MODULATION BY STEREOSELECTIVE INHIBITION OF CYCLOOXYGENASE 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 fie ld 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 mu M) produced a concentration- and time-d ependent 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, 1 0 and 100 mu M. The (R)-enantiomer was ineffective up to 10 mu M. 3 In domethacin (0.1-100 mu M) likewise produced a concentration- and time- dependent inhibition of spontaneous motility of the isolated renal pel vis: its maximal inhibitory effect was larger than that produced by (S )-ketoprofen and averaged 21, 40, 69 and 95% inhibition of motility in dex at 0.1, 1, 10 and 100 mu M respectively. In the presence of a maxi mally effective (100 mu M) concentration of (S)-ketoprofen, 100 mu M i ndomethacin produced >90% inhibition of residual motility. 4 In the gu inea-pig isolated ureter, phasic contractions were induced by EFS (5 m s pulse width, 60 V): (S)-ketoprofen (100-500 mu M) had no effect on t he EFS-evoked contractions. Indomethacin (100-500 mu M) produced a con centration-dependent inhibition and/or suppression of the EFS-evoked c ontractions. When contraction of the ureter was evoked by 80 mM KCl, i ndomethacin produced about 30 and 80% inhibition at 100 and 300 mu M, respectively, while (S)-ketoprofen (300 mu M) was ineffective. 5 The e ffect of (S)-ketoprofen or indomethacin (10 mu M each) on the propagat ion of myogenic impulses along the ureter was determined by use of a t hree chamber organ bath. The renal end of the ureter was electrically stimulated while recording the mechanical activity of the renal and bl adder ends of the ureter: addition of either (S)-ketoprofen or indomet hacin (10 mu M) did not effect propagation of impulses from the renal to the bladder end of the ureter, while nifedipine (10 mu M) promptly blocked the propagated contractions. 6 In sucrose gap experiments, (S) -ketoprofen (10-100 mu M) produced a time-dependent shortening of spon taneous action potentials of the guinea-pig renal pelvis and reduced t he amplitude and duration of the accompanying phasic contractions. Ind omethacin (10 mu M) produced comparable effects on the same parameters and significantly reduced the maximal amplitude of depolarization of the pacemaker potential. In the presence of 100 mu M (S)-ketoprofen, 1 00 mu M indomethacin promptly suppressed the residual pacemaker potent ial and contraction. 7 Neither (S)-ketoprofen nor indomethacin (10 mu M each for 60 min) affected the parameters of action potential and con traction 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 pel vis. The modulatory role of endogenous prostanoids involves an amplifi cation of electromechanical coupling in the renal pelvis while excitab ility, contractility or propagation of impulses along the ureter appea r almost independent of prostanoid generation. Previous reports of a t otal suppression of pyeloureteral motility by indomethacin may reflect a combination of COX inhibition and nonspecific effect on electromech anical coupling.