Dissociation of renin release and renal vasodilation by prostaglandin synthesis inhibitors JOSEPH L. BLACKSHEAR, WILLIAM S. SPIELMAN, FRANKLYN G. KNOX, AND J. CARLOS ROMERO Department of Physiology and Biophysics and the Nephrology Research Laboratories, Mayo Medical School and the Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55901
BLACKSHEAR,JOSEPH
L., WILLIAMS.SPIELMAN,FRANKLYN
G. KNOX, AND J. CARLOS ROMERO. Dissociation ofrenin release and renal vasodilation by prostaghdirz syntksis i&-t& itors. Am. J. Physiol. 237(l): F20-F24, 1979 or Am. J. Physiol.: Renal Fluid Electrolyte Physiol. 6( 1): F20-F24, 1979.-Renal blood flow (RBF) and renin secretion rate (RSR) were measured during step reductions of renal perfusion pressure (RPP) within and below the autoregulatory range of RBF in the presence or absence of prostaglandin synthesis inhibitors. In seven untreated dogs with reduction of RPP from 120 to 90 mmHg, RBF did not change and RSR increased from 662 t 90 to 2,138 t 121 ng/min (means t SE). When RPP was further reduced to 60 mmHg, RBF decreased by 22% and RSR* increased to 3,259 Jo:676 ng/min. After indomethacin administration renin release was 680 t 171 before and 1,044 k 162 ng/min after RPP was reduced from 120 to 90 mmHg without affecting RBF. These values are not significantly different. Indomethacin did not affect the increase in the release of renin up to 3,096 t 629 ng/min when RPP was reduced to 60 mmHg. Comparable effects in the release of renin were exerted by meclofenamate. Reduction of RPP from control pressure to 83 mmHg was not accompanied by any significant change in RBF either before or after meclofenamate. However, RSR increased from 677 t 317 to 2,701 t 851 ng/min before meclofenamate and from 249 k 209 to 515 + 288 ng/min after meclofenamate. Further reduction of RPP to 53 mmHg resulted in similar decreases in RBF before and after meclofenamate and increased RSR by 2,658 ,t 1,120 before and 2,206 t 721 ng/min after meclofenamate. The results suggest that inhibitors of prostaglandin synthesis attenuate the release of renin within but not below the autoregulatory range of RBF. autoregulation;
indomethacin;
meclofenamate;
renal blood flow
STUDIES HAVE DEMONSTRATED that the inhibition of prostaglandin synthesis by indomethacin or meclofenamate can block the release of renin induced by various maneuvers (3, 4, 6, 8, 23). Recently, it was reported that such inhibition blocks both the vasodilator response and the renin release response to ureteral occlusion (6). In each of the previous studies, the release of renin was induced by maneuvers that are associated with concomitant renal vasodilation. In each instance, the blockade of the renin release by prostaglandin synthesis inhibitors also inhibited the vasodilation. Eide et al. (11, 12) have suggested that the vasodilation during ureteral obstruction and reduced renal perfusion pressure is accompanied by renin release and that in both situations, PREVIOUS
F20
when vasodilation becomes maximal, renin release is no longer increased. Because the renal vasodilation of reduced renal perfusion pressure has been reported to remain intact after the administration of indomethacin (2, 5, 14, 15, 17), we wanted to investigate the effect on renin release. The present study was undertaken, therefore, to investigate the effects of prostaglandin synthesis inhibitors on renal blood flow and renin release during reduced perfusion pressure and to test whether renin release can be dissociated from renal vasodilation. MATERIALS
AND
METHODS
Group 1. Untreated and indomethacin- treated dogs. Fourteen mongrel dogs were fed a standard laboratory diet which was withheld 18 h before the experiment. Free access to water was allowed. Seven dogs were given an oral dose of indomethacin (10 mg kg-’ day-‘) in divided morning and evening doses for 2 days before the day of the experiment, and an intravenous dose (10 mg/kg) 30 min before the experiment. Group 2. Dogs tested before and after sodium meclofenamate. Six mongrel dogs were allowed food and free access to water until the morning of the experiment. After an initial experimental period in which renin secretion rate was measured before and during reductions in renal perfusion pressure, a dose of sodium meclofenamate (10 mg/kg) was administered intravenously, at least 30 min were allowed to elapse, and the experimental procedure was repeated. The dogs were anesthetized with sodium pentobarbital (30 mg/kg). A single kidney was exposed through a flank incision, and the dogs were placed in dorsal suspension. A flow probe was placed around the renal artery for determination of renal blood flow. Renal perfusion pressure was reduced by partial renal arterial occlusion with either a Blalock clamp or a silk snare. A needle was placed in the renal artery for measurements of renal artery pressure. A polyethylene catheter (PE-50) was placed via the gonadal vein into the renal vein for blood sampling. Measurements were made during two step reductions of renal artery pressure from base-line pressure to between 80 and 90 mmHg and from between 80 and 90 to between 50 and 60 mmHg. Femoral arterial and renal venous blood samples were taken at these three pressure
0363-6127/79/0000-0000$01.25
l
Copyright
0 1979 the American
l
Physiological
Society
Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (150.216.068.200) on January 10, 2019.
PROSTAGLANDINS
AND
RENIN
F21
RELEASE
levels for plasma renin activity within 5 min of stabilization of renal blood flow at each pressure. Renin secretion rates were calculated by multiplying the arteriovenous difference of plasma renin activity (nanograms of angiotension I generated per milliliter of plasma per hour) and renal plasma flow (as estimated from electromagnetically determined renal blood flows). Renin secretion rates were then expressed as nanograms per minute. Efficacy of indomethacin in blocking the synthesis of prostaglandin was assessed by measuring the renal blood flow response to a 1.0.mg intrarenal bolus injection of sodium arachidonate in five of the untreated dogs, in six of the indomethacin-treated dogs, and in six dogs before and after the administration of sodium meclofenamate. The sensitivity of the renal vasculature to exogenously administered prostaglandin Ez (PGEZ) was then determined by measuring the renal blood flow responses to intrarenal infusion of PGEz at 0.5 ng . kg-’ .min-‘. Indomethacin (Merck Sharp & Dohme) for intravenous administration was prepared as a suspension of indomethacin in sodium phosphate buffer, pH 8. Sodium meclofenamate was dissolved in 0.9% saline. Sodium arachidonate was prepared by adding sodium carbonate buffer, pH 8, to a vial of arachidonic acid (Nu-Check Prep) and stirring under nitrogen for 3 h. Fractions of this stock solution were diluted in 0.9% saline for intrarenal injection. Plasma renin activity was assessed by a radioimmunoassay method reported in previous studies (20). The specificity and reproducibility of such a method of measuring plasma renin activity in dogs also have been reported previously (16). Results were statisticaUy anaIyzed using analysis of repeated measures (18) and Hotelling T2 (18); values are expressed as means t SE. RESULTS
Group 1. Renal blood flow did not change significantly (from 134 t 18 to 137 t 20 ml/min) in untreated dogs when renal perfusion pressure was decreased from 120 to 90 mmHg (Fig. 1). A further decrease in renal perfusion pressure to 60 mmHg was accompanied by a significant (P < 0.01) reduction in renal blood flow to 108 t 17 ml/ min. In indomethacin-treated dogs, the reduction of renal perfusion pressure from 120 to 90 mmHg was not accompanied by the same efficiency in the autoregulatory response, as the average renal blood flow decreased from 131 t 17 to 118 t 14 ml/min. However, such a decrease was not statistically significant. In the treated dogs, a further reduction of renal perfusion pressure to 60 mmHg significantly (P < 0.01) reduced renal blood flow to 82 t 10 ml/min. Renal blood flow in indomethacin-treated dogs was not significantly different from that in untreated dogs at any perfusion pressure. In untreated dogs, the decrease in perfusion pressure from 120 to 90 mmHg was followed by a significant (P < 0.01) increase in renin secretion rate from 662 t 90 to 2,138 t 121 ng/min (Fig. I), whereas a further decrease of renal perfusion pressure to 60 mmHg was followed by an additional increase in renin secretion rate to 3,259 t 676 ng/min. This latter increment was not statisticahy
l
Untreated
0 Treated Q +u 2
lc?;
4000 1-c Q\ 3000 QP, @,r 2000 '\ts 1000
a
0
-a
.
P
BLACKSHEAR,JOSEPH
L., WILLIAMS.SPIELMAN,FRANKLYN
G. KNOX, AND J. CARLOS ROMERO. Dissociation ofrenin release and renal vasodilation by prostaghdirz syntksis i&-t& itors. Am. J. Physiol. 237(l): F20-F24, 1979 or Am. J. Physiol.: Renal Fluid Electrolyte Physiol. 6( 1): F20-F24, 1979.-Renal blood flow (RBF) and renin secretion rate (RSR) were measured during step reductions of renal perfusion pressure (RPP) within and below the autoregulatory range of RBF in the presence or absence of prostaglandin synthesis inhibitors. In seven untreated dogs with reduction of RPP from 120 to 90 mmHg, RBF did not change and RSR increased from 662 t 90 to 2,138 t 121 ng/min (means t SE). When RPP was further reduced to 60 mmHg, RBF decreased by 22% and RSR* increased to 3,259 Jo:676 ng/min. After indomethacin administration renin release was 680 t 171 before and 1,044 k 162 ng/min after RPP was reduced from 120 to 90 mmHg without affecting RBF. These values are not significantly different. Indomethacin did not affect the increase in the release of renin up to 3,096 t 629 ng/min when RPP was reduced to 60 mmHg. Comparable effects in the release of renin were exerted by meclofenamate. Reduction of RPP from control pressure to 83 mmHg was not accompanied by any significant change in RBF either before or after meclofenamate. However, RSR increased from 677 t 317 to 2,701 t 851 ng/min before meclofenamate and from 249 k 209 to 515 + 288 ng/min after meclofenamate. Further reduction of RPP to 53 mmHg resulted in similar decreases in RBF before and after meclofenamate and increased RSR by 2,658 ,t 1,120 before and 2,206 t 721 ng/min after meclofenamate. The results suggest that inhibitors of prostaglandin synthesis attenuate the release of renin within but not below the autoregulatory range of RBF. autoregulation;
indomethacin;
meclofenamate;
renal blood flow
STUDIES HAVE DEMONSTRATED that the inhibition of prostaglandin synthesis by indomethacin or meclofenamate can block the release of renin induced by various maneuvers (3, 4, 6, 8, 23). Recently, it was reported that such inhibition blocks both the vasodilator response and the renin release response to ureteral occlusion (6). In each of the previous studies, the release of renin was induced by maneuvers that are associated with concomitant renal vasodilation. In each instance, the blockade of the renin release by prostaglandin synthesis inhibitors also inhibited the vasodilation. Eide et al. (11, 12) have suggested that the vasodilation during ureteral obstruction and reduced renal perfusion pressure is accompanied by renin release and that in both situations, PREVIOUS
F20
when vasodilation becomes maximal, renin release is no longer increased. Because the renal vasodilation of reduced renal perfusion pressure has been reported to remain intact after the administration of indomethacin (2, 5, 14, 15, 17), we wanted to investigate the effect on renin release. The present study was undertaken, therefore, to investigate the effects of prostaglandin synthesis inhibitors on renal blood flow and renin release during reduced perfusion pressure and to test whether renin release can be dissociated from renal vasodilation. MATERIALS
AND
METHODS
Group 1. Untreated and indomethacin- treated dogs. Fourteen mongrel dogs were fed a standard laboratory diet which was withheld 18 h before the experiment. Free access to water was allowed. Seven dogs were given an oral dose of indomethacin (10 mg kg-’ day-‘) in divided morning and evening doses for 2 days before the day of the experiment, and an intravenous dose (10 mg/kg) 30 min before the experiment. Group 2. Dogs tested before and after sodium meclofenamate. Six mongrel dogs were allowed food and free access to water until the morning of the experiment. After an initial experimental period in which renin secretion rate was measured before and during reductions in renal perfusion pressure, a dose of sodium meclofenamate (10 mg/kg) was administered intravenously, at least 30 min were allowed to elapse, and the experimental procedure was repeated. The dogs were anesthetized with sodium pentobarbital (30 mg/kg). A single kidney was exposed through a flank incision, and the dogs were placed in dorsal suspension. A flow probe was placed around the renal artery for determination of renal blood flow. Renal perfusion pressure was reduced by partial renal arterial occlusion with either a Blalock clamp or a silk snare. A needle was placed in the renal artery for measurements of renal artery pressure. A polyethylene catheter (PE-50) was placed via the gonadal vein into the renal vein for blood sampling. Measurements were made during two step reductions of renal artery pressure from base-line pressure to between 80 and 90 mmHg and from between 80 and 90 to between 50 and 60 mmHg. Femoral arterial and renal venous blood samples were taken at these three pressure
0363-6127/79/0000-0000$01.25
l
Copyright
0 1979 the American
l
Physiological
Society
Downloaded from www.physiology.org/journal/ajprenal by ${individualUser.givenNames} ${individualUser.surname} (150.216.068.200) on January 10, 2019.
PROSTAGLANDINS
AND
RENIN
F21
RELEASE
levels for plasma renin activity within 5 min of stabilization of renal blood flow at each pressure. Renin secretion rates were calculated by multiplying the arteriovenous difference of plasma renin activity (nanograms of angiotension I generated per milliliter of plasma per hour) and renal plasma flow (as estimated from electromagnetically determined renal blood flows). Renin secretion rates were then expressed as nanograms per minute. Efficacy of indomethacin in blocking the synthesis of prostaglandin was assessed by measuring the renal blood flow response to a 1.0.mg intrarenal bolus injection of sodium arachidonate in five of the untreated dogs, in six of the indomethacin-treated dogs, and in six dogs before and after the administration of sodium meclofenamate. The sensitivity of the renal vasculature to exogenously administered prostaglandin Ez (PGEZ) was then determined by measuring the renal blood flow responses to intrarenal infusion of PGEz at 0.5 ng . kg-’ .min-‘. Indomethacin (Merck Sharp & Dohme) for intravenous administration was prepared as a suspension of indomethacin in sodium phosphate buffer, pH 8. Sodium meclofenamate was dissolved in 0.9% saline. Sodium arachidonate was prepared by adding sodium carbonate buffer, pH 8, to a vial of arachidonic acid (Nu-Check Prep) and stirring under nitrogen for 3 h. Fractions of this stock solution were diluted in 0.9% saline for intrarenal injection. Plasma renin activity was assessed by a radioimmunoassay method reported in previous studies (20). The specificity and reproducibility of such a method of measuring plasma renin activity in dogs also have been reported previously (16). Results were statisticaUy anaIyzed using analysis of repeated measures (18) and Hotelling T2 (18); values are expressed as means t SE. RESULTS
Group 1. Renal blood flow did not change significantly (from 134 t 18 to 137 t 20 ml/min) in untreated dogs when renal perfusion pressure was decreased from 120 to 90 mmHg (Fig. 1). A further decrease in renal perfusion pressure to 60 mmHg was accompanied by a significant (P < 0.01) reduction in renal blood flow to 108 t 17 ml/ min. In indomethacin-treated dogs, the reduction of renal perfusion pressure from 120 to 90 mmHg was not accompanied by the same efficiency in the autoregulatory response, as the average renal blood flow decreased from 131 t 17 to 118 t 14 ml/min. However, such a decrease was not statistically significant. In the treated dogs, a further reduction of renal perfusion pressure to 60 mmHg significantly (P < 0.01) reduced renal blood flow to 82 t 10 ml/min. Renal blood flow in indomethacin-treated dogs was not significantly different from that in untreated dogs at any perfusion pressure. In untreated dogs, the decrease in perfusion pressure from 120 to 90 mmHg was followed by a significant (P < 0.01) increase in renin secretion rate from 662 t 90 to 2,138 t 121 ng/min (Fig. I), whereas a further decrease of renal perfusion pressure to 60 mmHg was followed by an additional increase in renin secretion rate to 3,259 t 676 ng/min. This latter increment was not statisticahy
l
Untreated
0 Treated Q +u 2
lc?;
4000 1-c Q\ 3000 QP, @,r 2000 '\ts 1000
a
0
-a
.
P
