Abstract 14090: Direct Cardiac Positive Inotropic and Lusitropic Effect of Colforsin Daropate is Enhanced While Isoproterenol is Attenuated in Hypothyroidism
Background: Thyroid hormone (TH) has profound effects on the modulation of cardiac β-adrenergic regulation. In addition to β-adrenergic receptor (β-AR), Adenylate Cyclase (AC) is an important target for TH. It has been shown that cardiac-specific AC catalytic isoforms (V, VI) are negatively regulated by TH. Hypothyroidism (Hypo) upregulates cardiac AC, suggesting a mechanism for preserving cAMP accumulation and amplifying cardiomyocyte signaling. The physiological implication and functional significance of these changes in the cardiac dysfunction of Hypo are unclear. We tested the hypothesis that in Hypo, the myocardial response to β-AR stimulation with Isoproterenol (ISO) is attenuated, but the inotropic response to an AC stimulator of colforsin daropate (COLF) is enhanced. The hypothesis was evaluated in isolated left ventricular (LV) myocytes to avoid the confound influence of their chronotropic and coronary vasodilator actions.
Methods: We compared LV myocyte contraction and relaxation responses to ISO (10-8 M) and COLF (10-6 M), a water-soluble derivative of forskolin that directly stimulates AC, in 11 normal control (C) and 6 Hypo rats induced by methimazole (~30 mg/kg/day for 8 weeks in the drinking water).
Results: Compared to controls, in Hypo, there was myocyte systolic and diastolic dysfunction indicated by significant decreases in myocyte percent shortening, contraction (dL/dtmax) (58%, Hypo: 55.9±10.4 vs C:132.5±9.1μm/s) and relaxation (dR/dtmax) (51%, 50.8±12.9 vs 103.3±6.2 μm/s) accompanied by attenuated responses to ISO stimulation but enhanced responses to COLF. Compared to normal, in Hypo myocytes, superfusion of ISO produced significantly less increases in dL/dtmax (Hypo: 30% vs C: 67%) and dR/dtmax (31% vs 51%). In contrast, superfusion of COLF produced significantly greater increases in dL/dtmax (147% vs 52%) and dR/dtmax (155% vs 37%) in Hypo myocytes compared to normal.
Conclusions: Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization but increased AC activity sensitization. These results suggest that colforsin daropate may be preferable in the treatment of severe cardiac dysfunction in hypothyroid cardiomyopathy.
- © 2013 by American Heart Association, Inc.