The effects of veratrum derivatives upon the isolated intestine of the rabbit and upon the intact intestine of the trained unanesthetized dog.
Gourzis, James T
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The aims of this study were: (1) to determine the qualitative effects of Veriloid and pure veratrum alkaloids upon the isolated intestine of the rabbit and the intact intestine of the trained unanesthetized dog, and, (2) to determine the locus of such effect. A modified Magus apparatus utilizing a constant temperature bath and Tyrode solution were employed for the in vitro studies. Strips from two different rabbits were exposed at the same time in a 75 ml. muscle bath to appropriate concentrations of the test drugs. After preliminary experiments had proved the common spasmogenic property of these agents, it was decided to find the ED50 spasmogenic dose for each compound tested. Intestinal strips were exposed to minimum dilutions of: the veratrum drugs, and the response noted as either positive or ne gative. The criteria for a positive response were either an increase in the height of segmental activity, an increase in tone, or both. At minimal effective dosage, the former was the more common response, while the latter was mainly a phenomenon of higher dosage. ED50 spasmogenic doses of the pure alkaloids were compared to that of Veriloid (100 per cent) and the resulting ratio formed the spasmogenic potency for the particular agent. The spasmogenic potency for each agent was compared to its hypotensive potency for possible relationship and application to a method of assay; none was demonstrable. The locus of spasmogenic action was determined to be directly upon the muscle since the effects of veratrum were not altered by atropine. Similarly, Veriloid did not alter atropine blockade of acetylcholine (Ach), when given prior to atropine. The maximum Veriloid spasm could be augmented in all cases by administration of Ach. at the summit of this response; the same was true for Veriloid when given in response to Ach. Epinephrine always markedly relaxed the intestine when it was at the peak of a spasm due to Veriloid; similarly, Veriloid caused marked spasm in a strip relaxed by epinephrine. The tachyphylactic effects of these agents were studied. Tachy- phylaxis of the strips to second doses of Veriloid and pure alkaloids gradually waned as time passed, although the per cent response to a second dose of Veriloid was still only 23 per cent of the initial response after 1 hour with thorough washing; however, tachyphylaxis to pure alkaloids was nearly ended after 30 minutes. The size of the dose used bore no relationship to this phenomenon. The marked sensitivity of isolated rabbit intestine to minute amounts of veratrum, may offer an avenue for the measurement of any amount of this drug circulating in the patient's body fluids. The study on the intact intestine was made using 3 trained, unanesthetized female mongrel dogs, each operatively prepared with a Thiry- Vella fistula, an ileostomy, and a cecostomy. Kymograph tracings were taken directly via a balloon inserted into the intestinal loops, and attached to a multiple bromoform manometer. Intravenous Veriloid caused emesis in the dogs at a dose of 20 microgm. per kg. Emesis occurred without prior intestinal stimulation. Intraloop administration of Veriloid in doses up to 40 microgm. per kg. (2X oral ED50 emetic dose), produced neither local intestinal stimulation nor emesis. This was attributed to poor absorption from either the Thiry-Vella loop, or ileostomy, and no absorption from the cecostomy. The experiments on the intact animal appeared to indicate that intestinal spasmogenesis is not within the range of clinical intravenous dosage. Whether oral dosage causes local intestinal stimulation may be answered by recording intestinal motility in the dog following oral administration of veratrum.
Thesis (M.A.)--Boston University