Ritodrine- and terbutaline-induced hypokalemia in preterm labor: mechanisms and consequences.

The effects of ritodrine and terbutaline on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor. Timed blood and urine samples were obtained for two hours before and during six hours of intravenous ritodrine (N = 5) and terbutaline (N = 5) administered in pharmacologically equivalent doses. No differences were found in any parameters affecting potassium homeostasis or renal function between these drugs. A decrease in mean plasma potassium of 0.9 mEq/liter occurred after 30 minutes of drug infusion (4.2 +/- 0.1 to 3.3 +/- 0.1 mEq/liter, P < 0.005) before any significant changes in plasma glucose (75.0 +/- 4.7 to 93.7 +/- 6.1 mg/dl, P = NS) or plasma insulin (12.4 +/- 6.0 to 28.4 +/- 5.1 mU/ml, P = NS). The mean plasma potassium after four hours of drug infusion was 2.5 +/- 0.1 mEq/liter. Plasma insulin rose to a level known to induce cellular potassium uptake (39.2 +/- 7.7 mU/ml) after 60 minutes of drug therapy and remained at this level for four hours. Hyperlactatemia occurred at four hours (4.7 +/- 0.8 mmol/liter) and the plasma lactate/pyruvate ratio increased in a 10:1 ratio. Both drugs significantly reduced glomerular filtration rate, sodium, potassium, and chloride excretion and urinary flow rate. Changes in acid-base homeostasis, plasma aldosterone, or renal potassium excretion did not contribute to ritodrine-or terbutaline-induced hypokalemia. In 83 women with preterm labor randomly assigned to ritodrine (N = 42) or terbutaline (N = 41), the maximum decrease in plasma potassium occurred after six hours of drug infusion. During Holter monitoring, 3 of 14 women treated with ritodrine or terbutaline developed symptomatic cardiac arrhythmias at the lowest plasma potassium while no women treated with saline and morphine (N = 12) developed cardiac arrhythmias (P = 0.14). We conclude that ritodrine and terbutaline induce profound hypokalemia by stimulating cellular potassium uptake and both drugs cause significant renal sodium and fluid retention and cardiac arrhythmias. Careful monitoring of electrolytes, fluid balance, and cardiac rhythm should occur during tocolytic therapy with ritodrine or terbutaline.

Characterization and regulation of the mouse insulin receptor substrate gene promoter.

To evaluate the potential for regulation of the insulin receptor substrate IRS-1, we have cloned the mouse IRS-1 gene, identified its promoter, and analyzed promoter activity in the basal state and in response to stimulation. The 5'-region of the mouse IRS-1 gene lacks typical CAAT and TATA boxes but contains nine potential Sp1 binding sites consistent with a housekeeping gene. The 5'-region of the IRS-1 gene also has significant regions of homology with the promoters of the progesterone receptor gene, the insulin-like growth factor I receptor gene, and the androgen receptor gene. Multiple transcription start sites were identified 0.4-1.2 kilobases (kb) upstream from the start codon. Using a chloramphenicol acetyl transferase assay in Chinese hamster ovary (CHO) cells, basal promoter activity was present in the 3.2 kb 5'-flanking region of IRS-1 gene. Within this region, there were 184-base pair and 60-base pair negative regulatory elements at -3.2 kb and -1.6 kb surrounded by positive elements. By gel shift assay, a nuclear factor was identified in CHO cells which binds to -1606 and -1586 sequence in the negative regulatory element and appears to be distinct from C/EBP, CREB, and AP-1. In 3T3-F442A adipocytes dexamethasone treatment significantly decreased IRS-1 mRNA and IRS-1 protein. This was due to a decrease in the half-life of IRS-1 mRNA, with no change in IRS-1 promoter-chloramphenicol acetyl transferase activity. Insulin also decreased IRS-1 protein by approximately 60% within 9 h but did so without altering IRS-1 mRNA levels or chloramphenicol acetyl transferase activity. Thus, both insulin and dexamethasone down-regulate IRS-1 expression at the posttranscriptional level; with insulin this is probably due to an effect on protein half-life, whereas with dexamethasone the effect is due to a change in the half-life of IRS-1 mRNA.

Cloning of the mouse insulin receptor substrate-1 (IRS-1) gene and complete sequence of mouse IRS-1.

The mouse IRS-1 gene has been cloned and its structure determined. Mouse IRS-1 differs from rat by the absence of the potential C-terminal nucleotide binding site. Otherwise, the predicted IRS-1 protein is highly conserved between mouse, rat and humans, especially in the possible phosphorylation sites. The highly conserved nature of IRS-1 suggests the importance of these domains in the function of IRS-1 or its association with other proteins.

Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization.

Insulin receptor substrate-1 is a major substrate of insulin receptor Tyr kinase. We have now cloned the IRS-1 cDNA from human skeletal muscle, one of the most important target tissues of insulin action, localized and cloned the human IRS-1 gene, and studied the expression of the protein in Chinese hamster ovary cells. Human IRS-1 cDNA encodes a 1242 amino acid sequence that is 88% identical with rat liver IRS-1. The 14 potential Tyr phosphorylation sites include 6 Tyr-Met-X-Met motifs and 3 Tyr-X-X-Met motifs that are completely conserved in human IRS-1. Human IRS-1 has > 50 possible Ser/Thr phosphorylation sites and one potential ATP-binding site close to the NH2-terminal. The human IRS-1 gene contains the entire 5'-untranslated region and protein coding region in a single exon and was localized on chromosome 2 q36-37 by in situ hybridization. By Northern blot analysis, IRS-1 mRNA is rare and consists of two species of 6.9 and 6 kilobase. By using quantitative polymerase chain reaction after reverse transcription of total RNA from human fetal tissues, IRS-1 mRNA could be identified in all tissues. When human IRS-1 cDNA was expressed in Chinese hamster ovary cells, the protein migrated between 170,000-180,000 M(r) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was rapidly Tyr phosphorylated upon insulin stimulation. Thus, IRS-1 is widely expressed and highly conserved across species and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Apathetic thyrotoxicosis presenting as an abdominal emergency: a diagnostic pitfall.

Thyrotoxicosis may present with a hyperkinetic clinical picture typically associated with Graves' or Plummer's disease, or in an apathetic form characterized by lethargy, weakness, and withdrawal. Both the hyperkinetic and apathetic forms of thyrotoxicosis may be associated with or masked by predominantly extrathyroidal manifestations, occasionally referable primarily to the abdomen. We present two cases of apathetic thyrotoxicosis that suggested the need for urgent surgical intervention, and review the literature on apathetic thyrotoxicosis as an abdominal emergency, as well as laboratory studies and possible etiology.

Perfusion technology in the hypothyroid patient.

Cardiopulmonary bypass may, by necessity, have to be performed in patients who are frankly hypothyroid. In treating five such patients, all of whom required coronary revascularization, it was noted that fluid balance during perfusion was considerably different than that in the normal population. In order to attempt to evaluate this difference, ten consecutive euthyroid patients having revascularization and the five hypothyroid patients were compared to correlate all fluid absorbed and excreted with the duration of bypass, the serum sodium, and subsequent weight gain. Fluid intake, urine output, and retained fluid were significantly elevated in the hypothyroid as compared to the euthyroid group, while serum sodium following operation was not significantly different. While there are considerable data indicating that hypothyroidism is associated with abnormal salt and water excretion, there is no information concerning the alterations which occur during cardiopulmonary bypass. The present study indicates that hypothyroidism is associated with significant diuresis (without administration of exogenous diuretic agents during cardiopulmonary bypass). The proposed explanation for this diuresis rests with the assumption that with cardiopulmonary bypass and appropriate fluid administration, the contracted blood volume in hypothyroid patients expands acutely and a diuresis results.

Thyroid imaging with iodine-125 and technetium-99m.

Eighty-eight patients referred consecutively for thyroid imaging were studied. Each patient was scanned with a 3'' rectilinear scanner using both 125I and 99mTc. The paired scans were evaluated independently by two physicians experienced in thyroid evaluation and image analysis. The images were ranked on a scale from 1 to 5 as follows: 1) 125I scan much better than the 99mTc scan, 2) ..., 3) 125I scan and 99mTc scan the same, 4) ..., 5) 99mTc scan much better than 125I scan. The scores were statistically analyzed by the sign test and transformed normal score methods. Categories analyzed were: A. Hypothyroid, B. Euthyroid, C. Hyperthroid, (A-C based upon RAIU measurements), D. Cold Nodules, E. Graves Disease, F. Hot-Nodules, G. Multinodular Nontoxic Goiter, H. Miscellaneous and I. Normal. The significance of this study is that regardless of the classification we used, in no category was the 99mTc scan considered better than the 125I scan. This finding is at variance with the observations of some others comparing 99mTc with other iodine radioisotopes. 99mTc may have some procedural advantages and does deliver a lower radidation dose to the thyroid.