title: Triiodothyronine increases contractility independent of beta-adrenergic receptors or stimulation of cyclic-3',5'-adenosine monophosphate.
abstract: BACKGROUND
  Triiodothyronine regulates cardiac contractility; however, the mechanisms by which it produces its acute contractile effects remains unknown. We compared the acute effects of thyroid hormones (triiodothyronine [T3] and thyroxine [T4]) and of isoproterenol on the contractility of isolated rat hearts. In addition, we sought to determine whether the acute inotropic effects of thyroid hormones were mediated by beta-adrenergic receptors or by increased production of cyclic-3',5'-adenosine monophosphate (cAMP).
  
  
  METHODS
  A Langendorff heart preparation harvested from euthyroid male Sprague-Dawley rats was used. Drugs were administered through an aortic perfusion catheter. A pressure-transduced left-ventricular balloon catheter measured pressure and heart rate changes. Changes in the maximum positive rate of change in pressure (dP/dT) and maximum negative dP/dT were determined. Responses to varying doses of T3, T4, and isoproterenol were assessed in the presence and absence of beta-adrenergic receptor blockade with propranolol. cAMP production, measured by radioimmunoassay, was determined in myocardial cell suspensions after incubation with T3 or isoproterenol.
  
  
  RESULTS
  T3 0.74 nmol rapidly and significantly increased maximum dP/dT by 335 +/- 38 mmHg/s within 30 s after bolus injection; however, contractility was unchanged after as much as 12.9 nmol T4. The maximal increase in dP/dT after 0.8 nmol isoproterenol was comparable to that produced by T3. However, the cardiotonic actions of isoproterenol were significantly slower to develop (peaking at 60 vs. 15 s) and lasted longer than those of T3. Pretreatment with propranolol 1 mumol diminished the contractile effects of isoproterenol but had no effect on those of T3. Concentrations of isoproterenol that increase contractility also significantly increased cAMP production in isolated rat myocardial cells. However, T3 failed to increase cAMP production.
  
  
  CONCLUSIONS
  These results demonstrate that the acute inotropic effects of T3 are not shared by T4 and appear unrelated to beta-adrenergic receptor mechanisms or to generation of cAMP. Thus, T3 acutely stimulates cardiac contraction by mechanisms that differ from those of the more commonly used beta-adrenergic receptor agonists and phosphodiesterase inhibitors. Further studies are needed to identify the mechanisms underlying the acute contractile effects of T3 and to determine whether T3 will prove useful for increasing ventricular function in patients.
authors.affiliation: Department of Anesthesia, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1009, USA.
authors.forename: D G
authors.initials: DG
authors.lastname: Ririe
authors.forename: J F
authors.initials: JF
authors.lastname: Butterworth
authors.forename: R L
authors.initials: RL
authors.lastname: Royster
authors.forename: D A
authors.initials: DA
authors.lastname: MacGregor
authors.forename: G P
authors.initials: GP
authors.lastname: Zaloga
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology*; D013268:Stimulation, Chemical; D013974:Thyroxine / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D011943:Receptors, Adrenergic, beta; D014284:Triiodothyronine; D000242:Cyclic AMP; D007545:Isoproterenol; D013974:Thyroxine