TRIIODOTHYRONINE INCREASES CONTRACTILITY INDEPENDENT OF BETA-ADRENERGIC RECEPTORS OR STIMULATION OF CYCLIC-3',5'-ADRENOSINE MONOPHOSPHATE

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 [T-3] and thyroxine [T-4]) 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 T-3, T-4, 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 T-3 or isoproterenol. Results: T-3 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 T-4. The maximal increase in dP/dT after 0.8 nmol isoproterenol was comparable to that produced by T-3. However, the cardiotonic actions of isoproterenol were significantly slower to develop (peaking at 60 vs. 15 s) and lasted longer than those of T-3. Pretreatment with propranolol 1 mu mol diminished the contractile effects of isoproterenol but had no effect on those of T-3. Concentrations of isoproterenol that increase contractility also significantly increased cAMP production in isolated rat myocardial cells. However, T-3 failed to increase cAMP production. Conclusions: These results demonstrate that the acute inotropic effects of T-3 are not shared by T-4 and appear unrelated to beta-adrenergic receptor mechanisms or to generation of cAMP. Thus, T-3 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 T-3 and to determine whether T-3 will prove useful for increasing ventricular function in patients.