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(Hypertension. 1995;26:602-609.)
© 1995 American Heart Association, Inc.

Renal Circulation and Blockade of the Renin-Angiotensin System

Is Angiotensin-Converting Enzyme Inhibition the Last Word?

Norman K. Hollenberg; Naomi D. L. Fisher

From Brigham and Women's Hospital and Harvard Medical School, Departments of Radiology and Medicine, Boston, Mass.

	Abstract

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
Abstract The mechanism by which angiotensin-converting enzyme (ACE) inhibition influences renal perfusion and function has assumed growing importance as alternatives for blocking the system have emerged. Neither renin inhibitors nor angiotensin II (Ang II) antagonists are likely to trigger responses similar to ACE inhibitor–induced involvement of kinins, prostaglandins, or nitric oxide. Several observations suggest species variation in the contribution of these pathways to the renal response to ACE inhibition. In humans, recent investigation suggests that virtually all of the renal response is due to a fall in Ang II formation. Perhaps most persuasive is the surprising observation that the renal hemodynamic response to renin inhibitors exceeds by more than 50% the response to ACE inhibition in healthy humans. To the extent that kinins or prostaglandins contribute to the renal response to ACE inhibition, one would anticipate a smaller response to renin inhibition. Possible explanations include an unanticipated additional action of renin inhibitors, better tissue penetration of these highly lipophilic agents, or more effective blockade of Ang II formation through an action at the rate-limiting step or non–ACE-dependent Ang II generation. Substantial evidence favors the latter two possibilities. Whatever the explanation, these observations raise the intriguing possibility that the undoubted therapeutic efficacy of ACE inhibition in renal injury, documented most rigorously for type I diabetes mellitus, might be exceeded with the newer classes of agent.

Key Words: prostaglandins • renin • angiotensin II • kinins

	Introduction

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
An enormous contribution to our understanding of the role of the renin-angiotensin system in normal cardiovascular, renal, and endocrine physiology and in the pathogenesis of disease has come from pharmacological interruption of the system. Haber¹ provided a persuasive explanation: ablation of the source of a hormone, followed by its replacement, has been the crucial endocrine experiment. For the renin system, the angiotensin-converting enzyme (ACE) inhibitors provided a reasonable alternative to ablation over the past two decades.¹ In the case of renal perfusion and function, the primary focus of this article, ACE inhibitors were quickly shown to have a large vasodilator effect when the renin system was activated by diet or surgical trauma and other maneuvers in animal models^{2 3 4 5 6 7 8 9 10} and somewhat later in humans.^{11 12}

The use of a drug as a scientific tool raises a number of important issues; among them and perhaps most important is specificity. It must be the rare drug that has only one action. In addition to blocking formation of angiotensin II (Ang II), ACE inhibitors influence kinin degradation. The resultant potential for bradykinin accumulation and thereby vasodilator prostaglandin formation was recognized from the beginning.¹³ More recently the possibility that ACE inhibitors can also act as vasodilator agents via activation of endothelial vasodilator pathways involving nitric oxide or nitrosothiol compounds has been advanced. Endothelium-dependent vascular smooth muscle relaxation has been documented in response to ACE inhibition,^{14 15} and nitric oxide blunts the renal vascular response to Ang II.¹⁶ In early research efforts one approach to dealing with pharmacological specificity involved the parallel application of another class of blocker, the Ang II antagonist saralasin, for assessment of the renal response, ideally in the same model. This approach made it clear in animals^{4 8 9 10} and humans¹¹ that at least part of the renal vasodilator response to ACE inhibition reflected the reduction in Ang II formation. The limitation of this approach was imposed by the angiotensin-like actions of saralasin, which is a partial agonist.^{4 11} Thus, it could provide useful information on the direction but not the magnitude of the renal response.

Pharmaceutical science in the past decade has provided more than one new solution to this problem with the development of renin inhibitors and novel Ang II antagonists that are free of the partial agonist problem.^{17 18} We chose renin inhibition as the initial pathway for exploring the control of renal perfusion for several reasons. First, the remarkable substrate specificity of the renin reaction made mechanistic specificity of the renin inhibitor more likely, although by no means certain. Second, the fact that both ACE and renin inhibition would lead to a fall in plasma Ang II concentration facilitated comparison of the degree of blockade achieved. Finally, the identification of multiple Ang II receptor subtypes¹⁸ added another layer of complexity to the interpretation of studies that use Ang II antagonists to interrupt the system.

	The Magnitude of the Renal Vascular Response to ACE and Renin Inhibition

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
The hypothesis that we were testing was straightforward when we first assessed the renal hemodynamic response to a renin inhibitor.¹⁹ To the extent that ACE inhibitors reduced kinin degradation and induced vasodilator prostaglandin formation or activation of endothelial nitric oxide release, the renal vasodilator response to ACE inhibition should exceed the response to renin inhibition. Indeed, we thought that the difference in magnitude of the renal vascular response would provide a measure of the magnitude of the contribution of other vasodilators compared with reduced Ang II formation. To our surprise, the renal vasodilator response to a renin inhibitor, enalkiren, exceeded expectations from our experience with ACE inhibitors.¹⁹ In a follow-up, three-arm study comparing placebo, the same renin inhibitor enalkiren, and captopril, the placebo did nothing and captopril and enalkiren both led to renal vasodilation.²⁰ The response to enalkiren was larger than the response to captopril in six of nine healthy subjects.²⁰ The magnitude of the response to the renin inhibitor in this study confirmed our earlier observation, as did a more recent study with zankiren,²¹ another renin inhibitor that induced a larger renal vasodilator response than could have been anticipated from the ACE inhibitor experience.

The renal vascular response to renin inhibition at the top of the dose-response curve in these three studies is summarized in Fig 1 in a meta-analysis format. All studies were performed in healthy men younger than 40 years who were in balance on a 10 mEq sodium intake to activate the renin system. All were studied by the same group of physicians, nurses, dietitians, and technicians; on the same metabolic ward; and with the same techniques, including measurement of para-aminohippurate clearance as the index of renal perfusion. Also shown in Fig 1 are responses to three ACE inhibitors at the top of their dose-response curves. Although only the captopril treatment was part of one of the renin inhibitor studies,²⁰ the same conditions applied: the identical diet, entry criteria, evaluation, metabolic ward, techniques, and personnel and in some cases the same subjects under study.

View larger version (17K): [in this window] [in a new window]   Figure 1. Graphs show meta-analysis of change in renal plasma flow (RPF) with angiotensin-converting enzyme (ACE) and renin inhibition. All studies were performed in healthy subjects in balance on a highly restricted (10 mmol/d) sodium intake at the top of the dose-response curve for each agent. There were no within-class differences but a significantly larger response to renin inhibition (P<.001).

Meta-analysis was developed as a statistical technique to deal with data sets that result from underpowered studies.²² The goal is to salvage valuable information by pooling the results of studies that are too small individually to reveal what might be an important difference. The risk of drawing a false conclusion reflects the fact that in multiple small studies differences other than the one of interest can contribute to outcome. Despite this limitation, meta-analysis has found increasing utility. Our use of the meta-analysis format in this case is unusually favorable. All of the conditions, with the exception of the agents used, were identical. The data presented for each agent reflect the top of the dose-response curve for that agent. By ANOVA, there were no statistical differences among the three ACE inhibitors or between the two renin inhibitors, but the difference between ACE and renin inhibition was highly significant (P<.001). The renal vasodilator response to renin inhibition in humans (in the range of 140 mL/min per 1.73 m²) exceeded by more than 50% the response to ACE inhibition (averaging about 90 mL/min per 1.73 m²) when theory said it should be less. Therefore, it is time to examine and perhaps abandon the theory.

Although the models studied have varied widely, the available information gathered by other investigators on the renal response to the various renin inhibitors that have been developed suggests a robust renal response,^{23 24 25 26 27 28 29 30} compatible with our observations. An especially informative study was reported by El-Amrani et al,³⁰ who compared systematically the renal vascular response to an Ang II antagonist (DuP 753, losartan), an ACE inhibitor (lisinopril), and a renin inhibitor (RO 42-5892) in guinea pigs. Because renin structure varies with species, renin inhibitors display species specificity, and the guinea pig was selected for study because this renin inhibitor developed for primates is effective in the guinea pig. Doses of each agent were adjusted to induce an identical small but unambiguous fall in blood pressure and were administered coded and in a random sequence (Fig 2). This careful, elegant study design revealed remarkable differences in the renal response to these classes of agent. Despite an identical fall in blood pressure, the rises in renal plasma flow, glomerular filtration rate, diuresis, and natriuresis were substantially greater with the renin inhibitor.³⁰ Renin inhibition indeed exerts a renal vasodilator response that exceeds the effect of ACE inhibition.

View larger version (20K): [in this window] [in a new window]   Figure 2. Bar graphs show comparison of renal vasodilator and natriuretic responses to a renin inhibitor, angiotensin-converting enzyme (ACE) inhibitor, and angiotensin II antagonist (Ang II A) in the guinea pig. To match the varying agents for effectiveness, doses were adjusted to produce an identical depressor response. The potentiated response to renin inhibition compared with ACE inhibition and the Ang II antagonist was attributed to the capacity of the renin inhibitor to diffuse into the renal interstitium where part of the renin-dependent Ang II production occurs. RBF indicates renal blood flow; GFR, glomerular filtration rate; and MABP, mean arterial blood pressure. (From El-Amrani et al.30 )

	The Specificity of Renin Inhibitors

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
Although renin is a fastidious enzyme with great substrate specificity, one possibility is that the renin inhibitors act by an action unrelated to renin. Several observations make this unlikely. Especially persuasive is the observation that Ang II administration into the renal artery in dogs after renin inhibition completely reversed the diuresis and natriuresis induced by the renin inhibitor.²⁵ In accord in humans is the blunting of the renal vascular response to renin inhibition by a high salt intake¹⁹ and in low-renin hypertension.²⁰ The remarkable concordance in the primary renal vasodilator response to ACE and renin inhibition,²⁰ the concordance in the enhancement by ACE and renin inhibition of the response to Ang II,²⁰ and the fact that two different renin inhibitors induced a similar renal response all favor an action of renin inhibition via suppression of Ang formation.

The correlation between the responses to enalkiren and to captopril (Fig 3, r=.88) in our studies was remarkable, given the noise in clearance methods. Such concordance is exceedingly unlikely if the vasodilator response to renin inhibition involved as a major element a nonspecific vasodilator response.

View larger version (18K): [in this window] [in a new window]   Figure 3. Graph shows correlation between the increase in renal plasma flow (RPF) induced by the angiotensin-converting enzyme inhibitor captopril and the renin inhibitor enalkiren in healthy young subjects when in balance on a low salt diet. Variation attributable to the subject and not accounted for by plasma renin activity or angiotensin II concentration accounted for 80%. As angiotensin II formation in the vascular compartment did not vary among the subjects to account for the difference, the variation is far more likely to reflect intrarenal events. The fact that an angiotensin-converting enzyme and renin inhibitor induced essentially identical responses suggests that the response reflects reversal of angiotensin II formation. (From Fisher et al20 with permission.)

We and others have used the renal vascular response to Ang II to explore the mechanism of ACE inhibitor–induced renal vasodilator responses. Our premise was that vasodilation that reflected accumulation of kinins, prostaglandins, or nitric oxide would blunt the renal vascular response to Ang II, whereas vasodilation that occurred because of a reduction in Ang II formation would be associated with a neutral or even enhanced renal vascular response because of increased receptor availability or upregulation. The evidence favoring that construct was reviewed earlier.²⁰ Not only were the primary renal vasodilator responses to captopril and enalkiren in accord, both agents enhanced the renal vascular response to Ang II; that enhancement was also in remarkable accord from subject to subject.²⁰

In the aggregate these observations suggest that the renal vasodilator response to renin inhibition reflects primarily reduced Ang II formation.

	Alternative Mechanisms

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
If the renin inhibition–induced fall in Ang II formation is the responsible mechanism, as suggested by multiple observations, is there an explanation for the larger renal response? Several possibilities exist. El-Amrani et al³⁰ attributed the larger renal vascular response to renin inhibition in the guinea pig to "diffusion of the molecules into the renal interstitium, because much of the interaction between renin and substrate occurs at this level."⁴ Multiple lines of evidence are now accruing to indicate that a crucial contribution to pharmacological interruption of the renin system for the kidney actually occurs in the kidney. Recent studies with graded doses of ACE inhibitor in the rat indicate that there is substantial residual renal tissue Ang II despite the use of very large doses of the ACE inhibitors,³¹ doses that lie well above the top of the ACE inhibitor dose-response curve for blood pressure and plasma Ang II concentration. The renal tissue renin system is more difficult to block. Not only is the fall in plasma Ang II concentration larger than the fall in renal tissue Ang II, it occurs with lower ACE inhibitor doses.³¹ One possible explanation involves non–ACE-dependent Ang II formation. Also possibly relevant is the role of ACE inhibitor lipophilicity, which influenced the renal response at lower ACE inhibitor doses.³¹

Why should lipophilicity matter? To the extent that tissue penetration is determined by lipophilicity, renal tissue penetration and local action could be influenced by this feature. The attempt to improve the bioavailability of renin inhibitors by the oral route led to highly lipophilic agents,^{32 33 34} which might have enhanced their ability to penetrate tissue and thus block local Ang II formation.

There has been a series of impressive, but mixed, observations suggesting a contribution of kinins or prostaglandins to the renal vascular response to ACE inhibition in animal models.^{35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52} The possibility is emerging of quantitatively important species differences in the determinants of the renal vascular response to ACE inhibition. Evidence reviewed above suggests that in the guinea pig, renal responses to ACE inhibition probably reflect primarily the fall in local Ang II concentration.³⁰ ACE inhibition increased prostaglandin production in canine⁴⁵ but not rabbit³⁶ kidney. In similar protocols a partial agonist Ang II antagonist blunted the renal blood flow response to ACE inhibition in the dog and rat^{39 41} but not in the rabbit.⁴⁴ The development of bradykinin antagonists added strongly supportive evidence, as they blunted the renal blood flow response to ACE inhibition in dogs and rats^{45 49} but not in the rabbit.^{51 52} In the rat it is primarily medullary perfusion that is kinin dependent.⁵³ Thus, apparent species differences may reflect the relative contribution of medullary perfusion to total renal blood flow; in this case humans resemble rabbits far more than they do the rat or dog.^{54 55} Whatever the explanation, it is clear that one cannot extrapolate from studies on mechanisms by which the kidney responds to ACE inhibitors in animal models to the control of renal circulation in humans, even in health and much less when disease is superimposed.

This analysis, focused on the kidney, by no means denies the contribution of alternative pathways to the blood pressure response of various modes of pharmacological interruption of the renin system. Veniant et al⁵⁶ recently compared the depressor response to renin and ACE inhibition and to an Ang II antagonist in guinea pigs in a study analogous to that described for the kidney above.³⁰ The outcome for blood pressure differed strikingly from the responses of the kidney. After treatment with a renin inhibitor, an ACE inhibitor induced a further reduction in blood pressure. Conversely, after treatment with the ACE inhibitor, the renin inhibitor exerted no further action. In this light, it is of substantial interest that the recent detailed review by Linz et al⁵⁷ of the contribution of kinins to the cardiovascular actions of ACE inhibitors omits mention of the kidney.

	The Intrarenal Renin-Angiotensin System

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
The remarkable capacity of converting enzyme in the lung to form Ang II led to the concept that both the formation and function of Ang II are primarily systemic rather than intrarenal.⁵⁸ On the other hand, the view that angiotensin functions as a local renal hormone was defensible more than 30 years ago.^{59 60} By the early 1970s several independent lines of evidence supported a potential for a critical intrarenal focus for Ang II formation in the kidney. Although the total amount of converting enzyme in the kidney is considerably smaller than that of the lung, the available intrarenal activity is sharply localized to the juxtaglomerular apparatus, the area in which renin is released.^{61 62} Moreover, DiSalvo et al⁶³ showed that converting enzyme inhibitor infused into the renal artery blocked the local action of Ang I but not of Ang II. Ang I, therefore, must require conversion to have a renal action, and that conversion must occur within the kidney. This observation, of course, documents the potential for production and not production itself. The second line of evidence involved the finding that lymph draining the kidney contained a considerably higher concentration of Ang II than is found in either arterial or renal venous blood: it must have been generated within the kidney.^{64 65 66} Because only immunoreactive Ang II was measured in those experiments, the possibility existed that lymph contained a large amount of angiotensin fragments, making an artifactual contribution to the quantity apparently measured by radioimmunoassay. In the aggregate, these observations were supportive but did not provide definitive evidence.

Evidence favoring the intrarenal production of Ang II as a local hormone has continued to emerge from an increasing number of lines of investigation over the past two decades. Synthetic capability for all components of the renin-angiotensin system has been identified within the kidney and confirmed by application of molecular biological techniques.^{67 68 69 70 71 72 73} In situ hybridization has further localized angiotensinogen, renin, and ACE mRNA within the kidney. The location of renin and ACE mRNA would favor a local vascular action. On the other hand, the major site of expression for angiotensinogen mRNA is the proximal tubule, where control of sodium reabsorption may be involved; but that would not explain actions in the vascular compartment.

Further evidence for the ability of juxtaglomerular cells to generate Ang II has come from studies combining immunohistochemistry, tissue culture of juxtaglomerular cells, and purification of renal renin-containing granules.⁷⁴ Clearly, the renin and Ang II colocalize, and their presence in tissue culture rules out uptake of circulating elements of the renin-angiotensin system. Specifically relevant to this article is the observation that ACE inhibitors increase Ang I concentration in juxtaglomerular cells.⁷⁵ Clearly, these agents can penetrate juxtaglomerular cells. Lipophilicity is likely to be a determinant of tissue penetration.

Another contribution has come from the measurement of authentic tissue and lymph angiotensin peptide concentrations via high-performance liquid chromatographic separation of the angiotensin peptides to avoid cross-reacting breakdown fragments.^{31 76 77 78 79 80 81} Micropuncture studies confirmed high tubular fluid concentrations of Ang I and Ang II, further supporting local production.⁸⁰ The application of this approach to the measurement of renal cortical tissue Ang II levels has made it clear that the tissue concentration is much higher than that in plasma and shows local control.^{31 76 77 78 79 80 81} The anatomic location probably follows renin distribution very near the juxtaglomerular apparatus and the afferent and efferent arterioles.⁸² The concentration of immunoreactive Ang II is also very much higher in tubular fluid and superficial star arterioles than in arterial plasma.⁸⁰ The application of high-performance liquid chromatographic separation to the measurement of Ang II in lymph has made it clear that authentic Ang II is involved.⁸²

	Intrarenal Ang II Formation in Humans

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
Species differences in the determinants of the renal vascular response to ACE inhibition, reviewed above, make it important to identify evidence for intrarenal Ang II formation in humans. Three lines of evidence support an important intrarenal angiotensin formation and local action in humans. The first suggestive observation was that teprotide, the first ACE inhibitor, evoked a significantly greater renal vascular response when infused directly into the renal artery than after intravenous administration in healthy subjects in balance on a low sodium diet.¹¹ Intra-arterial administration was possible because the subjects were kidney donors. This potentiated response to local infusion suggests a critical concentration of ACE within the human kidney. Moreover, the renal vascular response was evident in 3 minutes but continued to rise thereafter with time, suggesting that diffusion distances in the kidney delayed the peak effect.

In a second line of investigation, studies performed with labeled Ang I demonstrated unambiguous local production of Ang I and Ang II by the kidney based on regional peptide-specific activity and extraction ratios.^{83 84} This technique, which provides clear evidence for the local source of hormone production, neatly complements the earlier perfusion studies that documented the physiological significance of the hormone.

More recently we pursued an unanticipated observation made during studies with the renin inhibitor enalkiren in humans.⁸⁵ As anticipated, plasma enalkiren concentration fell rapidly after the infusion of enalkiren ended, with levels suggesting that the half-life of the agent is less than 90 minutes. Plasma Ang II concentration, at nadir levels by the end of the enalkiren administration, rose consistently during the 90 minutes after enalkiren administration was discontinued. In contrast, renal plasma flow did not begin to fall when enalkiren was discontinued but instead continued at a peak level or even continued to rise. This discordance in the effects on plasma Ang II concentration and renal plasma flow after discontinuation of enalkiren was highly significant (P<.0005). Sustained renal vascular activity of the renin inhibitor, in marked contrast to waning activity in the plasma compartment, suggests that enalkiren exerted its main influence outside of the plasma compartment. The weight of available evidence suggests that enalkiren-induced interruption of local intrarenal formation of Ang II is responsible not only for the sustained renal vasodilator response but also for the surprising fact that the renal response to the renin inhibitor exceeded the response to ACE inhibition. Certainly, measurement of the authentic plasma Ang II concentration did not reveal a difference in the fall induced by renin or ACE inhibitor administration that could account for the difference in the renal response.

As opposed to the two earlier methods for documenting a local intrarenal renin–Ang II system, which demanded either arterial or renal venous catheterization, a method that is based on pharmacodynamics and the time course of the response, and which does not demand invasive vascular catheterization, would be attractive for extension to studies in humans with disease.

	The Renal Renin-Angiotensin System in Diabetes Mellitus

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
There is the distinct possibility that activation of the intrarenal renin-angiotensin system contributes to renal dysfunction in a number of settings. As one example, diabetes mellitus has long been thought of as a process characterized by low plasma renin activity, reflecting some combination of neuropathy, local renal injury, and volume expansion,^{86 87 88} although the evidence is mixed.⁸⁰ The therapeutic efficacy of ACE inhibition in preventing nephropathy in insulin-dependent diabetes mellitus is unambiguous.⁸⁹ The fact that Ang II antagonists are as effective as ACE inhibitors in delaying the progression of renal injury in animal models of diabetes has confirmed preliminary evidence in humans.^{90 91 92 93 94 95 96 97 98} An explanation for this paradoxical series of observations, namely, ACE inhibitor effectiveness despite suppressed plasma renin activity levels, arose from studies in rats with streptozotocin-induced diabetes mellitus in which a sharp reduction in plasma renin activity was documented but associated with an increase in both the renal tissue concentrations of renin and the mRNA supporting renin production.⁹⁹ The determinants of local intrarenal angiotensin formation and renin release are clearly separated by the diabetes process.

To pursue that observation in humans, we examined the renal vascular response to ACE inhibition in patients with type I (L.M.B. Laffel and N.K. Hollenberg, unpublished data) and type II¹⁰⁰ diabetes mellitus whom we studied when in balance on a high salt diet to suppress the renin-angiotensin system. In both patient populations plasma renin activity and plasma Ang II concentrations were suppressed, appropriately, by the high salt diet. In both type I and type II diabetes, despite the high salt diet and the appropriate renin response, the renal vasodilator response to ACE inhibition was enhanced with either captopril or enalapril and substantially exceeded the normal. As an index of the contribution to the renal vasodilator response made by a fall in Ang II concentration versus a kinin-dependent vasodilator response, Ang II was infused before and after ACE inhibitor administration. A striking enhancement of the renal vascular response to Ang II evident within 90 minutes of ACE inhibitor administration occurred in both groups. The ACE inhibitor action responsible for reducing renal vascular tone reflected a fall in Ang II. Such an observation suggests autonomy in the control of the intrarenal renin system in diabetes and raises the intriguing possibility that an agent that is more effective at blocking the intrarenal formation of Ang II, or its action, might be more effective in preventing the progression of renal injury in patients at risk.

	Implications

Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
Other than the intrinsic interest of the observations for those of us who are fascinated by the control of renal perfusion and function, what difference does a 50% larger rise in renal perfusion with renin inhibition make? The answer has several elements. At one level, serious consideration has been given to a contribution to the pathogenesis of glomerular sclerosis¹⁰¹ of Ang II–mediated renal hemodynamic responses that lead to glomerular hypertension. At another level, Ang II exerts a series of actions beyond hemodynamics, ranging from an influence on sodium transport to stimulation of hypertrophy and hyperplasia.^{102 103} The short-term renal hemodynamic response during renin and ACE inhibition can be seen as a surrogate, an easily measured marker of the magnitude of the reduction in Ang II formation.

There are more intriguing implications of the possibility that renin inhibitors induce more complete blockade of the intrarenal renin-angiotensin system. Prevention or retardation of renal injury in type I diabetes mellitus⁸⁹ and in other conditions¹⁰⁴ appears to involve a local intrarenal action, an influence beyond blood pressure reduction. The 50% reduction in the frequency of type I diabetic nephropathy progression in response to captopril is substantial. Is the mechanism in the 50% that do progress unrelated to Ang II formation? An equally likely alternative is that agents capable of inducing more complete blockade will reduce further progression of renal injury. The species specificity of renin inhibitors has largely limited their use in primate animal models, and no reports are available. Their clinical development never reached this stage.

Alternative means for specific pharmacological interruption of the renin-angiotensin system occur at the Ang II receptor level, as reviewed above. Agents in this class have been shown to reduce renal injury in a range of animal models and to reduce proteinuria in humans.^{90 91 92 93 94 95 96 97 98} Although reports of the short-term renal vascular response to Ang II antagonists have not described renal vasodilation to match the experience with renin inhibition, the conditions were not comparable to those in our studies, as more liberal sodium intake was allowed.^{92 105 106} There is no information on whether the available agents differ in their ability to penetrate tissue or influence the kidney.

To the extent that the renal response to renin-angiotensin system activation may not only participate in the progression of renal injury but also contribute to the sodium retention of heart failure and hypertension, these considerations could have substantial clinical implications. Indeed, the considerations may extend beyond the kidney to the heart and arteries.^{107 108} If Ang II antagonists that share the ability of renin inhibitors to penetrate tissue and thus influence the kidney can be identified, one would anticipate the possibility of a preferential action on renal disease that merits investigation. If Ang II antagonists with these features cannot be found, consideration should be given to the development of a renin inhibitor with these indications in mind.

	Acknowledgments

 
Personal research described in this review was supported in part by the National Institutes of Health NCRR GCRC M01 RR02635 grant to the Brigham and Women's Hospital General Clinical Research Center. It is a pleasure to acknowledge the nursing support of Charlene Malarick, RN; the research support of Diane Passan, MT; and the administrative support of Diana Capone in the preparation and submission of this manuscript.

	Footnotes

 
Reprint requests to Norman K. Hollenberg, MD, PhD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Received January 16, 1995; first decision February 10, 1995; accepted June 19, 1995.

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Top Abstract Introduction The Magnitude of the... The Specificity of Renin... Alternative Mechanisms The Intrarenal Renin-Angiotensin... Intrarenal Ang II Formation... The Renal Renin-Angiotensin... Implications References

 
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