Inhibition of Human and Pig Ureter Motility in Vitro and in Vivo by the K⁺ Channel Openers PKF 217-744b and Nicorandil

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).

Physiology and Pharmacology of the Human Ureter: Basis for Current and Future Treatments

“…Both drugs reduced the contraction frequency of the pig ureter after intravenous and topical administration in vivo. Therefore, both PKF 217-744b and nicorandil are seen as promising drugs for clinical application in patients with acute ureteral colic to relieve obstruction and facilitate stone passage or to relax the ureter before ureteroscopy [93] . Cromakalim, a potassium channel modulator, has also been shown to induce a concentration-dependent inhibition of contractions in the isolated human ureteric segments.…”

“…The relaxing properties of the ATP-sensitive K + channel opener and NO donor nicorandil and the new K + channel opener PKF 217-744b were investigated on isolated human ureteral tissue in vitro and in intact ureters of anesthetized pigs in vivo [93] . Both drugs reduced the contraction frequency of the pig ureter after intravenous and topical administration in vivo.…”

In vitro Evaluation of Ureteral Contractility: A Comparative Assessment of Human, Porcine and Sheep Ureteral Response to Vardenafil

“…Accordingly, changes in KCl-induced contraction were used to calculate the effect of diclofenac sodium and papaverine on isolated human ureteral smooth muscle. To address the lack of autonomic contractility in human tissue, other investigators recruit electrical field stimulation techniques or contractile agents, such as voltage-dependent calcium channel agonists, to artificially induce ureteral contractions [11,14,15]. The reason for not adopting any of these methods in the current study was that amplitude reduction alone after KCl stimulation in human ureters was sufficient to reveal the ureteral relaxation properties of vardenafil and to quantitate well its effectiveness.…”

In Vitro Effect of Iron Salts on Peristaltic Activity of Goat Ureter

“…Some of the species used for measuring ureteral peristalsis are: Dog ureter, [3] Sheep ureter, [4] Pig ureter, [5] Human ureter, [6] Guinea pig ureter/Rat ureter, [7] Rabbit ureter [8] and Chicken ureter. [9] In vitro experimentation using goat ureter does not require killing of the animals in the research laboratory, as the tissue can be obtained directly from the slaughter house.…”