Abstract The contribution of endogenous kinins to impairment in renal adaptation to a 6-day period of dietary sodium withdrawal associated with treatment with ramipril (5 mg/kg per day) and losartan (30 mg/kg per day) was evaluated by use of concomitant chronic administration of the bradykinin B2-receptor antagonist Hoe 140 (150 or 300 μg/kg per day via subcutaneous osmotic pump). A similar level of higher cumulative sodium excretion was observed in ramipril- and losartan-treated rats compared with untreated animals, and the effect of ramipril was not affected by Hoe 140. Similarly, the fall in arterial pressure and the renal vasodilatation associated with ramipril and losartan were not modified by Hoe 140. Glomerular filtration rate (785±73 μL/min per g KW in untreated sodium-depleted rats) decreased to a larger extent in ramipril-treated rats compared with losartan-treated rats (371±78 and 550±55 μL/min per g KW, respectively). Hoe 140 markedly prevented the alteration in glomerular filtration rate associated with ramipril, thus resulting in a final glomerular filtration rate (543±41 μL/min per g KW) similar to that observed with losartan. These findings demonstrate that despite a lack of influence on arterial pressure and sodium balance, accumulation of kinins markedly contributes to deterioration of the glomerular filtration rate induced by ramipril in sodium-depleted rats.
The renin-angiotensin system plays an important role in systemic and renal adaptation to dietary sodium removal. Such a role was clearly demonstrated by the fall in arterial pressure and excessive urinary sodium loss observed in rats treated with an ACEI during the initial 6-day period of dietary sodium restriction in previous studies.1 2 Because inhibition of ACE is associated with a decrease in the degradation of exogenous bradykinin in cultured vascular endothelial cells3 and potentiation of the vasodepressor effect of bradykinin in intact animals,4 it was hypothesized that part of the in vivo effect of ACEI could be related to accumulation of endogenous kinins. Contribution of kinins to the acute antihypertensive effect of ACEIs was suggested by the slight blunting of the hypotensive effect of these agents by kinin antagonists in spontaneously hypertensive rats5 and rats with two-kidney, one clip hypertension.6 7
In a previous study conducted in rats,8 the renal adaptive process to dietary sodium restriction was similarly affected by pretreatment with the type 1 angiotensin II receptor antagonist losartan and the ACEI enalapril. These results suggested that removal of the influence of angiotensin II was the major factor involved in the influence of ACEI on the early renal response to removal of dietary sodium. Moreover, it was observed that the use of enalapril was associated with a more marked deterioration of glomerular filtration rate compared with use of losartan, despite a similar fall in arterial pressure and identical negation of sodium balance.8 Such an observation raised the possibility that nonangiotensin mechanisms could be involved in the intrarenal effect of ACEI in sodium-depleted rats. In addition to marked stimulation of the renin-angiotensin system, dietary sodium restriction is associated with activation of the renal kallikrein-kinin system, as demonstrated by an increase in urinary kallikrein9 and kinin excretion.10 With use of Hoe 140, a new long-acting specific bradykinin B2-receptor antagonist devoid of bradykinin agonistic effect,11 12 the present study was designed to investigate the participation of endogenous kinins in the impairment of renal and systemic adaptive processes in response to dietary sodium restriction induced by the ACEI ramipril. In addition, the influence of Hoe 140 was evaluated in rats treated with losartan, a compound devoid of interaction with bradykinin metabolism and action.13
Experiments were conducted in 72 male Sprague-Dawley rats (IFFA CREDO, l’Arbresle, France) weighing 225 to 250 g at the beginning of the study. The rats were randomly divided into six treatment groups. Rats were housed in individual cages and fed an NS diet for 6 days followed by a 6-day period of LS diet. The NS diet consisted of sodium-free rat chow (<5 mmol of sodium per kilogram of chow) and distilled water containing 75 mmol of sodium per liter as drinking fluid. In rats given the LS diet, sodium was removed from the drinking fluid.
After a 3-day control period, losartan (DuP753, MK954, DuPont Merck Pharmaceutical Co; n=16), ramipril (Hoechst AG; n=16), and the combination of each compound with Hoe 140 (d-Arg, [Hyp3, Thi5, d-Tic7, Oic8]-bradykinin, Hoechst AG; n=8 in each group) was administered for 3 days before and during the 6-day period of dietary sodium restriction. Ramipril and losartan were given once daily (between 7:30 and 8:30 am) by gavage at doses of 5 and 30 mg/kg, respectively, and Hoe 140 was infused subcutaneously via osmotic pump (Alzet Corp) at a dose of 150 μg/kg per day. In an additional group of 8 rats treated with ramipril, Hoe 140 was administered at a higher dose of 300 μg/kg per day. Such doses were shown to provide chronic blockade of the vasodepressor effect of exogenous bradykinin in rats.14 15 A group of 16 rats that received a subcutaneous infusion of the vehicle of Hoe 140 (5% dextrose solution) via osmotic pump served as a control group.
Body weight, food and water intake, and urinary excretion of fluid, sodium, potassium, and creatinine were measured daily. Systolic arterial pressure was recorded in conscious rats (tail-cuff method; Narco Biosystems) before treatment and before and at the end of the LS period.
Renal Hemodynamics in Conscious Rats
At the end of the study, control animals and rats treated with ramipril, losartan, and the combination of each antagonist with the low dose of Hoe 140 (n=8 for each group) were prepared for assessment of renal hemodynamics in the conscious state. Briefly, rats were anesthetized with ether, and catheters were inserted into the left ventricle via the right carotid artery and into the lower aorta via the left femoral artery. Both catheters were tunneled subcutaneously and exteriorized at the back of the neck. While the rats were anesthetized (ie, 2 to 3 hours after the last gavage), the peak response of arterial pressure to intravenous boluses of angiotensin I, angiotensin II, and bradykinin (300, 150, and 900 ng/kg, respectively; Sigma) was evaluated. After a 3-hour recovery period, catheters were connected to a pressure transducer (Statham P23ID), and arterial pressure and heart rate were continuously recorded for 10 minutes in freely moving animals. Renal blood flow was determined by the microsphere technique as previously reported.16 Simultaneously, 1 mL of blood was sampled for radioactivity counting and determination of PRC, ACE activity, and plasma concentration of sodium, potassium, and creatinine. Animals were then killed by intraventricular injection of pentobarbital sodium, and kidneys were removed for radioactivity counting.
Study of Renal Function in Anesthetized Rats
The day before the clearance measurements were made, catheters were implanted into the right jugular vein and left femoral artery and exteriorized at the back of the neck while the rats were under ether anesthesia. On the day of the experiment, blood samples for plasma creatinine determination and peak arterial response to agonists were taken in conscious rats 2 hours after the last gavage. Animals were then anesthetized (pentobarbital sodium, 60 mg/kg IP), and the urinary bladder was catheterized via a mid-suprapubic incision. After a 1-hour equilibration period, renal function was estimated by the clearance of 99mTc-diethylenetriaminepentaacetic acid (DTPA) (glomerular filtration rate) and [131I]-orthoiodohippurate (effective renal plasma flow) by use of the continuous infusion technique with timed urine collections17 in control rats and rats treated with losartan, ramipril, and the combination of ramipril and Hoe 140 administered at a dose of 300 μg/kg per day (n=8 for each group). After completion of studies, blood was obtained by puncture of the renal artery and renal vein for the measurement of renal extraction of both tracers. Animals were then killed by intraarterial injection of pentobarbital sodium, and kidneys were removed, dried, and weighed. True renal plasma flow was calculated as effective renal plasma flow/extraction of orthoiodohippurate. The clearance of DTPA was validated through comparison with inulin clearance, and a ratio of DTPA to inulin clearance of 1.03 was found in our laboratory.17
All animal procedures were performed in accordance with French law and the ethical committee guidelines for animal research.
Analytical Methods and Statistical Analysis
Concentration of sodium and potassium was measured by flame photometry, and creatinine concentration was estimated by a colorimetric method. PRC was determined by radioimmunoassay of generated angiotensin I after incubation at pH 6.5 in the presence of an excess of exogenous rat renin substrate.18 ACE activity was assessed by its proteolytic activity on the synthetic substrate FAPGG [N-(3-[2-furyl]acryloyl)-Phe-Gly-Gly; Sigma]. The values of four clearance measurements were averaged to provide a single value for each rat. Extraction of tracers was calculated as (A–V)/A, where A and V represent plasma concentration of tracers in renal artery and vein, respectively.
Results are expressed as mean±SEM and were analyzed by one-factor ANOVA or ANOVA for repeated measures when appropriate. Differences between groups were assessed by the Fisher PLSD test for multiple comparisons, and within-group differences were determined with use of Student’s t test for paired values. A value of P<.05 was considered significant.
Efficacy of Pharmacological Blockade of Renin-Angiotensin System and Bradykinin Receptors
As summarized in Table 1⇓, complete blockade of the conversion of angiotensin I to angiotensin II, angiotensin II, and bradykinin receptors was achieved by ramipril, losartan, and both doses of Hoe 140, respectively. When expressed as percent change from basal value, the peak depressor effect of bradykinin was slightly but not significantly enhanced in ramipril-treated rats but not in losartan-treated rats compared with control animals. PRC was markedly increased compared with the vehicle group in all groups treated with ramipril or losartan, and no influence of Hoe 140 on this parameter was detected.
Influence of Hoe 140 on Systemic and Renal Effects of Ramipril and Losartan
Effect on Systolic Arterial Pressure in Conscious Animals
After a 3-day period of treatment by losartan or ramipril in rats maintained on the NS diet, SAP decreased from 129±2 to 107±2 mm Hg (P<.001) in losartan-treated rats and from 125±3 to 118±2 mm Hg (P<.005) in animals treated with ramipril. Concomitant administration of Hoe 140 did not affect the hypotensive responses to losartan (from 127±3 to 105±4 mm Hg) and ramipril (127±4 to 114±3 mm Hg and 125±1 to 118±3 mm Hg for the low and high doses of Hoe 140, respectively).
In response to dietary sodium restriction, SAP did not change in untreated rats (from 125±2 to 130±3 mm Hg), whereas it decreased in all treated groups. However, the fall in SAP associated with sodium depletion was not statistically different in rats treated with losartan (−21±3 mm Hg) or ramipril (−30±3 mm Hg) alone or combined with the low dose of Hoe 140 (the change in SAP from pre–LS diet was −23±7 and −26±5 mm Hg in the losartan plus Hoe 140 and ramipril plus Hoe 140 groups, respectively). In rats treated simultaneously with ramipril and the high dose of Hoe 140, the fall in SAP was −28±6 mm Hg, a value similar to that observed in rats treated with the low dose of Hoe 140. As shown in Fig 1⇓, final SAP in conscious rats was similar in all drug-treated groups.
Effect on Urinary Excretion of Electrolytes
During the 3-day period of treatment on ad libitum sodium intake, cumulative water and sodium balance were similar in ramipril- and losartan-treated rats compared with vehicle-treated animals. These parameters were not affected by concomitant administration of the low dose of Hoe 140 in ramipril- and losartan-treated rats or the high dose of Hoe 140 in ramipril-treated rats. In addition, body weight gain was similar in control rats and rats treated with ramipril or losartan alone (19±2 g versus 18±2 and 19±3 g, respectively) or combined with the low dose of Hoe 140 (20±2 and 19±2 g, respectively), as well as in animals receiving the combination of ramipril with the high dose of Hoe 140 (15±2 g).
In untreated rats, removal of dietary sodium was associated with a rapid decrease in urinary sodium to approximately 20 μmol over a 24-hour period, and the cumulative value of urinary sodium excretion within the 6-day period of observation was 429±65 μmol. As shown in Fig 2⇓, the renal adaptive process was markedly (P<.001) and similarly impaired by ramipril and losartan (cumulative sodium excretion of 1139±134 μmol and 1212±131 μmol over the 6-day period, respectively). Concomitant administration of Hoe 140 neither prevented the excessive sodium loss induced by ramipril (1139±134 μmol over the 6-day period in the ramipril group versus 1180±110 μmol and 1033±47 μmol over the 6-day period in rats concomitantly treated with the low or high dose of Hoe 140, respectively) nor influenced the impaired renal adaptation to sodium restriction induced by losartan (1212±131 μmol and 1011±73 μmol over the 6-day period in rats treated with losartan alone or with losartan combined with the low dose of Hoe 140, respectively).
Body weight gain during the 6-day period of sodium depletion was significantly attenuated in ramipril- and losartan-treated rats (6±2 g and 1±6 g, respectively) compared with control animals (23±2 g). No influence of concomitant administration of the low dose of Hoe 140 with ramipril and losartan or the high dose of Hoe 140 in ramipril-treated rats was detected. At the end of the sodium restriction period, plasma concentrations of sodium and potassium were not significantly affected by blockade of the renin-angiotensin system alone or in association with the bradykinin antagonist.
Effect on Renal Hemodynamics in Conscious Rats
As summarized in Table 2⇓, at the end of the 6-day period of dietary sodium restriction, mean arterial pressure was lower in rats given ramipril and losartan alone compared with untreated rats. Concomitant administration of Hoe 140 (150 μg/kg per day) did not modify the systemic effect of ramipril and losartan. In addition, a similar extent of renal vasodilation was observed in ramipril- and losartan-treated groups irrespective of the presence of the bradykinin antagonist.
Serum creatinine was higher in ramipril and losartan groups (101±6 μmol/L and 74±4 μmol/L, respectively) compared with vehicle-treated rats (40±2 μmol/L); however, serum creatinine was also higher (P<.05) in ramipril-treated rats than in losartan-treated animals. Concomitant administration of both doses of Hoe 140 consistently prevented the increase in serum creatinine induced by ramipril (final serum creatinine level of 64±5 and 66±5 μmol/L, respectively; P<.05 compared with the ramipril group), whereas the low dose of Hoe 140 had no influence on losartan-treated rats.
Effect on Renal Function in Anesthetized Rats
As shown in Fig 3⇓, at the end of the 6-day period of dietary sodium restriction, glomerular filtration rate as well as filtration fraction were reduced to a larger extent by ramipril compared with losartan-treated animals. The concomitant administration of the high dose of Hoe 140 partially blunted (by ≈40%) both the reduction in glomerular filtration rate and the decrease in filtration fraction observed in animals treated with ramipril. No difference in renal plasma flow was found between groups, whereas renal vascular resistance was reduced to a similar extent by ramipril and losartan. Concomitant administration of ramipril and Hoe 140 (300 μg/kg per day) did not affect the renal vasodilation associated with ramipril. Of note, renal extraction of orthoiodohippurate was 73±5% in the vehicle-treated group, and no significant influence of ramipril, losartan, or ramipril combined with Hoe 140 was detected.
In the present study, it was demonstrated that chronic blockade of bradykinin B2-receptor by Hoe 140 at doses of 150 and 300 μg/kg per day had no significant influence on the fall of arterial pressure, renal vasodilatation, or impairment in the adaptation of urinary sodium excretion to dietary sodium restriction induced by treatment with the ACEI ramipril and the type 1 angiotensin II receptor antagonist losartan. Despite the lack of effect on systemic pressure and cumulative negative sodium balance, Hoe 140 consistently blunted the deleterious effect of ramipril on serum creatinine and glomerular filtration rate in sodium-depleted rats. These observations suggest that accumulation of kinins may play an important role in the impairment of intraglomerular forces contributing to glomerular filtration rate resulting from sodium depletion in the presence of ACEI but not angiotensin II blockade.
In a recent study,8 it was observed that losartan (only when given at a dose of 30 mg/kg per day) and enalapril induced a similar impairment in the early adaptation of urinary excretion of sodium to dietary sodium removal. In addition, concomitant administration of losartan and enalapril had no additional consequences on arterial pressure and sodium balance. Such observations did not favor nonangiotensin-mediated mechanism(s) in the renal hemodynamic and tubular effects of chronic enalapril treatment in this model. The present study, which used the B2-receptor antagonist Hoe 140 at doses that completely inhibited the vasodepressor effect of exogenous bradykinin, strongly supports the assumption that kinins are not an important contributor to the effect of ACEI on the sodium conservation process in operation during the initial phase of dietary sodium restriction. In rats maintained on ad libitum sodium intake, Fenoy et al19 reported that additional renal vasodilation and increase in papillary blood flow and natriuresis were observed when captopril was administered soon after losartan; the effects of captopril were entirely prevented by a kinin B2-receptor antagonist structurally different from Hoe 140. In contrast, Hoe 140 did not affect the acute renal vasodilatory effect of captopril or the more lipophilic ACEI ramiprilat in sodium-replete rabbits.20 In addition, it was observed that chronic treatment by Hoe 140, a compound devoid of partial agonistic effect,11 did not yield unequivocal evidence for a role of endogenous kinins in the regulation of arterial pressure, renal hemodynamics, and sodium excretion in basal conditions.21 Of interest, chronic Hoe 140 administration at a dose of 500 μg/kg per day slightly blunted the chronic antihypertensive effect of ramipril in rats with two-kidney, one clip hypertension but not in spontaneously hypertensive rats, thus suggesting that kinins may contribute to the antihypertensive effect of ACEI only in a high-renin model, although the opposite might have been expected.7
The most prominent finding of the present study was the blunting by concomitant Hoe 140 administration of the deleterious effect of ramipril on glomerular filtration rate in sodium-depleted rats. In a previous study,8 we observed that the increase in serum creatinine and decrease in creatinine clearance were enhanced in enalapril-treated rats compared with losartan-treated rats at the end of the 6-day period of dietary sodium restriction. Moreover, combined administration of enalapril and losartan aggravated the effect of losartan alone, despite similar final arterial pressure and negative sodium balance. These observations suggested that, in the sodium-depleted condition, ACEI may exert an effect on intrarenal forces that contributes to regulation of the glomerular filtration rate, independent of blockade of the renin-angiotensin system. The effect of ACEIs on renal function during the initial course of dietary sodium restriction was not assessed by other groups. However, it was shown22 that a 6-day period of ACEI begun when a new sodium balance had been achieved resulted in a deterioration of inulin clearance. The same group also observed that glomerular filtration rate increased when ACEI was given in sodium-replete rats.22 In contrast, acute administration of an ACEI in sodium-replete and sodium-depleted dogs resulted in an increase in glomerular filtration rate in the presence or absence of renal artery constriction.23 In normotensive humans, it was shown24 that ACEI altered the renal adaptation of urinary sodium excretion to a change in sodium intake from 200 to 10 mmol per day; unfortunately, although serum creatinine was not affected, glomerular filtration rate was not measured. In a recent study, Doig et al25 observed that acute administration of losartan resulted in a significant fall in creatinine clearance in normal volunteers submitted to drastic sodium depletion (LS diet associated with furosemide) in whom arterial pressure markedly decreased (≈25 mm Hg). It is possible that blockade of the renin-angiotensin system is critical for the regulation of glomerular filtration rate only when a consistent fall in systemic pressure is achieved.
The present study demonstrates that endogenous kinins, via stimulation of B2-receptor, are the likely mediator of part of the deleterious effect of ACEI on renal function, independent of any influence on systemic pressure, renal hemodynamics, and sodium balance in the sodium-depleted state. In micropuncture studies conducted in water-deprived rats, enalapril resulted in a fall in single-nephron glomerular filtration rate, whereas angiotensin II blockade induced a slight increase in this parameter despite a similar renal vasodilatory effect of both drugs. It was also shown that the fall in efferent glomerular tone and glomerular capillary pressure was more marked after ACEI than after angiotensin II blockade. Interestingly, Hoe 140 entirely reversed the effect of enalapril on postglomerular tone, intraglomerular pressure, and ultimately single-nephron glomerular filtration rate.26 A primary effect of Hoe 140 on efferent glomerular tone is most likely, since in the present investigation, filtration fraction was higher in rats concomitantly treated with ramipril and Hoe 140 than in animals treated with ramipril alone; in fact, filtration fraction was similar in rats treated with losartan and the combination of ramipril and Hoe 140, thus suggesting that B2-receptor blockade tends to minimize the postglomerular dilatory effect of ramipril. In dogs, it was demonstrated27 that a nonhypotensive dose of bradykinin was associated with renal vasodilatation but no change in glomerular filtration rate, thus resulting in a decrease in filtration fraction. Moreover, acute infusion of a bradykinin antagonist in sodium-depleted dogs did not affect glomerular filtration rate but did decrease renal plasma flow, thus resulting in a rise in filtration fraction.28 These findings favor a predominantly dilatory effect of kinins on the efferent glomerular arteriole. Of interest, it was demonstrated that bradykinin induced relaxation of efferent glomerular arterioles precontracted by norepinephrine but had no effect on preglomerular microvessels isolated from the rabbit kidney.29 Nevertheless, an influence of Hoe 140 on the glomerular ultrafiltration coefficient cannot be excluded.30
Although kinin accumulation is probably involved in the deleterious effect of ACEI on glomerular filtration rate during severe water or sodium deprivation, kinins may have beneficial effects on cardiovascular and renal function and phenotype in other conditions. Despite a lack of effect on arterial pressure, chronic administration of kallikrein was reported to attenuate the rise in serum creatinine and proteinuria as well as in histological renal lesions in Dahl salt-sensitive rats.31 It was reported recently that long-term administration of Hoe 140 started during prenatal and early postnatal life resulted in a higher level of arterial pressure in rats.32 In addition, potentiation by Hoe 140 of the chronic effect of low doses of angiotensin II on arterial pressure was demonstrated.33
The present findings that Hoe 140 did not modify the effect of losartan and that renal function was similar in losartan-treated rats compared with rats treated with ramipril and Hoe 140 suggest that kinin accumulation resulting from the use of ACEI contributes approximately half of the deleterious renal effect of ACEI in sodium depletion. Whether this is valid in clinical conditions, such as renal artery stenosis, associated with a prominent role of the intrarenal renin-angiotensin system in maintenance of the glomerular filtration rate remains to be demonstrated.
Selected Abbreviations and Acronyms
|ACE||=||angiotensin converting enzyme|
|PRC||=||plasma renin concentration|
|SAP||=||systolic arterial pressure|
We would like to thank Dr Jacqueline Winicki (Hoechst, Paris, France) for providing us with the ACEI ramipril and the bradykinin antagonist Hoe 140. Abderraouf Hérizi is a recipient of a fellowship from the Société Française d’Hypertension.
- Received June 2, 1995.
- Revision received August 16, 1995.
- Accepted September 26, 1995.
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