ACE inhibition and the kidney: species variation in the mechanisms responsible for the renal haemodynamic response

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1 Editorial review Keywords: ACE inhibition, species variation Departments of Radiology and Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA Correspondence to: Professor Norman K Hollenberg Brigham and Women's Hospital, 75 Francis Street, Boston, MA 2115, USA. Tel: Fax: Accepted for publication 31st March 2 JRAAS 2;1: ACE inhibition and the kidney: species variation in the mechanisms responsible for the renal haemodynamic response M Cecilia Lansang, Norman K Hollenberg Introduction During the past two decades, when effective antihypertensive therapy has clearly reduced the incidence of stroke, and possibly coronary artery disease, the incidence of end-stage renal disease in patients who are predisposed because of hypertension and diabetes has continued to increase. 1 Viewed in this context, the remarkable efficacy of angiotensin-converting enzyme (ACE) inhibition in retarding the progression of nephropathy in patients with diabetes mellitus 2,3 and other forms of nephropathy 4,5 has been especially important. Less clear is the mechanism, or mechanisms, by which ACE inhibition reduces the progression of renal injury. This issue has taken on new importance with the development of an alternative approach to blocking the renin-angiotensin-aldosterone system (RAAS) at the AT 1 -receptor level. There are two schools of thought,reflecting the two main actions of ACE inhibitors. One argues that the influence of ACE inhibition on angiotensin II (Ang II) formation plays a minor role in changing natural history and that the important element involves inhibition of kininase II, and thereby activation of a host of vasodilator pathways involving bradykinin (BK), prostaglandin (PG), and nitric oxide (NO). 6 The alternative school of thought argues that the crucial action of the ACE inhibitor involves a reduction in Ang II formation: as there is significant intrarenal non-ace-dependent Ang II generation in humans, the AT 1 -receptor antagonists offer an additional potential as they will block the RAAS more effectively. 7 In a recent review, the possibility was raised that there were important species differences in the pathway by which ACE inhibition influences the kidney. 8 In this essay, we undertake to review the literature systematically, to ascertain whether examination of the evidence in detail will support this contention. Criteria An exhaustive literature search was performed, and from this we gathered the numerous range of measures that the various authors have used to assess the mechanisms by which ACE inhibitors act. These approaches are summarised in Table 1. One can measure the concentration of the relevant hormones in arterial or renal venous plasma. As one example, a range of studies have been made that involve measurement of BK, prostaglandins, and the byproducts of nitric oxide synthesis. As a second approach, one can assess the influence of these hormones through measurement of the biological response following the administration of a range of specific blockers. Thus, if an Ang II antagonist and an ACE inhibitor at the top of their dose-response curves induce an identical renal haemodynamic response, it seems unlikely that an additional action of the ACE inhibitor is involved. In what is probably a more rigorous experiment, one can add one of these agents to the maximum dose of the other to see if an additional response can be recruited. If an ACE inhibitor is given after Ang II antagonist pre-treatment at the top of its dose-response, further response would indicate an action beyond Ang II blockade,whereas a lack of additional vasodilation would suggest that ACE inhibitors act primarily through Ang II. As yet another approach, one can block the alternative vasodilator pathways in ACE inhibitor-treated models with antagonists to BK, prostaglandin synthesis, or nitric oxide synthesis, to ascertain whether a physiological response to one or more of these hormones had been triggered. For example, if the renal blood flow (RBF) induced by an ACE inhibitor is blunted by a kinin receptor antagonist, it is likely that kinins play a role in ACE inhibitor-induced vasodilation. On the other hand, an ACE inhibitor can be given following blockade of prostaglandins and kinins, to see if a further response can be elicited. If a kinin receptor antagonist or kallikrein inhibitor is followed by ACE inhibition and further response is obtained, then some other mechanism, most likely Ang II, is implicated. If no further response is seen, then kinins are solely responsible for the renal vasodilation. By the same reasoning, an ACE inhibitor given after pre-treatment with a non-steroidal anti-inflammatory drug (NSAID) would elicit a further rise in RBF if mechanisms other than prostaglandins are involved, and no further response if prostaglandins alone caused the vasodilation. Since the latter provides more direct evidence of the action of ACE inhibitors than measurement of hormone levels, we have given this approach major emphasis in our analysis. Species As our knowledge of the detailed action of ACE inhibitors derives largely from animal studies, it is important to explore species differences. If no evidence of species variation is found, it is very 119

2 Table 1 Criteria for the mechanism of ACE inhibition. I Measured renal blood flow A. Ang II antagonist compared with ACE inhibitor 1. Same effect B. Ang II antagonist followed by ACE inhibitor 1. No further response C. Kallikrein inhibitor followed by ACE inhibitor 1. No further response D. Kinin antagonist followed by ACE inhibitor 1. No further response E. NSAID followed by ACE inhibitor 1. No further response F. ACE inhibitor followed by kinin antagonist 1. No blunting of response 2 Blunting of response Figure 1 Mean renal blood flow (RBF) in five groups of sodium-restricted dogs pre- and 1-minutes postenalaprilat (.2 mg/kg IV). Group one was given enalaprilat alone and also served as a time control; group two was given saralasin, 1 µg/kg/min IV continuously, and then enalaprilat; group three was given saralasin, 1 µg/kg/min i.a. continuously and then enalaprilat; group four was given B563, 27 µg/min i.a. continuously, and then enalaprilat; group five was given saralasin, 1 µg/kg/min IV, and B563, 27 µg/min i.a. and then enalaprilat. The difference between the control value and value after enalaprilat for each experiment was calculated and subjected to one-way analysis of variance with repeated measures. After analysis of variance, the mean changes were compared between the five groups of experiments by Duncan's new multiple range test. p<.1, group one vs groups two, three, four, and five; p<.5, group five vs groups two and four. II. Measured hormones after ACE inhibition A. Bradykinin/kinin B. PG C. Nitric oxide D. Angiotensin 5 4 Pre-enalaprilat Post-enalaprilat n=6 likely that the mechanisms responsible in animal models also apply to humans. If, on the other hand, evidence of species variation is found, then we must be much more cautious in transferring the studies from animal models to humans. We have thus endeavoured to tease out the various experiments on the three species most commonly used for studying ACE inhibition, the dog, the rat, and the rabbit, and have attempted to compare them with the more limited human studies. As the analysis evolved, it became apparent to us that there were similarities between the first two species, the rat and dog, and thus they will be discussed together. The findings in the rabbit, on the other hand, appear to differ, and they will be reviewed separately. Evidence in dogs and rats In the dog and the rat, there are numerous data to support the contributions of both the RAAS and the kallikrein-kinin system (KKS) to the renal action of ACE inhibition.to illustrate, Zimmerman et al., studied the renal haemodynamic effects of enalaprilat in dogs. 9 When superimposed on administration of the Ang II antagonist, saralasin, enalaprilat still produced an increase in RBF, suggesting that the action of ACE inhibition could not be totally accounted for by Ang II. The BK antagonist B563 likewise partly attenuated the effect of enalaprilat on RBF. When given together, saralasin and B563 produced a much greater response. In this study, the RAAS and BK seemed to contribute equally in the RBF response. 9 (Figure 1). In the split hydronephrotic kidney model in rats, both the BK B2 receptor antagonist, HOE 14, and the Ang II antagonist valsartan blunted the renal vasodilation induced by quinapril, but the effect of HOE 14 was more marked than that of valsartan suggesting a greater influence of the kinins. 1 Numerous additional studies have supported a role for kinins in the renal action of ACE RBF (ml/min) Time contr 1 IV Sar 2 IA Sar 3 Group B563 Sar+B inhibitors. In dogs infused with EXP3174, an active metabolite of losartan, captopril induced an additional increase in RBF, which almost completely disappeared when the BK B2 antagonist HOE 14 was infused together with captopril. 11 Similarly, cilazaprilat increased RBF in dogs infused with the Ang II antagonist E4177; this increase was abolished by the subsequent infusion of the BK B2 receptor antagonist NAAB. 12 Further vasodilator response to ACE inhibition in the presence of Ang II blockade has been shown in dogs elsewhere. 13,14 In volume-expanded dogs treated with deoxycorticosterone acetate (DOCA) and a high-salt (HS) diet, the infusion of the BK B2 receptor antagonist CH 2 -D-Arg-[Hyp 3, Thi 5,8,D-Phe 7 ]BK inhibited the increase in effective renal plasma flow (ERPF) induced by either captopril or imidaprilat. 15 At the other extreme of volume in the acute water deprivation rat model given furosemide, the BK antagonist HOE 14 opposed the decrease in efferent arteriolar resistance caused by enalaprilat. 16 The kallikrein inhibitor aprotinin reduced the renal vasodilator effect of the ACE inhibitor YS-98 in dogs. 17 Taken as a whole, the contribution of kinins to the renal haemodynamic action of ACE inhibition in rats and dogs is unambiguous. A similar logic and results follow treatment with agents that block prostaglandin synthesis. In 12

3 Figure 2 Line graphs showing laser Doppler cortical (left panel) and papillary (right panel) blood flow signals in the control period and after administration of DuP 753 and captopril in rats given vehicle (n=6) or a kinin antagonist (2.5 µg/min, n = 4). Control cortical blood flow signal averaged and V in rats given vehicle or the kinin antagonist, respectively. Control papillary blood flow averaged V in vehicle-treated rats. Baseline papillary blood flow fell from to V after the kinin antagonist. Significant difference from control; significant difference from corresponding value in vehicle-infused group. Kinin antagonist Vehicle Cortical blood flow (% of control) Papillary blood flow (% of control) Control DuP 753 DuP captopril 8 Control DuP 753 DuP captopril dogs pre-treated with indomethacin, the renal vasodilator effect of the ACE inhibitor YS-98 was prevented, implying a possible PG-mediated effect. 17 In agreement, in dogs pre-treated with indomethacin, the increase in RBF caused by the ACE inhibitor SA-446 was suppressed. 18 However, other studies do not support a crucial role of PG. In salt-replete dogs given captopril during saralasin infusion, captopril did not increase RBF, but in those dogs that were treated with the prostaglandin synthesis inhibitor indomethacin, captopril increased RBF by 18%. 19 In a parallel study by the same group, nonhypotensive haemorrhage was utilised in dogs to increase plasma renin activity (PRA). Captopril did not cause a further increase in RBF in those treated with saralasin, but again elicited an increase in RBF in the dogs treated with indomethacin. 2 In dogs on a low-salt (LS) diet pretreated with either of two prostaglandin synthesis inhibitors, indomethacin or meclofenamate, captopril caused a marked increase in RBF, indicating that the acute renal vasodilator effect of captopril does not depend on renal prostaglandins. 21 In the same manner, the RBF response to captopril was not attenuated in dogs on a standard diet pre-treated with indomethacin. 22 The possibility that a different contribution of separate intrarenal vascular pathways contributed to renal responses was suggested by Fenoy et al. 23 In rats pre-treated with the Ang II antagonist DUP 753, papillary blood flow increased by 7% after administration of captopril; this rise was blocked by the kinin receptor antagonist D-Arg, [Hyp 3, Thi 5,8,D-Phe 7 ]-BK. On the other hand,captopril did not produce a further increase in cortical blood flow after pre-treatment with the Ang II antagonist losartan. These observations suggest that kinins mediate the response to ACE inhibition in terms of papillary blood flow and Ang II does so for cortical blood flow (Figure 2). The influence of salt intake on renal responses in the rat and dog One of the possible contributors to variation in the renal response to ACE inhibition is the state of the RAAS at the time of the study. One simple hypothesis would be that the reduction in Ang II formation dominates the renal vascular response to ACE inhibition in settings in which the renin system is activated, as in the case of the LS diet. Conversely, the contribution of the renin system to renal vascular tone, and thus the renal vascular response to ACE inhibition, might be blunted by a HS diet,which would have as its consequence a larger influence of non-renin-dependent mechanisms. In rats on a LS diet pre-treated with saralasin, captopril did not further decrease renal vascular resistance (RVR). In rats on a HS diet first treated with the kallikrein inhibitor aprotinin, captopril likewise did not change RVR. 24 Thus, Ang II was the dominant mechanism in rats on a LS diet whereas kinins exerted their main influence during HS balance. In a study in rats on a LS diet, one group was given saralasin and another group captopril. There was no significant difference in the RBF response between the two groups, suggesting that their mechanism was the same, i.e. blockade of Ang II. 25 The same conclusion was reached when a group of dogs on a LS diet underwent a similar experiment. Those that received the Ang II antagonist saralasin had the same RBF as those that received the ACE inhibitor captopril. 26,27 A number of observations do not conform to this simple model. Prior inhibition of BK B2 receptors with icatibant did not prevent the increase in RBF elicited by enalaprilat in dogs on a HS diet, but this rise was prevented in dogs on a LS diet, indicating that the RAAS was operative in the former and the kinins in the latter. 28 Likewise, in dogs studied either on LS or normal salt (NS) diet, the BK B2 receptor antagonist HOE 14 caused a partial blunting of 121

4 Figure 3 Summary of number of articles supporting either a major angiotensin II (Ang II) dependent pathway or a kinin-prostaglandin(pg)-nitric oxide(no) mechanism. Dominant Ang ll-dependent mechanism Major kinin-pg-no effect Number of articles Dogs Rats Rabbits Humans the increase in RBF induced by ramipril only in the LS group, again suggesting a role for BK in RBF regulation primarily during sodium deprivation. 29 Zimmerman et al. reported that saralasin infusion abolished the renal haemodynamic effect of captopril or enalapril in sodium-replete dogs, but did not completely eliminate this effect in sodiumrestricted dogs. 3 Again, it is possible that kinins are operative in the LS state. Collectively, the evidence in rats and dogs point to a combination of Ang II blockade and kallikrein-kinin system (KKS) activation in the mechanism of ACE inhibition. Under some circumstances, the KKS, like the RAAS, is activated under conditions of LS balance. 31 Evidence in rabbits Unlike the dog and rat, the majority of the available literature in the rabbit points to the RAAS as the dominant system, and fails to support the KKS as a major mediator underlying the renal response to ACE inhibition (Figure 3). In one early study, rabbits on a LS diet were given infusions of either the ACE inhibitor captopril or the Ang II antagonist saralasin. RBF increased to a similar extent in response to each of these two agents, suggesting that they shared the same action, i.e. interruption of the RAAS. 32 In a later study, Hollenberg and Passan studied rabbits given DOCA and HS diet to suppress the renin system, a strategy designed to highlight non-renindependent mechanisms. 33 Saralasin completely prevented the captopril-induced vasodilator response, attributing the ACE inhibitor effect to a decrease in Ang II formation. (Figure 4) Three additional reports mitigate against a role for kinins in this species. The increase in RBF caused by either ramiprilat or captopril in rabbits on a standard diet was not influenced by the presence of the BK antagonist HOE 14. Furthermore, ramiprilat and captopril produced little further increase in RBF in the presence of losartan. 34 HOE 14 likewise did not prevent the renal vasodilation produced by perindoprilat in newborn rabbits. 35 In another study in rabbits, combined inhibition of ACE (using captopril) and the neutral Figure 4 Captopril induced an increase in renal blood flow (RBF) in rabbits despite suppression of the reninangiotensin-aldosterone system (RAAS) by a high-salt diet, supplemented by DOCA treatment. Note that saralasin, the angiotensin antagonist, prevented entirely the renal vascular response, suggesting that the captopril-induced increase in RBF reflected a reduction in angiotensin II (Ang II) formation. RBF (ml/g/min) Superimposed on saralasin Time endopeptidase EP24 11 (using SCH 3937), produced a small increase in RBF compared with vehicle treatment. Pre-treatment with the BK antagonist HOE 14 did not influence the renal effects of captopril and SCH3937,suggesting that their influences are chiefly mediated by pathways not involving BK. 36 There is only one discordant study. In rabbits on normal rabbit chow, captopril caused an increase in RBF in the presence of either the Ang II antagonist losartan or saralasin. During a constant infusion of the BK B2 receptor antagonist BkA, captopril likewise increased RBF. During the combined infusion of losartan and BkA, however, the renal vasodilator effect of captopril was eliminated. 37 Taken as a whole, the data suggest that suppression of Ang II formation plays a larger role than does a reduction in BK degradation in the renal vascular response to ACE inhibition in the rabbit, compared with the rabbit and dog. 122

5 Abbreviations ACE Ang II BK DOCA ERPF HS KKS LS NO NS NSAID PG RAAS RBF RVR PRA angiotensin converting enzyme angiotensin II bradykinin deoxycorticosterone acetate effective renal plasma flow high salt kallikrein-kinin system low salt nitric oxide normal salt non-steroidal inflammatory drug prostaglandin renin-angiotensin-aldosterone system renal blood flow renal vascular remittance plasma renin activity Evidence in humans Despite the fact that the use of ACE inhibitors in treating human disease is widespread, their mode of action is still unclear, as the information available in humans is limited. Since the infusion of blockers into human subjects to study renal haemodynamic effects involves considerable time and expense, the measurement of plasma levels of the appropriate substances has been used by several investigators. A study in normotensive males showed that captopril increased the levels of PGE 2 -M, a potent vasodilator metabolite of prostaglandin E2, either on a LS or HS diet. There was no change in the plasma levels of 6-keto-prostaglandin F 1a (the stable product of prostacyclin), nor of thromboxane B 2 (the stable product of thromboxane A 2 ). 38 The same group evaluated prostaglandin levels in subjects with essential hypertension on a LS diet given captopril. They found a significant increase in prostaglandin E 2 metabolites and F 2a metabolites, with a decrease in levels of 6-keto-F 1a and no change in thromboxane B A few studies have been designed to evaluate the renal haemodynamic mechanisms of ACE inhibition. Hollenberg et al. demonstrated that infusion of either captopril or saralasin increased RBF in healthy individuals on a LS diet. The similar response was ascribed to a shared action, i.e. interference of the RAAS. Moreover, captopril caused a decrease in plasma Ang II concentration without any effect on circulating BK levels. 4 In a comparative analysis of the renal haemodynamic response to pharmacological interruption of the RAAS with ACE inhibitors, Ang II antagonists and renin inhibitors, in a model involving restriction of salt intake to activate the renin system in healthy young volunteers, the renal haemodynamic responses to Ang II antagonists and to renin inhibitors were comparable, and exceeded substantially the response to ACE inhibition, as shown in Figure This pattern of response would suggest that, in this regard, the human resembles the rabbit, with the action of ACE inhibition on the kidney predominantly reflecting a reduction in Ang II formation. This observation found strong support in the recent study on normotensive and hypertensive subjects in LS balance where the administration of captopril alone, captopril plus the BK receptor antagonist icatibant (HOE 14), or losartan alone decreased RVR to a similar extent. Again BK did not seem to contribute significantly to the mechanism of ACE. 42 Overall, available data suggest that there are important species differences in the mechanism(s) responsible for the renal haemodynamic response to ACE inhibition. In the rat and dog, there appears to be a substantial contribution from BK-dependent mechanisms. In the rabbit and humans, on the other hand, any contribution from this pathway appears to be minor, and the dominant mechanism involves a reduction in Ang II formation (Figure 3). Chi square analysis of the number of articles favouring either a dominant Ang II-dependent mechanism or a major kinin-pg- NO effect supports the latter for the first group (dogs and rats combined) and the former for the second group (rabbits and humans combined) (X 2 = 7.38, p<.1). Given growing evidence that chymase contributes to intrarenal Ang II formation via pathways that are not sensitive to ACE inhibition, the therapeutic implications of the Ang II antagonist class in humans are obvious. Acknowledgments This work was supported in part by National Institutes of Health (grants T32 HL-769, NCRR GCRC M1RR26376, P1AC59916, 1P5ML 53-1, and 1 R1 DK ) and Astra Pharmaceuticals. We are grateful for the assistance of Ms Diana Capone in the preparation and submission of this manuscript. References 1 Porush JG. Hypertension and chronic renal failure: the use of ACE inhibitors. Am J Kidney Dis 1998;31: Laffel LM, McGill JB, Gans DJ. 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N Engl J Med1998;339: Erratum The following error appeared in the March 2 issue of the JRAAS, reference: Park JB, Intengan HD, Schiffrin EL. Reduction of resistance artery stiffness by treatment with the AT 1 -receptor antagonist losartan in essential hypertension. JRAAS 2; 1: The date of acceptance of the final manuscript for publication should have been 8th February 2 and not 6th December