L‐thyroxine‐induced vasodilation impairment and increased vascular response to norepinephrine are mediated by dysfunctional NO release

Abstract

AbstractHyperthyroidism causes a series of changes in the cardiovascular system. The effects of excess thyroid hormone on NO‐mediated vasorelaxation and vasocontractility were investigated. A pathological hyperthyroid rat model was developed. Thoracic aorta was isolated and isometric changes were recorded in both control and thyroxine‐treated animals. In the vasorelaxation study, the overall acetylcholine‐induced vasorelaxation was greatly reduced in aortae from thyroxine‐treated animals. L‐NO‐arginine (100 mM) was used to define the NO‐dependent and NO‐independent components of acetylcholine‐induced relaxation: in control animals 56±2% of relaxation is NO‐dependent and 44±2% is NO‐independent and in the thyroxine model the ratio was 31±2% vs. 69±5%. L‐arginine (10 μM), an NO synthase substrate, did not increase the relaxation in the control (2%), but markedly increased relaxation (18%) in the thyroxine model. This indicates that L‐arginine could partially rescue the vasorelaxation impairment induced by L‐thyroxine. In vasocontractility studies, the maximal aorta responses to NE in the thyroxine group were reduced significantly, but the responses to low concentrations of NE were enhanced comparing with control. The basal release of NO from the endothelium is compromised in the thyroxine model: +28±5% in the thyroxin‐treated group vs. +39±5% in the control. (P<0.01). The AUC was shifted downward in both groups, but was relatively larger by –66±5% in the thyroxine model compared with –56±4% in control (P<0.01) after the application of L‐arginine. When L‐NO arginine was added to aortae pretreated with L‐arginine, vascular tone was increased in control tissues, but no change was observed in thyroxine‐treated tissues. In conclusion, chronic overdose of L‐thyroxine significantly impairs the acetylcholine‐induced vasorelaxation activity by affecting both the NO‐dependent and NO‐independent relaxing components of relaxation. The impaired maximal contraction of vascular smooth muscle to high concentrations of NE is likely attributed to the imbalance of energy supply and the enhancement of the vascular tension to NE at low concentration is attributed both to an impairment of the basal release of NO and to an overload of intracellular calcium. Drug Dev. Res. 58:116–121, 2003. © 2003 Wiley‐Liss, Inc.