Natriuretic Response to Neutral Endopeptidase Inhibition Is Blunted by Enalapril in Healthy Men
Abstract We studied six healthy male subjects in a randomized, placebo-controlled, single-blind fashion to determine the comparative effects on renal hemodynamics and natriuresis of the angiotensin-converting enzyme inhibitor enalapril (5 mg on each of 5 days preceding the study), the neutral endopeptidase inhibitor candoxatrilat (200 mg IV), and the combination of enalapril and candoxatrilat. Enalapril pretreatment alone, compared with placebo, produced slight nonsignificant increments in absolute and fractional sodium excretions and a marked increase in effective renal plasma flow but no change in glomerular filtration rate. Candoxatrilat alone produced marked augmentation of both absolute and fractional sodium excretions. The candoxatrilat-mediated increment in absolute sodium excretion was significantly correlated with increases in urinary cGMP and plasma atrial natriuretic peptide in response to this drug, but neither effective renal plasma flow nor glomerular filtration rate was altered compared with placebo. Combining enalapril pretreatment with candoxatrilat significantly attenuated the increments in absolute and fractional sodium excretions in response to the neutral endopeptidase inhibitor. Blood pressure was reduced by enalapril alone compared with placebo, whereas candoxatrilat treatment alone led to a marginal but significant enhancement of blood pressure. The combination of enalapril and candoxatrilat abolished any significant blood pressure change compared with placebo. Thus, candoxatrilat-mediated natriuresis occurs via a renal tubular rather than glomerular mechanism and is blunted by enalapril. This attenuation by enalapril may occur by interference with angiotensin II–dependent effects on the renal tubule or on systemic blood pressure.
Synthetic α-human atrial natriuretic peptide (α-hANP or hANP [99-126]) has been shown to have favorable effects on systemic and renal hemodynamics and on natriuresis when infused intravenously into chronic heart failure (CHF) patients.1 However, the therapeutic use of hANP in CHF is limited by the need for intravenous administration of the peptide because of its poor oral absorption and short half-life in vivo. This has prompted the development of pharmacological inhibitors of neutral metalloendopeptidase EC 18.104.22.168,2 3 which is an enzyme located in brain, lung, and especially in the kidney and is the principal enzymatic means of degrading endogenous ANP. Neutral endopeptidase (NEP) inhibitors, which increase circulating levels of endogenous ANP, have favorable hemodynamic and natriuretic effects in CHF similar to those observed in response to exogenous ANP infusion.4 5 If NEP inhibitors come into clinical use in CHF, they may be coprescribed in some instances with angiotensin-converting enzyme (ACE) inhibitors, which are now of proven efficacy in all functional grades of CHF.6
In view of the diverse physiological interactions between ANP and the renin-angiotensin-aldosterone system (RAAS), particularly in the kidney,7 8 one might anticipate interaction between NEP inhibitors and ACE inhibitors in terms of their renal effects. Indeed, ACE inhibitors have been shown to alter significantly the renal hemodynamic and natriuretic effects of infused ANP.9 10 11 12 More recently, ACE inhibitors have been shown to enhance the cardiovascular and renal effects of NEP inhibition in experimental models of hypertension13 14 and heart failure.15 16 17
We undertook the present study to examine in healthy men the natriuretic potential of the NEP inhibitor candoxatrilat, of ACE inhibition, and of the combination of ACE inhibition and candoxatrilat. We wished to determine whether ACE inhibition and candoxatrilat are additive, synergistic, or antagonistic with respect to natriuresis and glomerular dynamics and to identify whether any changes in natriuresis observed are due to alteration in glomerular filtration rate (GFR), in tubular sodium reabsorption, or even in systemic blood pressure (BP). We also wished to examine the safety of combined NEP inhibition and ACE inhibition in healthy men, particularly with regard to effects on BP.
Six normotensive healthy young male volunteers (21 to 26 years) were studied after they had given written informed consent to a protocol approved by the Ethics Committee of Ninewells Hospital and Medical School, Dundee, where the study was performed. One week before the first study day, volunteers submitted a 24-hour urine sample for verification of urinary sodium excretion (UNaV) in the range of 120 to 180 mmol/24 h. Subjects adhered to a similar meal plan for the 4 days before each treatment period and abstained from alcohol for 24 hours before each study day and from caffeine and nicotine for 12 hours before study and until the completion of each study period. While participating in the study, subjects were free from any drug treatment other than study medication.
Volunteers were studied over four 6-hour periods, each at least 10 days apart, between 8 am and 2 pm. Enalapril was administered openly before 2 of the 4 study days. On these two occasions, 5 mg of the ACE inhibitor was taken at 10 pm on each of the four evenings before study and a further 5 mg at 8 am on the study morning. On each study morning, subjects attended the clinical laboratory at 8 am, having eaten a light breakfast at 6:30 am. Subjects were requested to void to completion, and body weight was recorded. Thereafter for the next 6 hours subjects remained semirecumbent in bed apart from standing briefly at 20-minute intervals to pass urine.
At 8:30 am, bolus intravenous injections of 10 mg/kg p-aminohippurate sodium (PAH, MSD) and 50 mg/kg inulin (Inutest, Laevosan-Gessellschaft) were followed by infusions of 15 mg/min PAH and 25 mg/min inulin (in 0.9% saline) for the next 310 minutes administered through an intravenous cannula in the right forearm. We used a standard overhydration protocol, so subjects were asked to drink 20 mL/kg water between 8:30 and 8:55 am. From 9 am onwards, subjects emptied their bladder every 20 minutes and consumed the same volume of water as the voided urine plus 1 mL/min for insensible losses. By 10 am, urine flow and plasma inulin and PAH concentrations had reached steady state. Thereafter, two pretreatment 20-minute urine collections were made for determination of baseline inulin and PAH clearances, UNaV, urinary potassium excretion (UKV), and osmolality.
At 10:40 am, either 200 mg candoxatrilat or placebo was administered in a randomized, double-blind fashion over 5 minutes through an intravenous cannula in the left forearm. Over the ensuing 180 minutes, aliquots were taken from each 20-minute urine collection for determination of urinary inulin, PAH, sodium and potassium concentrations, and osmolality. In addition, from 9:40 am until 1:40 pm, urine collections were pooled hourly and aliquots taken from each pooled 60-minute sample for assay of urinary cGMP. Venous blood samples for assay of plasma PAH and inulin were taken through the left forearm cannula at the midpoint of each 20-minute urine collection period before dose and at the midpoint of each alternate collection after dose. Every 40 minutes from 9:50 am until 1:30 pm, venous blood was sampled for assay of serum sodium and potassium concentrations and for measurement of hematocrit. Supine venous samples were taken before candoxatrilat (or placebo) dosing (10:30 am) and at 60-minute intervals thereafter until 1:30 pm for determination of plasma ANP, renin, and aldosterone levels. BP and heart rate were recorded every 20 minutes throughout the study from 9:40 am until 1:40 pm with a semiautomatic sphygmomanometer (Dinamap Vital Signs Monitor 1846, Critikon), the cuff being placed around the subject’s left upper arm. Measurements were made with subjects both in the semirecumbent position and after standing for 2 minutes, before each urine voiding. The four study sessions used the following treatment permutations in random order: 5 mg enalapril PO×5 plus placebo IV, 5 mg enalapril PO×5 plus 200 mg candoxatrilat IV, no pretreatment plus placebo IV (control limb), and no pretreatment plus 200 mg candoxatrilat IV.
Venous blood samples for aldosterone, PAH, and inulin concentrations were collected into chilled lithium-heparin tubes; samples for renin were collected into chilled potassium-EDTA tubes; and samples for ANP were collected into chilled potassium-EDTA tubes each containing 200 μL (4000 kallikrein inhibitory units) aprotinin (Trasylol, Bayer UK Ltd). Venous samples for sodium and potassium concentrations and osmolality were collected into chilled plain glass tubes. Samples were centrifuged immediately at 2000g for 15 minutes at 4°C and separated. Plasma and serum samples were stored at −20°C until analysis together with urine aliquots (10 mL) for estimation of PAH, inulin, sodium, potassium, and cGMP concentrations and osmolality.
Serum and urinary electrolytes were measured with a model 943 flame photometer (Instrumentation Laboratories). Plasma and urinary PAH were determined with a centrifugal analyzer (Cobas Bio, Hoffmann–La Roche) with p-dimethylaminobenzaldehyde (Sigma Chemical Co) as the color reagent; plasma and urinary inulin were determined with an SP6-500 UV spectrophotometer (Pye Unicam) with resorcinol (Sigma) as the color reagent. Urinary cGMP was measured by radioimmunoassay as described by Richman et al.18 ANP samples were extracted through an Amprep C8 column (Amersham International plc) and analyzed with a radioimmunoassay kit (Amersham). Aldosterone was also measured by radioimmunoassay with a commercially available kit (Diagnostic Products Ltd). Plasma renin activity (PRA) was measured by radioimmunoassay with a commercially available kit (CIS UK) of angiotensin I (Ang I) generated by a 90-minute incubation at 37°C. Intra-assay coefficients of variation were as follows: plasma PAH, 2.1%; urinary PAH, 1.7%; plasma inulin, 2.1%; urinary inulin, 1.2%; ANP, 7.8%; aldosterone, 6.6%; and PRA, 9.8%.
Mean arterial pressure (MAP) was calculated as diastolic BP+(systolic BP−diastolic BP)/3. Clearance (C) was calculated for different substances as UV/P, where U is urinary concentration, V is urine flow rate, and P is plasma concentration. Inulin clearance (CINU) was used as a measure of GFR and PAH clearance (CPAH) as a measure of effective renal plasma flow (ERPF). Clearance of sodium (CNa) was also determined as UV/P. With the use of these indexes, the following parameters (expressed as percentages) were then calculated as follows:
Statistical comparisons between results obtained by the four treatment schedules were undertaken using repeated-measures ANOVA followed by post hoc t tests with appropriate correction for the use of multiple tests. In addition, relationships between specific pairs of parameters were assessed by determining product moment correlation coefficients using linear regression analysis. Statistical evaluations were performed with statgraphics software, version 4.0. In all analyses, a value of P≤.05 was considered significant.
Enalapril Pretreatment Plus Placebo Infusion
Compared with the limb of the study incorporating no pretreatment/placebo injection (control limb), a significant increase in urine flow rate (UV) was observed in response to enalapril/placebo injection (enalapril limb) associated with marginal increases in absolute UNaV and FENa, which failed to achieve statistical significance at the 5% level (both P=.08). Associated with these changes were a significant rise in ERPF and falls in RVR and FF but no change in GFR. Urinary cGMP showed a slight nonsignificant decrement in response to enalapril. Semirecumbent and standing levels of systolic and diastolic BP were significantly lower in response to enalapril than to control, and semirecumbent and standing heart rates were marginally though not significantly higher than in response to control. UKV was not significantly altered by enalapril. Compared with the control limb, neither hematocrit nor circulating levels of aldosterone or ANP were altered, but the characteristic significant rise in PRA in response to ACE inhibition was observed.
No Pretreatment Plus Candoxatrilat Injection
The marked increases in UV, UNaV, and FENa observed in response to no pretreatment plus candoxatrilat injection (candoxatrilat limb) far exceeded the increases observed in these parameters in response to enalapril. The rise in each of these parameters was incremental, reaching a peak at 140 minutes after candoxatrilat, before gradually declining thereafter. However, no significant changes versus control were observed in ERPF, GFR, RVR, or FF. Urinary cGMP excretion rose markedly compared with the control limb. Semirecumbent and standing levels of systolic and diastolic BP as well as standing heart rate were significantly higher in this limb than in the control limb. UKV was not significantly altered compared with control. Hematocrit and circulating levels of renin and aldosterone were unaltered, but plasma ANP was slightly and significantly increased compared with control.
Enalapril Pretreatment Plus Candoxatrilat Injection
Enalapril pretreatment plus candoxatrilat injection yielded increments in UV, UNaV, and FENa that, although exceeding the increments observed in these parameters in the enalapril/placebo injection limb, were significantly less than those achieved in response to candoxatrilat in the absence of enalapril pretreatment. The rise in urinary cGMP in response to enalapril/candoxatrilat was marginally though not significantly lower than the increment observed in response to candoxatrilat without enalapril pretreatment. In contrast to the other limbs of study, the enalapril/candoxatrilat combination produced an apparent divergence in the time-response profiles of different urinary parameters. Thus, UNaV and FENa had evidently reached a plateau and were beginning to decline by 240 minutes, whereas UV and urinary cGMP appeared to be still increasing at this point. Thus, the peak responses to candoxatrilat of UV and urinary cGMP (but not UNaV or FENa) appear to be slightly delayed in the presence of enalapril. Compared with control, a significant rise in ERPF and significant falls in RVR and FF were observed, but the changes were less than those observed in the enalapril/placebo injection limb. As in the other limbs of study, GFR was unchanged. BP indexes were similar to those observed in the control limb, but both semirecumbent and standing heart rates were significantly higher than in response to control. In contrast to their effect on UNaV, UKV was significantly augmented by the combination of candoxatrilat and enalapril. As in the other limbs of study, hematocrit and plasma aldosterone were unchanged, whereas the slight but significant elevation of plasma ANP was less than in the candoxatrilat without enalapril limb. The elevation of PRA in response to ACE inhibition was similar to that observed in the enalapril/placebo injection limb.
The statistical significance of different treatment effects versus control have been described in the text and are displayed in Tables 1⇓ and 2⇓ and Figs 1⇓ and 2⇓. Table 3⇓ also summarizes, in terms of the more important parameters studied, the statistical significance of differences obtained between individual limbs of study other than control.
Correlations Between Urinary cGMP, Plasma ANP, and UNaV
When data from all four treatment schedules were pooled, urinary cGMP excretion was found to be highly significantly related to both plasma ANP (P<.00001) and UNaV (P<.00001), although the correlation coefficients were only moderate (r=.44 and .43, respectively). Plasma ANP was significantly correlated with UNaV (P=.02) but with a rather weak correlation (r=.21).
The NEP inhibitor candoxatrilat in our subjects produced a marked short-term enhancement of natriuresis. This candoxatrilat-mediated natriuresis occurred in the absence of any observed increment in either ERPF or GFR but was associated with a marked increase in FENa, indicating a renal tubular mechanism as the source of the effect. In keeping with and similar to these findings, Margulies et al2 in anesthetized dogs and Cavero et al19 in the canine heart failure model have shown that the natriuretic response to an NEP inhibitor (SQ 28,603) occurs in the absence of renal hemodynamic changes but in association with a marked increase in FENa.
We observed that the increment in plasma ANP in response to NEP inhibition was relatively slight compared with the magnitude of the natriuretic response, and other investigators2 3 have made a similar observation. We also noted a poor, albeit statistically significant, correlation between plasma ANP and UNaV. In view of these findings and because the enzyme NEP 24.11 is involved in cleavage of a wide range of peptide substrates apart from ANP, including bradykinin and substance P,20 the possibility must be considered that enhancement of levels of one or more of these other substrates is at least in part responsible for the candoxatrilat-induced natriuresis. However, animal data demonstrate that the natriuretic response to candoxatrilat is virtually abolished by pretreatment with ANP antisera,21 providing strong evidence that the response is ANP dependent. It may be, as indicated by micropuncture studies,8 that the intrarenal peritubular level of ANP governs renal tubular responses to the hormone and that the intrarenal concentration of ANP is augmented to a relatively greater degree by candoxatrilat than the circulating level. In keeping with this proposal, Cavero et al19 demonstrated that administration of exogenous ANP to mimic plasma levels achieved with NEP inhibition failed to enhance sodium and water excretions.
Our observation that enalapril pretreatment significantly attenuated candoxatrilat-induced natriuresis is in keeping with observations of a number of previous studies which have demonstrated that the short-term natriuretic response in healthy humans to infused hANP (99-126) is similarly blunted by ACE inhibition.9 10 11 12 In attempting to explain these and our own findings, we will consider a number of possible mechanisms of interaction of ANP with the RAAS.
Radioligand binding studies indicate that colocalization of receptors for Ang II and ANP occurs in brain, adrenal, blood vessels, and kidney, specifically in the glomerulus, vasa recta, and proximal tubule.22 This is consistent with the demonstrable functional interactions between ANP and Ang II at these diverse sites.
In contrast to its peripheral actions, Ang II acts within the brain to promote natriuresis and diuresis, and these centrally mediated effects are opposed by ANP.23 Thus, it would be difficult to explain the observed effects on natriuresis of the enalapril-candoxatrilat combination on the basis of a central interaction between Ang II and ANP. Similarly, the adrenal response to an increase in plasma ANP or to ACE inhibition would be, in either instance, to inhibit aldosterone secretion,7 which would favor an additive effect of the two drugs in promoting natriuresis rather than the observed attenuation. In fact, compared with control, we observed no significant effects of any treatment on circulating levels of aldosterone.
Compared with the control treatment limb or the enalapril/candoxatrilat limb, which yielded comparable BP levels, a slightly but significantly higher level of systemic BP was observed in response to candoxatrilat alone. This candoxatrilat-mediated increase in BP (and its suppression with enalapril pretreatment) might be explained by potentiation of endogenous Ang II, which is another NEP substrate. Indeed, Richards et al24 found that candoxatrilat reduced the clearance of infused Ang II and enhanced its pressor effect in healthy humans. The small BP increment we observed is unlikely alone to have accounted for the difference in natriuresis between candoxatrilat/placebo and enalapril/candoxatrilat treatments, in that previous studies have observed a pronounced natriuresis after NEP inhibition, apparently in the absence of any effect on systemic BP.2 3 4 5 19 However, the sensitivity of the natriuretic effects of ANP to changes in BP are well known.25 Therefore, it is possible that the rise in BP could have potentiated the natriuretic effects of candoxatrilat. Interestingly, the slope of the pressure-natriuretic response in dogs has recently been shown to be steepened by increasing the intrarenal concentration of ANP,26 a response that might be mediated by RAAS suppression in that it is abolished by pretreatment with an ACE inhibitor and by subsequently maintaining circulating Ang II at a constant level. This provides a possible explanation for the attenuation by enalapril of the natriuretic response to candoxatrilat. However, such a proposal must remain speculative at present, not least because it has been difficult to demonstrate pressure natriuresis in humans.
Significant glomerular interactions have been demonstrated between Ang II and ANP at the level of the afferent arteriole and within the mesangium.8 However, such interactions appeared not to be of major importance in our study because GFR was not measurably altered by either enalapril or candoxatril nor by the combination of the two compared with placebo. Also compared with placebo, an increment in ERPF and fall in FF were observed in response to enalapril alone and to a lesser extent in combination with candoxatrilat. These enalapril-mediated alterations in ERPF and FF, through their influences on renal delivery of sodium and peritubular Starling forces, respectively, would assist rather than oppose renal sodium excretion27 and therefore do not explain the attenuation by enalapril of candoxatrilat-induced natriuresis. Similarly, enalapril, like ANP, will tend to redistribute intrarenal blood flow in favor of increased medullary blood flow through the vasa recta,8 which would again assist rather than oppose natriuresis.
Another possible mechanism for attenuation by enalapril of candoxatrilat-induced natriuresis is through an interaction between ANP and Ang II at the level of the proximal renal tubule. Thus, Cavero et al19 have previously observed, in response to NEP inhibition, a significant increase in fractional excretion of lithium, which is a marker of reduced sodium reabsorption at the proximal tubule.
Further evidence for a proximal site of interaction is provided by animal and in vitro work. There is marked colocalization of receptors for ANP and Ang II within the proximal tubule.22 28 Ang II, in promoting sodium reabsorption, has now been shown to act primarily at the proximal tubule by stimulating a luminal sodium/hydrogen antiport mechanism.27 In rat, dog, and humans, ANP decreases fractional reabsorption of lithium, indicating that the proximal tubule is a major site of action for ANP.8 Increasing evidence from micropuncture studies, primarily in the rat, indicates that peritubular ANP has no direct action on proximal sodium and water fluxes but acts indirectly by inhibiting Ang II–stimulated proximal reabsorption.8 Enalapril, by partially inhibiting intrarenal Ang II formation, may prevent full expression of the natriuretic response to ANP and thus to candoxatrilat. The resulting attenuation of candoxatrilat-mediated natriuresis may not be offset fully by the comparatively smaller direct natriuretic effects of enalapril that result from antagonism of the RAAS.
Another completely different mechanism of interaction to consider at the proximal tubule is that candoxatrilat and enalapril may compete for the proximal tubular anion secretory system. Such an interaction might decrease the amount of candoxatrilat in the tubular fluid, which in turn could reduce candoxatrilat-mediated inhibition of tubular NEP.
In considering the proximal tubule as a possible important site of this interaction, it is worth noting that controversy exists as to whether proximal tubule cells possess28 or lack8 particulate guanylate cyclase, the enzyme that mediates an increase in cGMP levels in some cells in response to ANP. Thus, the increment in urinary cGMP we observed in response to candoxatrilat may or may not be linked primarily to the natriuretic response and could instead be a marker of ANP activity in other parts of the nephron, for example, the glomerulus.8 The observation that urinary cGMP excretion was highly significantly correlated (P<.000001) with UNaV does not necessarily argue against the suggestion that their association may be indirect rather than direct. The r value of .43 gives an r2 value of .18, which means that only 18% of the variability in UNaV is explained by its linear association with urinary cGMP.
We observed a significant short-term increment in UKV in response to the combination of candoxatrilat and enalapril and lesser though not statistically significant increments in response to either drug alone. This facilitatory response pattern contrasts with the effect on natriuresis of combining the two drugs and suggests that the kaliuresis may be mediated by a different mechanism to the natriuretic response, perhaps at the distal tubules. One may speculate that the kaliuresis could have resulted from increased distal tubular delivery of sodium, but this area was not addressed directly in the present study and will require further evaluation.
Further study is also required to determine whether the primary finding of this study, the attenuation by enalapril of candoxatrilat-mediated natriuresis in healthy men, is a phenomenon also observed in the setting of CHF. This may not be the case, as evidence indicates that in experimental heart failure in animals, ACE inhibition may enhance rather than attenuate the natriuretic response to infused ANP29 and similarly may enhance both the renal15 16 and cardiovascular16 17 effects of NEP inhibition.
We express our thanks to Frances Zaccarini for typing this manuscript and to Sister Jess Robson, Lesley MacFarlane, Wendy Coutie, and Gordon Clark for technical assistance.
- Received February 28, 1994.
- Revision received April 26, 1994.
- Accepted December 15, 1994.
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