Effects of adrenocortical steroids on the propulsive motility of small intestine.

STREETEN, DAVID H. P., BASIL I. HIRSCHOWITZ, KEITH S. HENLEY AND H, M. POLLARD. (U. Michigan Med. School, Ann Arbor, Mich., and Howard Hughes Med. Inst .) E$ects ~j adrenoc&ical sier&ds on the @~pdsive motility of small intestine. Am, J. Physiol. 189(I) : x08-1 12. rg57.-Adrenal cortex extract in low concentrations (I : 1400-1: 250) increases the peristaltic CODtractions of small intestine and restores to fatigued intestinal segments normal peristaltic activity and the ability to propel fluid against a pressure gradient, in vitro (modified Trendelenburg technique). Adrenal cortex extract in high concentrations (I : 150-1: 25) reversibly inhibits or abolishes peristalsis irt vitro. In adrenalectomized rats in tivu, adrenal cortex extract increases the rate of propulsion of dyes along the small intestine in moderate doses (I ml b.i. ,d.), and decreases propulsion in large doses (5 ml b,i.d.). Cortisone, hydrocortisone and corticosterone in the amounts present in stimulant doses of adrenal cortex extract had no effect on intestinal propulsion, irt vk. Doses of aldosterone (0.1 and 0.5 pg b.i.d.) comparable with the amounts contained in the extract used and large doses of the electrolytecontrolling steroids, desoxycorticosterone (24 and 5 mg) and corticosterone (2.5 mg), reproduced the stimulant effects of the extract, in viva. It is possible that the effects of aldosterone may be of significance in controlling intestinal motility under physiological and some pathological conditions. T HIS STUDY W observation ‘as promp ted by the chance that low concentrations of l adrenal cortex extract greatly increased peristalsis in actively contracting intestinal segments and restored apparently normal motility to intestine which had become “fatigued” by prolonged periods of peristalsis in vitro. The results described here, some of whic.h have been reported elsewhere in abstract (I), indicated that the st .imulant action of adrenal cortex extract on motility is reproducible in z’ivo, and is probably attributable to the aldosterone contained in the extract. Experiments in Vitro Methods. Segments of small intestine, 6-10 cm in length, from rabbits, dogs and human subjects (undergoing intestinal resection for carcinoma) were placed in a bath of Tyrode’s solution and distended by an intraluminal pressure of 2-3 cm, as described in Received for publication October I I, 1956. * Investigator for the Howard Hughes Medical Institute. a recent modification (2) of Trendelenburg’s (3) classical method. Intestinal segments suspended in this way showed both longitudinal and circular muscle contractions which continued as long as the segments were distended, and could be recorded on a revolving kymograph drum. Results. When adrenal cortex extract (‘Eucortone,’ Allen and Hanburys) was added in increasing doses to the organ bath in which the gut was suspended, it was found that volumes between 0.05 and 0.3 ml of extract in the 79ml bath used (i.e. concentrations of from I : 1400 to I : 250) consistently increased either the amplitude of peristaltic contractions or the frequency of the large peristaltic contractions, or both, with a consequent increase in the rate of fluid propulsion by the segment. Such a stimulant effect on peristalsis is seen in figure I, where the addition of 0.1 ml adrenal cortex extract (ACE), added to the bath at the first arrow, within 1-2 minutes increased both the amplitude and the frequency of the 108 by 10.2.32.247 on Jne 9, 2017 http://ajple.physiology.org/ D ow nladed fom ADRENOCORTICAL STEROIDS AND MOTILITY OF SMALL INTESTINE I09 large tracing) circular without muscle contractions significant effect (lower on the longitudinal contractions (upper tracing). The tone of the circular muscle layer was slightly increased, while that of the 1 ongitudinal layer was decreased by the adrenal cortex extra ct, as reflected by the upward and downward trends of the baselines of the lower and uppe r tra,cings, respectively. VVhen the adrenal extract was washed from the organ bath at IV, the stimulant effects of the extract immediately disappeared. In 24 out of a total of 25 such experiments on rabbit small bowel, adrenal cortex extract produced the same stimulant effects on peristalsis, with or without the effects on the tone and amplitude of contractions of the longitudinal muscle layer 8. A simi stimulant action was consistently observed .lar in four experiments on dog and human intestine. After contracting actively for several hours against a constantly maintained intraluminal pressure, preparations of small intestine began to show a gradual reduction in the amplitude of contractions. Eventua!ly, contractions became so small that active propulsion of fluid against a pressure gradient could no longer be accomplished in an apparatus which allowed of direct measurement of the rate of fluid propulsion (2). When this stage had been reached, the addition of adrenal cortex extract (usually in concentrations of 1.4 X IO-~) restored peristaltic activity. This effect is shown in figure 2. Whereas 0.025 ml extract added to the bath at each of the arrows, I and 2, had no noticeable effect on the amplitude of the very small, ‘fatigued’ contract-ions, a third dose of 0.05 ml added at -3, and bringing the total concentration of extract in the bath up to 0.1: ml./75 ml (I: 750) strongly increased the amplitude of peristaltic (‘on t t-act ions (lower tracing), while reducing the longitudinal muscle tone slightly. These effects were reversed and the small contractions were resumed when the adrenal extract was washed from the bath at W. Contractions restored through the addition of adrenal cortex extract always continued as long as the extract remained in the bath, though no attempt was made to define the total duration of this effect. Neither neostigmine nor any other drug or hormone was found to be capable of increasing the peristaltic activity of intestine ‘fatigued’ in this way by prolonged contraction in the bath. FIG. I. Stimulant effects of adrenal cortex extract on peristaltic contractions of a fresh preparation of rabbit jejunum. In all figures, upper &a&g shows longitudinal contractions, Lower fracing peristaltic contractions, and time tracing is in minutes. Adrenal cortex extract, 0.1 ml, added to the 75 ml bath at A.C.E., and washed from the bath at W. FIG. 2. Stimulation of peristaltic activity in fatigued terminal ileum of rabbit produced by ACE, added to the 75-ml bath in doses of 0.025 ml at I and 2, and 0.05 ml (making a total concentration of I : 750) at 3. Adrenal cortex extract devoid of the preservative added by the manuluct urer retained its stimulant properties. Saline extracts of the solvents used in the extraction procedure and samples of the solvent used to take up the steroids at the end of the manufacturing process were devoid of any action on intestinal moti1ity.l Inhibitory efecfs uj larger amow& of extract. Higher concentrations of adrenal cortex extract, between 0.5 and 3.0 ml/75 ml (i.e. from I : 150 to I : 25) produced inhibition rather than stimulation of peristaltic contractions in fresh preparat.ions of intestine. Concentrations of l Both preservative-free ‘Eucortone’ and samples of the solvents used by the manufacturer, were supplied through the kind courtesy of Mr. C. J. Eastland, Allen and Hanburys Ltd., Ware, Herts, England. by 10.2.32.247 on Jne 9, 2017 http://ajple.physiology.org/ D ow nladed fom STREETEN, HIRSCHOWITZ, HENLEY AND POLLARD more than I : 75 frequently abolished peristalsis altogether, while considerably reducing the longitudinal contractions. This effect is shown in figure 3, where the addition of 0.1 ml extract at I slightly increased the amplitude and frequency of peristaltic contractions, while 0.5 ml added at 2 had no additional effect. When the further dose of 0.4 ml was added at 3, bringing the concentration up to I : 75, contractions became smaller, and another dose of 0.5 ml added at gr almost completely abolished peristaltic activity. Normal motility was restored at W. on washing the extract from the bath