Chronic administration of cardiovascular drugs: altered energetics and transmembrane signaling.
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.
Chapados
R A
RA
Charles A. Dana Research Institute, Harvard Medical School, Boston, Massachussetts.
Gruver
E J
EJ
Ingwall
J S
JS
Marsh
J D
JD
Gwathmey
J K
JK
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004077:Digoxin / Q000494:pharmacology*; D004095:Dihydropyridines / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism; D015398:Signal Transduction; D013565:Sympatholytics / Q000494:pharmacology*; D013997:Time Factors; D014422:Turkeys
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D011955:Receptors, Drug; D013565:Sympatholytics; D004077:Digoxin; D000262:Adenylyl Cyclases