Effect of prostaglandin inhibition by indomethacin on plasma active and inactive renin concentration in men' P. LBJNEN,$. STABSSEN,R. FAGARD,AND A. AMBRY Hypertension Unit, Department of Pathophysiology, University sf Leuveto (K. U. Leuven), Eeuven, Belgium
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Received September 13, 19914 LIJWEN,P., STAESSEN, J., FAGARD, W., and AMERY,A. 1891. Effect of prostaglandin inhibition by indomethacin on plasma active and inactive renin concentration in men. Can. J. Physiol. Pharmacol. 69: 1355- 1359. The effect of inhibition of prostaglandin synthesis by indomethacin on active renin and on acid-activable inactive renin was studied in nine healthy, sodium-replete men, both at rest and exercise. These volunteers were investigated after pretreatment with placebo or indomethacin, 150 mg daily for 3 days. Indomethacin induced a decrease in active ( p = O.Q8$),total ( p < O.001), and inactive ( p = 0.82) renin at rest recumbent on average by 42, 19, and 876, respectively, and at rest sitting on average by 45, 15, and 3 % , respectively. Inhibition of prostaglandins with indomethacin reduced ( p < 8.001) active and total renin at each level of work load but not ( p = 0.32) inactive renin. However, the exercise-induced stimulation ( p < 0.05) of active and total renin still occur during indomethacin. Indomethacin reduced ( p < 0.001) at rest sitting and at maximal exercise the plasma concentrations of immunoreactive prostaglandins E, by 58 and 54 %, respectively, prostaglandin F,, by 36 and 39 % , respectively, and 13,14-dihydro- 15-keto-prostaglandin Fa by 38 and 60% , respectively. The urinary excretion of immunoreactive prostaglandin E, and FZa was also reduced. Key words: indomethacin, prorenin, active renin, prostaglandins. LIJNBN,P., STABSEN,J., FAGARE), R., et AMERY,A. 1991. Effect of prostaglandin inhibition by indomethacin on plasma active and inactive renin concentration in men. Can. 9. Bhysiol. Pharmacol. 69 : 1355- 1359. On a examine l'effet de l'inhibition de la synthkse des prostaglandines par l'indom6thacine sur la rknine active et la r6mine inactive acido-activable chez neuf hommes en recharge sodique, saim, tant au repos qu'i l'effort. Ces volontaires ont kt6 examinks aprhs un pritraitement avec placebo ou indom6thacine, B une dose de 150 mg quotidiennement pendant 3 jours. L7indom6thacinea induit une diminution de rCnine active ( p = 0,0M), totale ( p < 0,001) et inactive ( p = 0,02), au repos en psition couchke, en moyenne de 42, 19 et $%, respectivement, et au repos en position assise, en rnoyemne de 45, 15 et 3 1,respectivement. L'inhibition des prostaglandines par l'indomkthacine a r6duit la r6nine active et totale ( p < 8,001) 2i chaque niveau d'effort, mais n'a pas rdduit la renine inactive ( p = 0,32). Toutefois, la stimulation de rknine active et totale induite par l'effort ((p < 8,05) s'est maintenue avee l'indomethacine. LYindom6thacinea r6duit ( p < 0,001) au repos, en psition assise et B l'effort maximal, les concentrations plasmatiques de prostaglandines E, imunorCactives Be 50 et 5476, respectivement, de prostaglandines P;,, immunorCactives de 34 et 39 % respectivernent, et de 13,14-dihydro- 15-kktoprostaglandines Fa imunor6actives de 38 et 6096, respectivement. E'excrktion urinaire de prostaglandines E, et F2, imunor6actives a aussi kt6 r6duit.e. f i t s c l h : indomethacine, prsrknine, r6nine active, prostaglandines. [Traduit par la rgdaction]
Prostaglandins are able to stimulate the secretion of active renin (Gerkr et al. 1979). Inhibition of their synthesis through indornethacin administration is able to reduce active renin levels that are either increased or already seduced by antihypertensive drugs (Bedrinelli et d. 1980; Salvetti et d. 1982). In the present study, we investigated the effect of fatty acid cyclo-oxygenase inhibition by indomethacin on active a d total renin, as well as on acid-activable inactive r e i n , at rest and during exercise in sodium-replete men.
Methods Subjects Nine h d t h y , nomotensive men volunteered for the present study after all test procedures had been explained. Age averaged 24.4 years (range: 2 1 -30 years), height averaged 179 cm (range: 148- 185 m), and M y weight averaged 73.7 kg (range: 45 -87 kg). They remained on an ad libitum diet throughout the study. Experimental protocol The tests were performed in an air-conditioned laboratory, where room temperature was stabilized at 18-22°C and humidity at 'This paper was presented at the Satellite Symposium of the 13th Scientific Meeting of the International Society of Hypertension, entitled Activation and Function of Prorenin, held in Montreal, QuC., June 22, 1990, and has undergone the Journal's usual peer review. Printed in Canada / HmprimC au Canada
40 -60 % . The subjects performed three graded and uninterrupted exercise tests until exhaustion, sitting on a bicycle ergometer. The first exercise test was a pretest to assess the subject's maximal exercise capacity and antedated the second experiment by 1 week to 4 months. The initial external work load of 10 W was increased by 10 W every minufe. The oxygen uptake at the maximum work load was determined (Vo, m u ) and the external work loads at which 30 and 60% of VQ, max were reached were calculated. Stqrting 3 days before the second and third test, the volunteers received three capsules daily to be taken during meals and containing placebo or indomethacin (58 mg). These capsules were identical in appearance, allowing a double-blind analysis of the data. Five subjects took indomethacin first and four took placebo first. The subjects collected their 24-h urine on the days immediately preceding the second and third exercise test, referred to as first and second collection. On the morning of these tests a small catheter (Vygon 115.09) was introduced into the brachial artery for sampling of arterial blood. Thereafter they rested in the recumbent position (RR) for 30 min; then they assumed the sitting position (RS) on the ergometer bicycle for 15 min, and finally the exercise test was started at 10 W for 1 min and the work load stepwise increased by 18 W every min until exhaustion. Biochemicat variables Active, inactive, and totat p l a s m renin concentration Arterial blood was withdrawn at 30 min RR, at 15 min RS, and at 40, 68,and 100% of VQ, max for assay s f active, inactive, and total plasma renin concentration (PRC). Blood (5 mL) was withdrawn in an ice-cooled tube containing 125 mmol L-I EDTA and 25 mmol . L-I o-phenanthroline in distilled water, centrifuged immediately in
CAN. J. PHYSIOL.PHARMACOL. VOk. 69, 1991
TABLE1. Urinary excretion of immunoreactive prostaglandin E2 and h;,, during placebo and indomethacin treatment in nine healthy, male subjects Prostaglandin (nmol 24 h- I) iPGE,
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by 99.248.14.206 on 01/07/15 For personal use only.
iPGh;,,
Treatment
First collection
Second collection
P
Placebo Indomethacin Placebo Indomethcin
0.98 (0.42 -4.88) 0.44 (0.21 - 1.78) 2.64 (1.45-4.31) 1.47 (0.97 -2.74)
0.77 (0.33 -4.75) 0.41 (0.20- 1.04) 2.44 (1.51-4.62) 1.62 (8.72 -2.88)
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by 99.248.14.206 on 01/07/15 For personal use only.
Received September 13, 19914 LIJWEN,P., STAESSEN, J., FAGARD, W., and AMERY,A. 1891. Effect of prostaglandin inhibition by indomethacin on plasma active and inactive renin concentration in men. Can. J. Physiol. Pharmacol. 69: 1355- 1359. The effect of inhibition of prostaglandin synthesis by indomethacin on active renin and on acid-activable inactive renin was studied in nine healthy, sodium-replete men, both at rest and exercise. These volunteers were investigated after pretreatment with placebo or indomethacin, 150 mg daily for 3 days. Indomethacin induced a decrease in active ( p = O.Q8$),total ( p < O.001), and inactive ( p = 0.82) renin at rest recumbent on average by 42, 19, and 876, respectively, and at rest sitting on average by 45, 15, and 3 % , respectively. Inhibition of prostaglandins with indomethacin reduced ( p < 8.001) active and total renin at each level of work load but not ( p = 0.32) inactive renin. However, the exercise-induced stimulation ( p < 0.05) of active and total renin still occur during indomethacin. Indomethacin reduced ( p < 0.001) at rest sitting and at maximal exercise the plasma concentrations of immunoreactive prostaglandins E, by 58 and 54 %, respectively, prostaglandin F,, by 36 and 39 % , respectively, and 13,14-dihydro- 15-keto-prostaglandin Fa by 38 and 60% , respectively. The urinary excretion of immunoreactive prostaglandin E, and FZa was also reduced. Key words: indomethacin, prorenin, active renin, prostaglandins. LIJNBN,P., STABSEN,J., FAGARE), R., et AMERY,A. 1991. Effect of prostaglandin inhibition by indomethacin on plasma active and inactive renin concentration in men. Can. 9. Bhysiol. Pharmacol. 69 : 1355- 1359. On a examine l'effet de l'inhibition de la synthkse des prostaglandines par l'indom6thacine sur la rknine active et la r6mine inactive acido-activable chez neuf hommes en recharge sodique, saim, tant au repos qu'i l'effort. Ces volontaires ont kt6 examinks aprhs un pritraitement avec placebo ou indom6thacine, B une dose de 150 mg quotidiennement pendant 3 jours. L7indom6thacinea induit une diminution de rCnine active ( p = 0,0M), totale ( p < 0,001) et inactive ( p = 0,02), au repos en psition couchke, en moyenne de 42, 19 et $%, respectivement, et au repos en position assise, en rnoyemne de 45, 15 et 3 1,respectivement. L'inhibition des prostaglandines par l'indomkthacine a r6duit la r6nine active et totale ( p < 8,001) 2i chaque niveau d'effort, mais n'a pas rdduit la renine inactive ( p = 0,32). Toutefois, la stimulation de rknine active et totale induite par l'effort ((p < 8,05) s'est maintenue avee l'indomethacine. LYindom6thacinea r6duit ( p < 0,001) au repos, en psition assise et B l'effort maximal, les concentrations plasmatiques de prostaglandines E, imunorCactives Be 50 et 5476, respectivement, de prostaglandines P;,, immunorCactives de 34 et 39 % respectivernent, et de 13,14-dihydro- 15-kktoprostaglandines Fa imunor6actives de 38 et 6096, respectivement. E'excrktion urinaire de prostaglandines E, et F2, imunor6actives a aussi kt6 r6duit.e. f i t s c l h : indomethacine, prsrknine, r6nine active, prostaglandines. [Traduit par la rgdaction]
Prostaglandins are able to stimulate the secretion of active renin (Gerkr et al. 1979). Inhibition of their synthesis through indornethacin administration is able to reduce active renin levels that are either increased or already seduced by antihypertensive drugs (Bedrinelli et d. 1980; Salvetti et d. 1982). In the present study, we investigated the effect of fatty acid cyclo-oxygenase inhibition by indomethacin on active a d total renin, as well as on acid-activable inactive r e i n , at rest and during exercise in sodium-replete men.
Methods Subjects Nine h d t h y , nomotensive men volunteered for the present study after all test procedures had been explained. Age averaged 24.4 years (range: 2 1 -30 years), height averaged 179 cm (range: 148- 185 m), and M y weight averaged 73.7 kg (range: 45 -87 kg). They remained on an ad libitum diet throughout the study. Experimental protocol The tests were performed in an air-conditioned laboratory, where room temperature was stabilized at 18-22°C and humidity at 'This paper was presented at the Satellite Symposium of the 13th Scientific Meeting of the International Society of Hypertension, entitled Activation and Function of Prorenin, held in Montreal, QuC., June 22, 1990, and has undergone the Journal's usual peer review. Printed in Canada / HmprimC au Canada
40 -60 % . The subjects performed three graded and uninterrupted exercise tests until exhaustion, sitting on a bicycle ergometer. The first exercise test was a pretest to assess the subject's maximal exercise capacity and antedated the second experiment by 1 week to 4 months. The initial external work load of 10 W was increased by 10 W every minufe. The oxygen uptake at the maximum work load was determined (Vo, m u ) and the external work loads at which 30 and 60% of VQ, max were reached were calculated. Stqrting 3 days before the second and third test, the volunteers received three capsules daily to be taken during meals and containing placebo or indomethacin (58 mg). These capsules were identical in appearance, allowing a double-blind analysis of the data. Five subjects took indomethacin first and four took placebo first. The subjects collected their 24-h urine on the days immediately preceding the second and third exercise test, referred to as first and second collection. On the morning of these tests a small catheter (Vygon 115.09) was introduced into the brachial artery for sampling of arterial blood. Thereafter they rested in the recumbent position (RR) for 30 min; then they assumed the sitting position (RS) on the ergometer bicycle for 15 min, and finally the exercise test was started at 10 W for 1 min and the work load stepwise increased by 18 W every min until exhaustion. Biochemicat variables Active, inactive, and totat p l a s m renin concentration Arterial blood was withdrawn at 30 min RR, at 15 min RS, and at 40, 68,and 100% of VQ, max for assay s f active, inactive, and total plasma renin concentration (PRC). Blood (5 mL) was withdrawn in an ice-cooled tube containing 125 mmol L-I EDTA and 25 mmol . L-I o-phenanthroline in distilled water, centrifuged immediately in
CAN. J. PHYSIOL.PHARMACOL. VOk. 69, 1991
TABLE1. Urinary excretion of immunoreactive prostaglandin E2 and h;,, during placebo and indomethacin treatment in nine healthy, male subjects Prostaglandin (nmol 24 h- I) iPGE,
Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by 99.248.14.206 on 01/07/15 For personal use only.
iPGh;,,
Treatment
First collection
Second collection
P
Placebo Indomethacin Placebo Indomethcin
0.98 (0.42 -4.88) 0.44 (0.21 - 1.78) 2.64 (1.45-4.31) 1.47 (0.97 -2.74)
0.77 (0.33 -4.75) 0.41 (0.20- 1.04) 2.44 (1.51-4.62) 1.62 (8.72 -2.88)
