NS-398 (a selective cyclooxygenase-2 inhibitor) decreases agonist-induced contraction of the human ureter via calcium channel inhibition.
OBJECTIVE
Recently, it has been demonstrated that ureteral obstruction is associated with increased cyclooxygenase (COX)-2 expression and that selective COX-2 inhibitors provide potent analgesia with fewer side effects in patients with ureteral stones. Moreover, selective COX-2 inhibitors have been shown to decrease in vitro contractility of the human ureter. We aimed at evaluating the effects of the selective COX-2 inhibitor NS-398 on human ureteral smooth muscle contractility and compare its potency with that of nonselective COX inhibitors, COX-1 inhibitors, and other COX-2 inhibitors.


METHODS
Ureteral samples were obtained from human adult subjects undergoing radical nephrectomy. After isolating the upper ureteral strips, we analyzed the contractile responses of the ureteral strips to high potassium (KCl 35 mM) and Bay K 8644 and the relaxation responses of a nonspecific COX inhibitor (indomethacin), a COX-1 inhibitor (SC-560), and a COX-2 inhibitor (NS-398 and celecoxib) to KCl and Bay K 8644-induced contraction by measuring isometric tension.


RESULTS
NS-398 produced dose-dependent (10⁻⁹-10⁻⁵ M) relaxation of KCl (35 mM)-precontracted strips of the ureter, whereas indomethacin (10⁻⁸-10⁻⁵ M) and SC-560 (10⁻⁹-10⁻⁵ M) did not. Both tonic and phasic contraction of Bay K 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-2(trifluoromethylphenyl)pyridine-5-carboxylate) (1 μM) were significantly inhibited by NS-398 (10⁻⁵ M). Another selective COX-2 inhibitor, celecoxib, did not show potent inhibitory effects as strong as those of NS-398.


CONCLUSIONS
We concluded that NS-398 reduces tonic or phasic contraction by inhibiting the action of voltage-dependent calcium channels. NS-398 has dual inhibitory effects with COX-2 inhibition on ureteral spasms due to renal or ureteral colic.
Department of Urology, Seoul Medical Center, Seoul, Republic of Korea.
Shin Young
SY
Lee
Moo Yeol
MY
Lee
Soo Hyun
SH
Park
Tae Hyoung
TH
Kim
Young Tae
YT
Moon
June Hyun
JH
Han
Soon Chul
SC
Myung
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000328:Adult; D015220:Calcium Channels / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009578:Nitrobenzenes / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D014513:Ureter / Q000187:drug effects* / Q000502:physiology*
D015220:Calcium Channels; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester