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Chronic administration of cardiovascular drugs: altered energetics and transmembrane signaling
R A Chapados1, E J Gruver, J S Ingwall
1Charles A. Dana Research Institute, Harvard Medical School, Boston, Massachussetts.
Abstract:
The effects of clinically used cardioactive agents in furazolidone-induced cardiomyopathy in the turkey poult have been recently reported, and note-worthy differences in cardioprotective efficacy of adrenergic effectors, calcium channel blockers, and cardiac glycosides have been noted in animal and human studies of heart failure. We therefore investigated the effects of chronic oral administration of cardioactive agents on ventricular tissue from normal turkey poults, and we determined whether these agents altered cardiac function, energetics, or transmembrane signaling pathways in a manner that might contribute to the varying degrees of cardioprotection and therapeutic efficacy reported previously. Creatine content was significantly higher in propranolol- and atenolol-treated animals. There was also higher lactate dehydrogenase and creatine kinase activities, reflecting an overall increase in energy reserve. Treatment with the calcium channel antagonists verapamil and nifedipine produced a significant increase in adenylyl cyclase activity and beta-adrenergic receptor density. Nifedipine treatment resulted in upregulation of both beta-adrenergic receptors and dihydropyridine receptors. This finding was associated with enhanced peak twitch force at all extracellular Ca2+ concentrations. We demonstrate for the first time that clinically used pharmacological agents (nifedipine and propranolol) result in alteration in two transmembrane signaling pathways, with associated alterations in physiological performance. Moreover, agents without cardioprotective effect in furazolidone-induced cardiomyopathy did not induce alterations in transmembrane signaling or energetics in normal hearts.
Insights
Clinically used cardioactive drugs alter heart function and energy reserves in normal turkey poults. Agents with known cardioprotective effects changed transmembrane signaling pathways and physiological performance.
Area of Science:
- Cardiovascular Pharmacology
- Animal Models of Cardiac Disease
Background:
- Cardioprotective efficacy of cardioactive agents varies across studies.
- Understanding mechanisms of action in healthy hearts is crucial.
Purpose of the Study:
- Investigate chronic oral administration effects of cardioactive agents on normal turkey poult ventricular tissue.
- Determine if agents alter cardiac function, energetics, or transmembrane signaling pathways.
Main Methods:
- Chronic oral administration of cardioactive agents to turkey poults.
- Analysis of ventricular tissue for creatine content, enzyme activities, and receptor density.
- Assessment of cardiac function and transmembrane signaling pathways.
Main Results:
- Propranolol and atenolol increased creatine content and enzyme activities (LDH, CK), indicating enhanced energy reserve.
- Verapamil and nifedipine increased adenylyl cyclase activity and beta-adrenergic receptor density.
- Nifedipine upregulated beta-adrenergic and dihydropyridine receptors, enhancing peak twitch force.
Conclusions:
- Clinically used agents like nifedipine and propranolol alter transmembrane signaling and physiological performance in normal hearts.
- Agents lacking cardioprotective effects did not induce significant changes in signaling or energetics.
- Findings provide insights into differential drug efficacy and mechanisms.