No abstract

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).

1 The in¯uence of 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on the ureter motility was investigated in vivo on intact ureters of anaesthetized pigs. Drugs were administered intravenously or topically. 2 5-HT induced a dose-dependent increase in the frequency of ureter contractions in anaesthetized pigs when given intravenously (0.0001 ± 1 mg kg 71 ; ED 50 0.066 mg kg 71 ) or topically (0.001 ± 1 mg ml 71 ; EC 50 0.043 mg ml 71 ). Signi®cant increases in heart rate and blood pressure were observed when the drug was given intravenously but not topically. 3 The 5-HT 2A agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) increased the frequency of ureteral contractions in a dose-dependent manner (1 ± 300 mg kg 71 i.v.). Calculation of ED 50 indicated this compound to be about 1.5 times more potent with an e cacy of 23% compared to 5-HT. 4 The 5-HT 2A/2C antagonist, ketanserin (0.5 mg kg 71 ) and the 5-HT 2C antagonist, methysergide (1 mg kg 71 ) antagonized the 5-HT-induced ureter peristalsis when given intravenously. Contraction amplitude, blood pressure and heart rate were not a ected by the antagonists. 5 Intravenous (0.0001 ± 1 mg kg 71 ) and topical (0.0001 ± 1 mg ml 71 ) ketanserin signi®cantly decreased the frequency of spontaneous ureteral contractions to about 30% of controls, which could be partly reversed by 5-HT (0.3 mg kg 71 i.v.). The contraction amplitude, contractions of the contralateral, saline perfused ureter, heart rate and mean arterial blood pressure were not a ected. 6 Thus, contractility of porcine ureter is mediated by 5-HT 2 receptors. Their antagonists ketanserin and methysergide seem to be promising drugs for treatment of acute ureteric colic or in preparing the ureter for ureteroscopy.

No abstract