The effects of the depolarizing agent, batrachotoxin (BTX), and of various analogs were studied on rat phrenic nerve-diaphragm muscle preparations at 37 degrees C. The structural modifications of BTX included: 1) replacement of the 20alpha-pyrrole-3-carboxylate moiety; 2) alterations of substituents on the pyrrole moiety; 3) clevage of the 3alpha, 9alpha-hemiketal linkage; and 4) quaternization of the tertiary nitrogen of BTX. All of the compounds except batrachotoxinin A (BTX-A), which lacks the 20alpha-substituent, depolarized the postsynaptic membrane, transiently increased the frequency of spontaneous transmitter release to 400 to 600 sec- minus 1 and finally produced blockade of the directly and indirectly elicited muscle twitches. Of the compounds tested, only BTX-A potentiated the muscle twitches. The concentration which elicits a 50% depolarization of the muscle membrane in 1 hour was determined for all the compounds except for BTX-A and for dihydrobatrachotoxin which lacks the 3alpha, 9alpha-hemiketal linkage; these two analogs never depolarized the postsynaptic membrane by more than 10 to 15%. BTX, the 20alpha-2, 4, 5-trimethylpyrrole-3-carboxylate of BTX-A and the 20alpha-ester of BTX-A with 2-ethyl-4-methylpyrrole-3-carboxylic acid (homobatrachotoxin) were the three most potent toxins with doses of 4.5, 12 and 18 times 10- minus 9 M eliciting a 50% membrane depolarization in 1 hour. The quaternary derivative of BTX, the 20alpha-4, 5-dimethylpyrrole-3-carboxylate of BTX-A and 20alpha-2,4-dimethyl-5-acetylpyrrole-3-carboxylate of BTX-A were 24-, 65- and 110-fold less potent than BTX as depolarizing agents, whereas the 20alpha-p-bromobenzoate of BTX-A was 220-fold less potent. Each of these derivatives had the ability to increase sodium permeability since the increase in spontaneous miniature end-plate potential frequency and membrane depolarization were reversed by tetrodotoxin or by reducing the external sodium concentration. BTX was found to be more effective at alkaline pH (pH 9.0), at which it exists almost entirely in the un-ionized form, than at physiological or acidic pH(6.0). The results indicate that the analogs of BTX act by a mechanism similar to that of the parent compound, but that their potency differs and certain compounds may have a more selective action on either the pre- or postsynaptic membrane. For maximal depolarizing activity, a substituted pyrrole moiety is necessary at the 20alpha-position of BTX-A and 3alpha, 9alpha-hemiketal linkage must remain intact providing rigidity for the pentacyclic steroid nucleus.
Mice injected intraperitoneally with Ehrlich ascites carcinoma were killed after varying intervals 2 to 21 days after injection. Tissue specimens from the kidney, spleen and heart were examined histochemically for mono‐amines in the adrenergic fibres and the noradrenaline content of the kidney was chemically determined. The mono‐amine‐indicating fluorescense was subjectively estimated as absent or faint in a greater number of slides, and correspondingly as clear in a smaller number of slides in the ascitic group than in the controls, the difference being highly significant. This applied to the adrenergic fibres of the blood vessels of the kidney, to the arterioles of the spleen and to the adrenergic fibres of the myocardium. A highly significant reduction in the chemically determined content of noradrenaline was found in the kidney of ascitic mice as compared with the controls.
Ultrasound guided fine-needle biopsy of mass lesions affecting the hepatobiliary tract in 67 patients is reported. A free-hand approach was used without a special biopsy transducer. All aspirates were sufficient and relevant. A correct cytologic diagnosis was reached in 91 per cent of the 57 malignant cases. In addition, malignancy was correctly suggested in 5 cases. In 33 per cent of the cases with unknown primary tumor, cytology determined the origin of the malignancy. No complications occurred.
