A DIRECT INHIBITORY EFFECT OF ERYTHROMYCIN ON RAT URINARY BLADDER SMOOTH MUSCLE AVIRAM NISSAN,* NADEER MAUDLEJ, NAHUM BEGLAIBTER, YUVAL HASKEL, HERBERT R. FREUND AND MENACHEM HANANI From the Department of Surgery and Laboratory of Experimental Surgery, Hadassah University Hospital, Mount Scopus, Hebrew University-Hadassah Medical School, Jerusalem, Israel ABSTRACT Erythromycin (EM) exerts a dual effect on the contractility of smooth muscle. An excitatory effect mediated via motilin receptors is expressed mainly in the smooth muscle of the stomach and duodenum. The other, a direct inhibitory effect mediated via an unknown mechanism, has been described in guinea-pig and human gallbladder, in the longitudinal smooth muscle of the guinea-pig small intestine and in bronchial smooth muscle. In the present study, the effect of EM on the isolated urinary bladder of the rat was examined using isometric force measurements. The muscarinic agonist carbachol evoked contractions that were reduced by EM in a concentration-dependent manner; at 5  10 -4 M by 46% [from 1.04  0.42 gm. to 0.56  0.22 gm., (p 0.001)] and at 10 -3 M by 57% [from 1.04  0.42 gm. to 0.45  0.20 gm., (p 0.001)]. The inhibitory effect of EM was not altered by the nerve blocker tetrodo- toxin. Electric field stimulation of 0.5 Hz, 1 Hz, and 2 Hz contracted the urinary bladder. Erythromycin at 5  10 -4 M reduced the contractions evoked at 0.5 Hz by 15% [from 0.60  0.22 gm. to 0.51  0.20 gm., (p = 0.004)] and at 10 -3 M by 23% [from 0.60  0.22 gm. to 0.46 + 0.12 gm., (p 0.001)]. Erythromycin failed to affect the contractions evoked by bradykinin, phenyl- ephrine or substance P. It is concluded that EM has a direct inhibitory effect on the rat urinary bladder smooth muscle. KEY WORDS: erythromycin, bladder, rat, smooth muscle, muscle contraction The prokinetic activity of erythromycin (EM) was first described in 1984 by two independent groups. 1, 2 This activity of EM resembles that of the gastrointestinal hormone moti- lin, which is released periodically in the fasting state. In humans and dogs motilin induces phase III activity and is believed to play a role in the regulation of the migrating motor complex. 3 Erythromycin was shown to displace motilin from its receptors, 4 and has been proposed to act as a motilin agonist. Improvement of gastric emptying in patients with diabetic gastroparesis treated with EM was the first clinical application of these properties. 5 Erythromycin has been also found to exert an inhibitory effect on isolated longitudinal muscle of guinea-pig small intestine 6 and on isolated human bronchial smooth muscle. 7 We recently described an inhibitory effect of EM on isolated guinea-pig and human gallbladder contractions evoked by carbachol or electrical stimulation, 8 as well as in human intestinal smooth muscle strips. 9 Involuntary urinary blad- der contractions occur in disorders such as detrusor hypere- flexia, urinary tract infections, and in obstructive prostatic hypertrophy. Most of the pharmacological agents in clinical use for inhibition of involuntary bladder contractions inhibit muscarinic acetylcholine receptors or exert a direct effect on smooth muscle. 10 These agents, though helpful, leave much to be desired in terms of efficacy and reduction of side effects in the treatment of involuntary bladder contractions. The lack of motilin receptors on urinary bladder smooth muscle favors an inhibitory rather than excitatory effect and makes EM a putative agent in the treatment of urinary bladder contractions. The aim of the present study was to investigate the effect of EM on the urinary bladder smooth muscle using the iso- lated rat urinary bladder. MATERIALS AND METHODS The study protocol was approved by the Institutional An- imal Care and Use Committee. Male Sprague-Dawley rats (mean weight 310 gm.) were sacrificed by cervical dislocation. Whole urinary bladders were removed and placed in a bath filled with Krebs solution [composition (in mM): NaCl-120.7, KCl-5.9, MgSO 4 -1.2, NaHCO 3 -14.4, NaH 2 PO 4 -1.5, CaCl 2 -2.5, and glucose-11.5] through which a mixture of 95% O 2 and 5% CO 2 was bubbled. The temperature was maintained at 37C. One end of the preparation was fixed to a tissue holder, and the other end was connected to an isometric force transducer (Statham UC2). The resting tone was 1 gm. After reaching equilibrium, the preparations were electrically stimulated with two platinum ring electrodes using a Grass S88 stimu- lator. Stimulus parameters were 55 V amplitude, 0.5 msec. duration at 0.5–2 Hz for 15 seconds. Chemical stimulation was obtained by adding drugs to the bath. The contractile responses were recorded by a Hewlett Packard 7544-a re- corder. Erythromycin lactobionate was dissolved in distilled water immediately before use. It was added to the bath and the preparation was stimulated electrically and chemically. After each exposure to erythromycin, the electrical and chemical stimulations were repeated to verify return to control levels. After testing the action of a drug, the bath solution was replaced several times until the preparation returned to basal activity and tone. Drugs used in the present set of experiments were eryth- romycin lactobionate (Abbot Laboratories, USA), carbamyl choline chloride (carbachol), phenylephrine hydrochloride, bradykinin, tetrodotoxin, and benzyl alcohol (from Sigma, USA). Accepted for publication October 12, 1998. * Requests for reprints: Department of Surgery, Hadassah Univer- sity Hospital, Mount Scopus, Jerusalem, PO Box 24035, il-91240, Israel. 0022-5347/99/1613-1006/0 THE JOURNAL OF UROLOGY Vol. 161, 1006 –1009, March 1999 Copyright © 1999 by AMERICAN UROLOGICAL ASSOCIATION,INC. Printed in U.S.A. 1006