infusion, simultaneous with a 4-fold cAMP increase.
CONCLUSIONS: This experiment shows a hypothermia-induced in vivo and in vitro increase of cardiac β-adrenoceptor sensitivity, and simultaneous lack of inotropic effects of Epi in the presence of increased TPR. Our findings therefore indicate that hypothermia-induced reduction in inotropic effects of Epi is due to substantial elevation of TPR, rather than β-adrenoceptor dysfunction.
METHODS: Isolated rat myocardial cells were incubated with the radioactive β-adrenoceptor ligand [(3)H]-CGP12177 and propranolol, used as a displacer. Cells were subjected to normothermia (37 °C) or hypothermia (15 °C). After incubation, radioactivity was measured to estimate β-adrenoceptor affinity for propranolol (IC50), as a measure of β-adrenoceptor sensitivity. In separate in vivo experiments, Epi (1.25 μg/min) was administered the last 5min of experiments in normothermic (37 °C, 5h), hypothermic (4h at 15 °C) and rewarmed rats (4h at 15 °C, and subsequently rewarmed to 37 °C). Hemodynamic parameters were monitored during infusion. Hearts were thereafter freeze-clamped and tissue cAMP was measured.
RESULTS: In vitro measurements of IC50 for propranolol showed a hypothermia-induced increase in β-adrenoceptor sensitivity at 15 °C. Corresponding in vivo experiments at 15 °C showed decreased cardiac output and stroke volume, whereas total peripheral resistance (TPR) increased during Epi infusion, simultaneous with a 4-fold cAMP increase.
CONCLUSIONS: This experiment shows a hypothermia-induced in vivo and in vitro increase of cardiac β-adrenoceptor sensitivity, and simultaneous lack of inotropic effects of Epi in the presence of increased TPR. Our findings therefore indicate that hypothermia-induced reduction in inotropic effects of Epi is due to substantial elevation of TPR, rather than β-adrenoceptor dysfunction.