Modulation by stereoselective inhibition of cyclo-oxygenase of electromechanical coupling in the guinea-pig isolated renal pelvis.
1. The effects of the (S)- and (R)-enantiomers of the cyclo-oxygenase (COX) inhibitor, ketoprofen, have been investigated on the spontaneous activity of the guinea-pig isolated renal pelvis and on electrical field stimulation-(EFS) induced contractions of the guinea-pig ureter in comparison with the effects of the achiral COX inhibitor, indomethacin. 2. (S)-ketoprofen (0.1-100 microM) produced a concentration- and time-dependent inhibition of the spontaneous myogenic activity of the renal pelvis. The maximal inhibitory effect (% inhibition of motility index) averaged 29, 42, 47 and 56% inhibition of control values at 0.1, 1, 10 and 100 microM. The (R)-enantiomer was ineffective up to 10 microM. 3. Indomethacin (0.1-100 microM) likewise produced a concentration- and time-dependent inhibition of spontaneous motility of the isolated renal pelvis: its maximal inhibitory effect was larger than that produced by (S)-ketoprofen and averaged 21, 40, 69 and 95% inhibition of motility index at 0.1, 1, 10 and 100 microM respectively. In the presence of a maximally effective (100 microM) concentration of (S)-ketoprofen, 100 microM indomethacin produced > 90% inhibition of residual motility. 4. In the guinea-pig isolated ureter, phasic contractions were induced by EFS (5 ms pulse width, 60 V): (S)-ketoprofen (100-500 microM) had no effect on the EFS-evoked contractions. Indomethacin (100-500 microM) produced a concentration-dependent inhibition and/or suppression of the EFS-evoked contractions. When contraction of the ureter was evoked by 80 mM KCl, indomethacin produced about 30 and 80% inhibition at 100 and 300 microM, respectively, while (S)-ketoprofen (300 microM) was ineffective. 5. The effect of (S)-ketoprofen or indomethacin (10 microM each) on the propagation of myogenic impulses along the ureter was determined by use of a three chamber organ bath. The renal end of the ureter was electrically stimulated while recording the mechanical activity of the renal and bladder ends of the ureter: addition of either (S)-ketoprofen or indomethacin (10 microM) did not effect propagation of impulses from the renal to the bladder end of the ureter, while nifedipine (10 microM) promptly blocked the propagated contractions. 6. In sucrose gap experiments, (S)-ketoprofen (10-100 microM) produced a time-dependent shortening of spontaneous action potentials of the guinea-pig renal pelvis and reduced the amplitude and duration of the accompanying phasic contractions. Indomethacin (10 microM) produced comparable effects on the same parameters and significantly reduced the maximal amplitude of depolarization of the pacemaker potential. In the presence of 100 microM (S)-ketoprofen, 100 microM indomethacin promptly suppressed the residual pacemaker potential and contraction.7. Neither (S)-ketoprofen nor indomethacin (10 microM each for 60 min) affected the parameters of action potential and contraction of the guinea-pig ureter evoked by EFS. Both drugs produced a sustained membrane depolarization.8. The present findings demonstrate that stereoselective COX inhibition affects pacemaker potentials and contractility (electromechanical coupling) in the guinea-pig renal pelvis. The modulatory role of endogenous prostanoids involves an amplification of electromechanical coupling in the renal pelvis while excitability, contractility or propagation of impulses along the ureter appear almost independent of prostanoid generation. Previous reports of a total suppression of pyeloureteral motility by indomethacin may reflect a combination of COX inhibition and nonspecific effect on electromechanical coupling.
Santicioli
P
P
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Carganico
G
G
Meini
S
S
Giuliani
S
S
Giachetti
A
A
Maggi
C A
CA
D000818:Animals; D001696:Biomechanical Phenomena; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004558:Electric Stimulation; D005071:Evoked Potentials; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D007660:Ketoprofen / Q000494:pharmacology*; D007682:Kidney Pelvis / Q000378:metabolism*; D008297:Male; D010138:Pacemaker, Artificial; D013237:Stereoisomerism; D014513:Ureter / Q000187:drug effects
D016861:Cyclooxygenase Inhibitors; D007660:Ketoprofen; D007213:Indomethacin