OBJECTIVE: Total peripheral vascular resistance (TPR) decreases in thyrotoxicosis and increases in hypothyroidism. Several mechanisms may be involved, including adaptation to changes in heat production and direct non-genomic effects of tri-iodothyronine (T3) on vascular smooth muscle cells. The aim of this study was to see if changes in TPR are related to changes in plasma concentrations of the endothelial hormones adrenomedullin and endothelin-1 as well as other hormones affecting vasculature. DESIGN: A prospective study. SUBJECTS: Eleven hypothyroid patients (pretreatment: thyroid-stimulating hormone (TSH) 68 (38-201) mU/l, T3 0.7 (0.35-1.5) nmol/l, fT4 3.0 (2.0-5.9) pmol/l, median (range)) and 14 with hyperthyroidism (pretreatment: TSH 0.02 (<0.01-0.06) mU/l, T3 6.4 (2.3-13.0) nmol/l, fT4 56.1 (22.9-70.0) pmol/l) were studied before treatment and 3 months after reaching the euthyroid state. Blood collection was carried out simultaneously with the recording of finger arterial pressure (FINAP). Cardiac output and TPR were derived from stroke volume computations by modelling flow from the FINAP signal. RESULTS: Thyroid-function tests of hypothyroid and thyrotoxic patients did not differ after restoration of the euthyroid state. TPR, expressed in arbitrary units (AU), decreased after correction of hypothyroidism (from 1.32+/-0.65 to 0.96+/-0.36 AU, P=0.04) and increased after correction of hyperthyroidism (from 0.75+/-0.18 to 1.10+/-0.35 AU, P=0.007). Adrenomedullin concentrations did not change during the transition from the hypothyroid state 3.2(0.9-11.0) pmol/l to the euthyroid state 4.9(0.9-8.6) pmol/l, but decreased after treatment of hyperthyroidism, from 5.2(0.9-11.0) pmol/l to 2.2(0.9-5.4) pmol/l. Plasma endothelin-1 was undetectable in all samples. Changes in TPR upon treatment correlated with log DeltafT4 (r=-0.65, P=0.001), log DeltaT3, (r=-0.57, P=0.006), Delta noradrenaline (r=0.54, P=0.02) and Delta ANP (atrial natriuretic peptide) (r=-0.59, P=0.004). Multiple linear regression analysis indicated that only T3 was an independent determinant of TPR. Changes in T3 accounted for 46% of the variability in the changes in TPR. CONCLUSIONS: TPR is reduced in thyrotoxicosis and increased in hypothyroidism. Restoration of the euthyroid state normalizes TPR. Changes in TPR are not related to plasma adrenomedullin concentrations, but 46% could be explained by changes in T3. Altered ANP secretion and adrenergic tone may contribute to the T3-induced changes in TPR.