Determination of replacement and suppressive doses of thyroxine.

Suppression daily doses of thyroxine (T4) were determined and the daily amounts of T4 required to replace T4 were established in 217 hypothyroid patients. Patients with Hashimoto's thyroiditis treated daily with 2-3 micrograms/kg lean body mass or 1-2 micrograms/kg body weight T4 had normal serum thyrotrophin (TSH) concentrations, normal response to TSH-releasing hormone (TRH) and normal systolic time intervals but doses higher than 3 micrograms/kg lean body mass or 2 micrograms/kg body weight decreased serum TSH concentrations, with no response to TRH and systolic time intervals typical of hyperthyroidism. In 13/32 (41%) hypothyroid patients with Graves' disease following 131I and/or surgery, the daily T4 replacement dose was similar to that in Hashimoto's thyroiditis patients but in 12 (38%) patients daily doses of 2-3 micrograms/kg lean body mass or 1-2 micrograms/kg body weight T4 increased serum T4 and suppressed TSH levels, and in six (9%) lower doses were required to control hypothyroidism. The T4 suppression dose for patients with thyroid cancer was more than 3 micrograms/kg lean body mass or 2 micrograms/kg body weight, whereas approximately 30% of non-toxic nodular goitre patients required less than 3 micrograms/kg lean body mass. It is concluded that replacement or suppression doses of T4 should be individually determined and that different criteria should be applied for their calculation depending on the thyroid abnormality.

Block of contracture in skinned frog skeletal muscle fibers by calcium antagonists.

The ability of a number of calcium antagonistic drugs including nitrendipine, D600, and D890 to block contractures in single skinned (sarcolemma removed) muscle fibers of the frog Rana pipiens has been characterized. Contractures were initiated by ionic substitution, which is thought to depolarize resealed transverse tubules in this preparation. Depolarization of the transverse tubules is the physiological trigger for the release of calcium ion from the sarcoplasmic reticulum and thus of contractile protein activation. Since the transverse tubular membrane potential cannot be measured in this preparation, tension development is used as a measure of activation. Once stimulated, fibers become inactivated and do not respond to a second stimulus unless allowed to recover or reprime (Fill and Best, 1988). Fibers exposed to calcium antagonists while fully inactivated do not recover from inactivation (became blocked or paralyzed). The extent of drug-induced block was quantified by comparing the height of individual contractures. Reprimed fibers were significantly less sensitive to block by both nitrendipine (10 degrees C) and D600 (10 and 22 degrees C) than were inactivated fibers. Addition of D600 to fibers recovering from inactivation stopped further recovery, confirming preferential interaction of the drug with the inactivated state. A concerted model that assumed coupled transitions of independent drug-binding sites from the reprimed to the inactivated state adequately described the data obtained from reprimed fibers. Photoreversal of drug action left fibers inactivated even though the drug was initially added to fibers in the reprimed state. This result is consistent with the prediction from the model. The estimated KI for D600 (at 10 degrees and 22 degrees C) and for D890 (at 10 degrees C) was approximately 10 microM. The estimated KI for nitrendipine paralysis of inactivated fibers at 10 degrees C was 16 nM. The sensitivity of reprimed fibers to paralysis by D600 and D890 was similar. However, inactivated fibers were significantly less sensitive to the membrane-impermeant derivative (D890) than to the permeant species (D600), which suggests a change in the drug-binding site or its environment during the inactivation process. The enantomeric dihydropyridines (+) and (-) 202-791, reported to be calcium channel agonists and antagonists, respectively, both caused paralysis, which suggests that blockade of a transverse tubular membrane calcium flux is not the mechanism responsible for antagonist-induced paralysis. The data support a model of excitation-contraction coupling involving transverse tubular proteins that bind calcium antagonists.

Contractile activation and recovery in skinned frog muscle stimulated by ionic substitution.

Contractile activation of skinned (sarcolemma removed) skeletal muscle fibers stimulated by ionic substitution has been studied. Stimulating solutions contained varying amounts of Cl- and K+ with the [K+] x [Cl-] product kept constant at 368 mM2. Activation is a graded function of the ionic content of the stimulating solution. Mechanical threshold is reached when the [Cl-] is changed from 4 to 6.5 mM. Maximal activation occurs at 20 mM Cl-. After stimulation, fibers do not respond to a second stimulus unless allowed to recover. Contractile height reaches 50% of control levels after 30 s in the standard recovery solution (4 mM Cl). Full recovery is reached after approximately 2-4 min. The degree of contractile recovery after a constant interval (30 s) depends on the ionic composition of the recovery solution. Contractile recovery decreases 50% when the [Cl-] of the recovery solution is raised from 4 to 5.5 mM. The activation and recovery phenomena described for skinned fibers stimulated by ionic substitution are similar to those described for intact cells stimulated by elevated [K+]. This finding is consistent with the hypothesis that depolarization of resealed transverse tubules triggers release of Ca2+ from the sarcoplasmic reticulum of skinned fibers.