Intravenous phenylephrine increases, and isoproterenol and fenoterol decrease the frequency and amplitude of ureteral contractions in the pig. The same effects are observed with the topical administration of phenylephrine, which causes a significant local but not systemic side effect. Topical administration of isoproterenol and fenoterol produced local as well as systemic effects, suggesting absorption by the urothelium. However, to our knowledge a drug that relaxes ureteral peristalsis in pigs without causing systemic side effects has not yet been identified.

The effects of 5-hydroxytryptamine (5-HT), HTF 919, a new 5-HT(4) agonist, and the antagonists SB 203-186 (5-HT(4)) and tropisetron (5-HT(3)) on intestinal motility were tested in vitro on isolated preparations of horse ileum and pelvic flexure. Concentration-response curves were created by cumulative application of the agonists with or without preincubation of the antagonists. The 5-HT preparation induced a concentration-dependent contraction in equine ileum and pelvic flexure. The results indicate that 5-HT receptors are present in all parts of equine intestine investigated in this study. Tropisetron was found to act as a noncompetitive antagonist in all locations of the equine intestine. SB 203-106 was confirmed as an antagonist to 5-HT in the equine ileum circular muscle, in pelvic flexure circular and longitudinal muscle. Nevertheless, a discernible increase of smooth muscle contractions caused by HTF 919 could only be observed in pelvic flexure. In accordance with an earlier study in the guinea pig, in the equine gut HTF 919 acted as a partial agonist for the 5-HT(4) receptor with an affinity constant in the nanomolar range. It is concluded that 5-HT receptors, and especially their subtypes, may represent a promising target for the treatment and prevention of gastrointestinal (GI) motility disorders in horses.

The relaxing property of the K ϩ channel opener and nitric oxide donor nicorandil and the new K ϩ channel opener PKF 217-744b was investigated on isolated human ureteral tissue in vitro and in intact ureters of anesthetized pigs in vivo. In addition, nicorandil and its antagonists, glibenclamide and methylene blue, were tested on isolated pig ureter tissue in vitro. Nicorandil decreased the frequency of spontaneous contractions in isolated pig ureter rings. This effect was antagonized by glibenclamide and methylene blue suggesting that the nicorandil induced relaxation of the ureter is mediated by activation of ATP-sensitive K ϩ channels and involvement of soluble guanylate cyclase. Moreover, nicorandil and PKF 217-744b reduced the amplitude of electrically induced contractions in isolated human ureter rings. Calculations of EC 50 values showed that PKF 217-744b [EC 50 ϭ 4.83 ϫ 10Ϫ8 M] was more potent than nicorandil [EC 50 ϭ 4.38 ϫ 10Ϫ5 M]. Both drugs reduced the contraction frequency of the pig ureter after intravenous and topical administration in vivo. Intravenous, but not topical, administration of nicorandil and PKF 217-744b significantly decreased arterial blood pressure but did not affect the heart rate. The in vitro findings suggest that K ϩ channel opening and nitric oxide release mediate the effect of nicorandil. Our in vivo results indicate that PKF 217-744b and nicorandil are promising drugs for clinical application in patients with acute stone colic to relieve obstruction and facilitate stone passage or to relax the ureter before ureteroscopy.Pharmacological relaxation of the ureter smooth muscle would facilitate the treatment of ureter stone colic and possibly enhance stone passage as well as prepare the ureter for easier endoscopic access. Although considerable studies have been made, a specific and potent agent to relax ureters has not yet been found. K ATP channel openers are well known to achieve smooth muscle relaxation.Physiologically, decreased cellular concentrations of ATP, i.e., during metabolic stress and hypoxia or ischemia, cause opening of K ATP channels and subsequently induce a hyperpolarized state of the cell membrane. The response of the K ATP channel to metabolic challenge is regulated by adenylate kinase phosphotransfer, which amplifies metabolic signals (Carrasco et al., 2001;Zingman et al., 2001). The K ATP channel complex functions not only as a K ϩ conductance but also as an enzyme regulating nucleotide-dependent channel gating through an intrinsic ATPase activity of the sulfonylurea receptor subunit, an ATP binding cassette protein (Bienengraeber et al., 2000).