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Isoproterenol-dependent decrease in oxygen uptake and respiratory enzyme activities in rat myocardial tissue and
J J Poderoso1, S Fernandez, M C Carreras
1Laboratory of Oxygen Metabolism, University Hospital, School of Medicine, University of Buenos Aires, Argentina.
Objective:
Myocardial damage induced by isoproterenol is believed to be secondary to increased oxygen demands on the heart. Our objective was to test an additional primary action of isoproterenol on tissue and mitochondrial oxidative metabolism and to compare these effects with the effects of other adrenergic agents in the presence of adrenergic inhibitors.
Design:
Prospective, dose-response study.
Setting:
Research laboratory at a university hospital.
Subjects:
Fifty Sprague-Dawley female rats (200 to 350 g), slightly anesthetized with ether and divided into several groups.
Interventions:
In 26 rats, the heart was removed, cut into fine slices (0.5-mm thickness), and placed in an ice-cold buffer. In 22 animals, the hearts were perfused in the Langendorff manner and chopped and processed for mitochondrial studies.
Measurements And Main Results:
We determined the following: a) the direct "in vitro" effects of isoproterenol and related catecholamines on normal oxygen uptake using myocardial slices; b) rat heart oxygen consumption and mitochondrial oxygen uptake from isolated organs, perfused with isoproterenol; c) measurements of enzyme activities in submitochondrial particles from the same perfused hearts; and d) the direct effects of isoproterenol on normal mitochondria isolated from normal nonperfused hearts. The oxygen uptake was determined polarographically with a Clark-type electrode and enzymatic activities were assayed by spectrophotometric reduction of cytochrome c at 550 nm with different mitochondrial substrates. Isoproterenol (0.01 to 100 nM) decreased the oxygen uptake by the heart slices in a dose-dependent manner. In comparison, epinephrine or norepinephrine per se did not change the parameter. However, with the addition of alpha-adrenergic receptor inhibitors, oxygen uptake decreased to values similar to those values obtained with isoproterenol. Also, mitochondria isolated from hearts perfused with isoproterenol had decreased state 3 respiratory rates (by 50%) and decreased respiratory control ratios (by 30%), without changes in adenosine 5'-diphosphate/oxygen ratios. The respiratory chain enzyme activities were also lowered.
Conclusions:
The data suggest that while isoproterenol increases "in vivo" oxygen uptake by the working rat heart, isoproterenol can simultaneously decrease maximal adenosine 5'-diphosphate-induced mitochondrial oxygen uptake and in vitro myocardial tissue oxygen uptake, probably by modifying the mitochondrial respiratory enzymes. This action could be counteracted by alpha-adrenergic agonist effects.
Insights
Isoproterenol decreases myocardial oxygen uptake by affecting mitochondrial function, despite increasing overall heart oxygen demand. Alpha-adrenergic inhibitors can counteract this effect, suggesting a complex interaction in cardiac metabolism.
Area of Science:
- Cardiovascular Physiology
- Mitochondrial Metabolism
- Adrenergic Pharmacology
Background:
- Isoproterenol-induced myocardial damage is traditionally linked to increased cardiac oxygen demand.
- A potential direct effect of isoproterenol on tissue and mitochondrial oxidative metabolism requires investigation.
Purpose of the Study:
- To investigate the direct effects of isoproterenol on myocardial tissue and mitochondrial oxidative metabolism.
- To compare these effects with other adrenergic agents, considering the role of adrenergic inhibitors.
Main Methods:
- A prospective, dose-response study was conducted using Sprague-Dawley female rats.
- Myocardial slices and isolated mitochondria were used to assess oxygen uptake and enzyme activities.
- Hearts were perfused in the Langendorff manner, and oxygen consumption was measured polarographically.
Main Results:
- Isoproterenol dose-dependently decreased oxygen uptake in myocardial slices.
- Isolated mitochondria from isoproterenol-perfused hearts showed reduced respiratory rates and control ratios.
- Epinephrine and norepinephrine did not affect oxygen uptake unless alpha-adrenergic inhibitors were present.
Conclusions:
- Isoproterenol exhibits a dual effect: increasing in vivo cardiac oxygen demand while decreasing in vitro mitochondrial oxygen uptake.
- This inhibitory action on mitochondrial respiration is likely mediated by effects on respiratory enzymes.
- Alpha-adrenergic agonists may counteract the negative impact of isoproterenol on mitochondrial function.
