Inhibition of human and pig ureter motility in vitro and in vivo by the K(+) channel openers PKF 217-744b and nicorandil.
The relaxing property of the K(+) channel opener and nitric oxide donor nicorandil and the new K(+) 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(+) 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) = 4.83 x 10(-8) M] was more potent than nicorandil [EC(50) = 4.38 x 10(-5) 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(+) 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.
Institute of Veterinary Pharmacology, Inselspital, University of Bern, CH-3010 Bern, Switzerland.
Ruth
R
Weiss
Meike
M
Mevissen
Daniela S
DS
Hauser
Günter
G
Scholtysik
Christopher J
CJ
Portier
Bernhard
B
Walter
Urs E
UE
Studer
Hansjörg
H
Danuser
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005905:Glyburide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D020108:Nicorandil / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013552:Swine; D014513:Ureter / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015220:Calcium Channels; C431514:N-(3,4-dihydro-2,2-dimethyl-3-hydroxy-6-(2-methyl-4-pyridinyl)-2H-1-benzopyran-4-yl)-3-(2,6-3H)pyridinecarboxamide; D011725:Pyridines; D020108:Nicorandil; D005905:Glyburide