Comparative Study of Meloxicam and Indomethacin on Ovine Ureteral Motility

Objective: To test the potentially toxic urinary tract effects of indomethacin in comparison with a novel COX-2 inhibitor, meloxicam. Method: In vitro experiments were performed using isolated ring segments of sheep ureter mounted in organ-baths. Changes in isometric tension and frequency of rhythmic contractions were assessed in control and lipopolysaccharide (LPS)-treated preparations prior to and after administration of the tested drugs. Results: Sheep ureteral rings displayed reproducible spontaneous rhythmic contractions which were abolished by indomethacin (10–6 M) and not by meloxicam (10–6 M) under control conditions. However, in LPS-treated preparations, to induce COX-2, meloxicam produced a slight inhibitory action. Conclusion: Indomethacin blocks normal motility through inhibition of COX-1, while meloxicam does not interfere with ureteral peristalsis. Meloxicam only exerts a slight inhibition in inflammation-induced preparations due to the specific action as an inhibitor of COX-2. Further studies are needed to evaluate and compare the effects of meloxicam and indomethacin from other measures of effects of COX-1 and COX-2. OOOOOOOOOOOOOOOOO Received: June 18, 1997 Revised: September 30, 1997 Dr. Mariam Yousif Department of Pharmacology and Toxicology Faculty of Medicine, PO Box 24923 Safat 13110 (Kuwait) Tel. +965 531 2300 ABC Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com © 1998 S. Karger AG, Basel 1011–7571/98/0073–0198$15.00/0 Accessible online at: http://BioMedNet.com/karger Introduction Prostaglandins or eicosanoids are not only involved in a large number of pathological conditions such as inflammation, pain and septic shock but also serve normal physiological processes like kidney function, blood clotting, parturition and gastro-intestinal function. Prostaglandin synthesis is governed by a key enzyme, cyclo-oxygenase (COX). New research has shown that it exists in two distinct isoforms: COX-1 and COX-2. COX-1 is a D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 12 :0 3: 27 A M Meloxicam and Ureter Med Principles Pract 1998;7:198–202 199 constitutive enzyme that is always present and responsible for the generation of small amounts of eicosanoids that govern normal organ function. COX-2 is induced by disease processes such as inflammatory stimuli and cytokines [1–5]. The therapeutic actions of non-steroidal anti-inflammatory drugs (NSAID) like aspirin and indomethacin depend on the inhibition of COX-2, whereas the undesirable side-effects such as gastric bleeding and nephropathy are due to inhibition of COX-1 [5]. This discovery has led to intense research to synthesize drugs that specifically inhibit COX-2 but not COX-1 in order to avoid adverse effects. One of the first of these drugs was meloxicam. Meloxicam is a new NSAID derived from enolic acid. The antiinflammatory potency of meloxicam in the rat is higher than that of well-established NSAIDs [6], and in vitro studies showed that meloxicam had no antagonistic properties against normal mediators [6, 7]. The spectrum of selective activities of the standard NSAIDs against the two enzymes ranges from a high selectivity for inhibiting COX-1 (e.g. indomethacin) to equal potency for inhibiting COX-1 and COX-2 (e.g. diclofenac) [8]. In this study, we have investigated the effects of meloxicam and indomethacin in vitro with a technique we previously described using ovine ureteral ring segments [9– 11]. The aim of our study was to determine the specificity of meloxicam in inhibiting normal ureteral contractility in control preparations and those which were in vitro stimulated with the bacterial endotoxin lipopolysaccharide (LPS) to induce COX-2. Materials and Methods Male sheep kidneys with attached ureters were obtained from freshly slaughtered animals. Ureteral preparations were always taken from the same location. Rings of 4 mm length were cut and suspended in Krebs-Henseleit solution at pH 7.4 in 25-ml organbaths aerated with 95% O2 and 5% CO2 at 37°C. Isometric tension was recorded with UFI dynamometers and a Lectromed recorder system. The preparations were allowed to equilibrate under a pretension of 1.5– 2.0 g for 30 min and during this period, the Krebs’ solution was changed at 15-min intervals. After establishing a stable pattern of rhythmic contractions, 250 Ìl of bacterial endotoxin LPS was added to the organ-bath and left to incubate for 30 min. Thereafter, meloxicam or indomethacin (10–7–10–6 M ) was added to the bath in the presence of LPS. In control preparations, meloxicam or indomethacin (10–7–10–6 M ) was also added to the organ-bath in LPS-free Krebs’ solution.