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The β3 Adrenergic Receptor Antagonist L-748,337 Attenuates Dobutamine-Induced Cardiac Inefficiency While Preserving Inotropy in Anesthetized Pigs

Permanent link
https://hdl.handle.net/10037/23595
DOI
https://doi.org/10.1177/10742484211048762
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Date
2021-09-23
Type
Journal article
Tidsskriftartikkel
Peer reviewed

Author
Rødland, Lars; Rønning, Leif Reidar Brenk; Kildal, Anders Benjamin; How, Ole-Jakob
Abstract
Excessive myocardial oxygen consumption (MVO2) is considered a limitation for catecholamines, termed oxygen cost of contractility. We hypothesize that increased MVO2 induced by dobutamine is not directly related to contractility but linked to intermediary myocardial metabolism. Furthermore, we hypothesize that selective b3 adrenergic receptor (b3AR) antagonism using L-748,337 prevents this. In an open-chest pig model, using general anesthesia, we assessed cardiac energetics, hemodynamics and arterial metabolic substrate levels at baseline, ½ hour and 6 hours after onset of drug infusion. Cardiac efficiency was assessed by relating MVO2 to left ventricular work (PVA; pressure–volume area). Three groups received dobutamine (5 mg/kg/min), dobutamine þ L-748,337 (bolus 50 mg/kg), or saline for time-matched controls. Cardiac efficiency was impaired over time with dobutamine infusion, displayed by persistently increased unloaded MVO2 from ½ hour and 47% increase in the slope of the PVA–MVO2 relation after 6 hours. Contractility increased immediately with dobutamine infusion (dP/dtmax; 1636 + 478 vs 2888 + 818 mmHg/s, P < 0.05) and persisted throughout the protocol (2864 + 1055 mmHg/s, P < 0.05). Arterial free fatty acid increased gradually (0.22 + 0.13 vs 0.39 + 0.30 mM, P < 0.05) with peak levels after 6 hours (1.1 + 0.4 mM, P < 0.05). By combining dobutamine with L-748,337 the progressive impairment in cardiac efficiency was attenuated. Interestingly, this combined treatment effect occurred despite similar alterations in cardiac inotropy and substrate supply. We conclude that the extent of cardiac inefficiency following adrenergic stimulation is dependent on the duration of drug infusion, and b3AR blockade may attenuate this effect.
Publisher
SAGE
Citation
Rødland, Rønning, Kildal, How. The β3 adrenergic receptor antagonist L-748,337 attenuates dobutamine-induced cardiac inefficiency while preserving inotropy in anesthetized pigs. Journal of Cardiovascular Pharmacology and Therapeutics. 2021:1-10
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