Effects of ZD7288, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, on term-pregnant rat uterine contractility in vitro.
The uterus is a myogenic organ that is able to produce discrete spontaneous action potentials and contractions without any stimuli. Myometrial excitability is governed by ion channels including Ca+2and K+channels, but whether or not other channels such as hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which play an important role in regulating cellular excitability, are also involved has not been reported in uterine smooth muscles. The aim of the present study was to examine whether blocking HCN channels with a specific blocker ZD7288 would modulate the uterine contractility in a rat model. Using longitudinal uterine strips from term-pregnant rats, the effects of varying concentrations of ZD7288 (50 μM, 100 μM, and 200 μM) were examined on uterine contractions generated spontaneously or by oxytocin (5 nmol/L) and on uterine strips depolarized by high-KCl (60 mM/L), or activated by L-type Ca2+channels agonist (Bay K8644; 1 μM). Application of ZD7288 at concentrations of 200 μM and 100 μM, but not 50 μM, significantly decreased the amplitude of spontaneous uterine contractions. In addition, 200 μM of ZD7288 significantly reduced the force of contractions induced by oxytocin with a pronounced reduction while the tissues were depolarized by high-KCl solution, or activated by Bay K8644. The present study provides pharmacological evidence suggesting that pregnant uterine contractility is modulated by HCN channels and that these channels might represent a therapeutic target for controlling premature activation of uterine activity associated with preterm labor.
Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia. Electronic address: mfalotaibi@ksu.edu.sa.
Mohammed
M
Alotaibi
Department of Basic Sciences; College of Dentistry, Princess Nora University, Riyadh, Saudi Arabia.
Karima
K
Kahlat
King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia.
Taoufik
T
Nedjadi
Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia.
Laiche
L
Djouhri
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008564:Membrane Potentials; D010121:Oxytocin / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology*; D017208:Rats, Wistar; D014590:Uterine Contraction; D014599:Uterus / Q000187:drug effects* / Q000502:physiology
D054815:Cyclic Nucleotide-Gated Cation Channels; D011743:Pyrimidines; C082246:ICI D2788; D010121:Oxytocin; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Contraction; HCN channels; Smooth muscle; Uterus; ZD7288