inositol-1-4-5-trisphosphate and Hypothyroidism

In this study, we examined changes in the biochemical and inotropic events of the alpha(1)-adrenoceptor signaling pathway in hypothyroid rat hearts. Hypothyroidism was induced by treating experimental animals with 0.05% 6-n-propyl-2-thiouracil (PTU) in drinking water for 7 weeks. A significant decrease of beta- and an increase in alpha(1)-adrenoceptor density as well as an increase in the basal activity of the phosphoinositide (4,5) bisphosphate hydrolyzing phospholipase C was observed in sarcolemmal membranes purified from hypothyroid hearts as compared to age-matched euthyroid controls. Following stimulation with 10 microM phenylephrine (in the presence of 10 microM atenolol), the increase of contractile parameters over baseline values was significantly higher in hypo- than euthyroid hearts, while the opposite occurred under beta-stimulation with 0.1 microM isoproterenol. Interestingly, the increase in phenylephrine-mediated positive inotropy was accompanied by a significant increase in the sarcolemmal phospholipase C activity and in the inositol 1,4,5-trisphosphate content in hypothyroid as compared to euthyroid controls. Our results suggest that cardiac alpha(1)-adrenoceptor and its associated phosphoinositide signaling pathway may act as a reserve for catecholamine inotropic response in hypothyroidism, where the beta-adrenoceptors are compromised.

Topics: Animals; Antithyroid Agents; Cell Membrane; Heart; Hypothyroidism; Inositol 1,4,5-Trisphosphate; Male; Phosphatidylinositol 4,5-Diphosphate; Propylthiouracil; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Sarcolemma; Signal Transduction; Stimulation, Chemical; Type C Phospholipases; Up-Regulation

1. Mechanical responses to various stimulants and the distribution of adrenoceptor subtypes were investigated in smooth muscle cells of the rat aorta in eu- (control), hyper- and hypo-thyroid states. 2. Concentration-response relationships for K showed that the KCl EC50 value was slightly higher (28.4 mM K) in hypothyroid than in euthyroid and hyperthyroid states (22.5 mM and 22.8 mM K, respectively). The order of maximum amplitudes of KCl contraction was control greater than hypothyroid greater than hyperthyroid. 3. The EC50 values for the noradrenaline (NA)-induced contraction for eu-, hypo- and hyper-thyroid states were 7.4, 12.5 and 5.5 nM, respectively. The density of alpha 1-adrenoceptors was increased to 1.4 times the control in the hypothyroid state and reduced to 0.26 times the control in the hyperthyroid state. 4. The EC50 values for the phenylephrine-induced contraction in eu-, hypo- and hyper-thyroid states were 43.4, 247 and 41.5 nM, respectively, and those for clonidine 104, 1360 and 56.5 nM, respectively. The IC50 values for prazosin against 0.1 microM NA-induced contractions in eu-, hypo- and hyper-thyroid states were 5.8, 3.5 and 0.7 nM, respectively, and those for yohimbine 8.9, 5.4 and 4.1 microM, respectively. 5. The IC50 values for isoprenaline against phenylephrine-induced contractions were 63 nM and 2.4 microM in hyper- and eu-thyroid states, respectively, and the corresponding IC25 values for eu- and hypo-thyroid states were 72 and 423 nM, respectively. The density of beta-adrenoceptors was increased to 3.91 times the control in the hyperthyroid and reduced to 0.68 times the control in the hypothyroid states. 6. NA consistently increased the amount of inositol 1,4,5-trisphosphate (1P3) within 30s in the three thyroid states. In the hypothyroid state, the amount of IP3 was slightly increased and in the hyperthyroid condition, it occurred to a lesser extent than in the euthyroid state. 7. The results indicate that in hypothyroidism, the density of alpha,-adrenoceptors is increased and that of ,Beta-adrenoceptors reduced in vascular beds. The latter but not the former is accompanied by corresponding mechanical responses. In hyperthyroidism, the density of alpha 1-adrenoceptors is decreased and beta-adrenoceptors increased with parallel changes in mechanical responses.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Aorta, Thoracic; Catecholamines; Hyperthyroidism; Hypothyroidism; Inositol 1,4,5-Trisphosphate; Isometric Contraction; Isoproterenol; Male; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Rats; Rats, Inbred Strains