TY - JOUR T1 - CERTAIN ASPECTS OF THE EFFECTS OF LEVORPHANOL ON WATER METABOLISM IN RATS JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 368 LP - 376 VL - 139 IS - 3 AU - Heber H. Newsome AU - Wayne Tobin AU - James M. Fujimoto Y1 - 1963/03/01 UR - http://jpet.aspetjournals.org/content/139/3/368.abstract N2 - Three groups of rats of at least 40 rats each were placed on a schedule of increasing twice daily doses of levorphanol. At intervals during the course of levorphanol administration the rats' capacity to excrete standard water loads was tested. An antidiuretic effect of levorphanol as indicated by increased excretion times was observed during the early stages of drug administration. However, as the course of levorphanol treatment progressed, the initial antidiuretic effect diminished, and the excretion of the water load returned toward control levels indicating development of tolerance to levorphanol. Most interestingly, in two of the three groups of chronically treated rats the excretion rates became faster than control values. Thus a reversal of effects from antidiuresis to active diuresis occurred during the course of levorphanol administration. In rats not treated with levorphanol, no change in excretion times occurred during comparable water load studies. Levallorphan, an antagonist, not only blocked the antidiuretic activity of levorphanol but consistently produced an active diuretic response when administered with levorphanol. In a single experiment during the diuretic phase of chronic levorphanol administration, levallorphan produced an antidiuretic effect in conjunction with levorphanol. Levallorphan alone had no effect on the water excretion time. The response to Pitressin and Pituitrin was tested in two of these levorphanol treated groups. A slight decrease in the kidney's sensitivity to Pitressin or Pituitrin was suggested. Nicotine, when given during the diuretic phase of the chronic levorphanol treatment, appeared to have lost some of its antidiuretic effect as compared to the nicotine response of control rats. A bioassay procedure revealed substantial antidiuretic activity in the blood of rats given an initial dose of levorphanol. An even greater antidiuretic activity was found in the blood of chronically treated rats receiving a larger dose of levorphanol. Levorphanol itself was shown not to be the antidiuretic material. In confirmation of a previous experiment, during the later days of levorphanol treatment the rats in two groups became polydipsic and polyuric. The polydipsia was thought to occur before the polyuria. Levallorphan blocked the polydipsia. Acute or chronic treatment with levorphanol had no apparent effect on normal plasma osmolality. However, following water gavaging, the pattern of the plasma dilution differed markedly between control rats, rats treated a short time with levorphanol, and those on prolonged treatment. The results obtained correlate well with the findings in the excretion time experiments. ER -