ACE inhibitors and AT1 receptor antagonists: Is two better than one?

Abstract

In clinical trials, pharmacological inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors slow the progression of renal disease to end-stage renal failure, thus attesting the central role of angiotensin II (Ang II) in the pathophysiology of chronic renal injury. The development of orally active Ang II subtype 1 (AT1) receptor antagonists has provided an alternative system of inhibiting the RAS, thereby creating a novel potential therapy for chronic renal diseases. AT1 receptor antagonists differ from ACE inhibitors in the effects on the RAS and on bradykinin metabolism. Elevations in bradykinin levels by ACE inhibitors and stimulation of angiotensin subtype 2 receptors resulting from AT1 receptor antagonists may produce therapeutic effects unique to each class of drug. Nevertheless, in animal models of chronic renal disease, ACE inhibitors and AT1 receptor antagonists exert equivalent renoprotection, implying that their renoprotective effects result primarily from inhibition of Ang II-mediated stimulation of angiotensin subtype 1 receptors. In Fawn-hooded hypertensive rats1.Ziai F. Ots M. Provoost A.P. et al.The angiotensin receptor antagonist, irbesartan, reduces renal injury in experimental chronic renal failure.Kidney Int. 1996; 50: S132-S136Google Scholar, a model of genetically determined hypertension and progressive renal injury, and in rats with passive Heymann nephritis2.Benigni A. Tomasoni S. Gagliardini E. et al.Blocking angiotensin II synthesis/activity preserves glomerular nephrin in rats with severe nephrosis.J Am Soc Nephrol. 2001; 12: 941-948Crossref PubMed Google Scholar, a model of human membranous glomerulopathy, treatment with an ACE inhibitor or with an AT1 receptor antagonist lowered blood pressure and glomerular capillary pressure to a similar degree and afforded equivalent renal protection. Clinical data comparing ACE inhibitor and AT1 receptor antagonist therapy in renal disease are limited to short-term studies, which indicate that AT1 receptor antagonists have equivalent effects to ACE inhibitors on the major determinants of renal disease progression, specifically blood pressure and proteinuria. In hypertensive patients with renal impairment, the AT1 receptor antagonist, candesartan, exerted a renal vasodilator effect similar to that observed during treatment with the ACE inhibitor, enalapril3.Mimran A. Ribstein J. Angiotensin receptor blockers: Pharmacology and clinical significance.J Am Soc Nephrol. 1999; 10: S273-S277PubMed Google Scholar. Some concerns have been raised about the completeness of the RAS blockade achieved by either ACE inhibitors or AT1 receptor antagonists. Because enzymes, as chymase, can substitute for ACE, the ACE inhibitor may not completely block Ang II formation, whereas increases in Ang II levels may compete with the AT1 receptor blocker at the receptor site. For this reason it has been suggested that an ACE inhibitor/AT1 receptor antagonist combination may offer a better therapeutic effect than treatment with either agent alone. In fact, in rats with renal ablation4.Taal M.W. Brenner B.M. Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists.Kidney Int. 2000; 57: 1803-1817Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar and in rats with passive Heymann nephritis (abstract; Zoja C et al, J Am Soc Nephrol 12:830A, 2001), the combination of ACE inhibitors and AT1 receptor antagonist induced a greater renal protection than either treatment alone. Data on the use of combination of ACE inhibitor and AT1 receptor antagonist therapy in humans are few. In 12 sodium-depleted normal subjects a greater reduction in blood pressure and greater increases in plasma renin activity were observed after the addition of the AT1 receptor antagonist losartan to enalapril treatment than after doubling the dose of enalapril, suggesting that the combination resulted in more effective inhibition of the RAS4.Taal M.W. Brenner B.M. Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists.Kidney Int. 2000; 57: 1803-1817Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar. In 11 patients with chronic renal disease of various etiologies, the addition of an AT1 receptor antagonist to ACE inhibitor therapy induced a further 30% reduction in proteinuria and no change in creatinine clearance after 2 weeks of combined treatment5.Zoccali C. Valvo E. Russo D. et al.Antiproteinuric effect of losartan in patients with chronic renal diseases.Nephrol Dial Transplant. 1997; 12: 234-235Crossref PubMed Scopus (38) Google Scholar. In this issue of Kidney International, Delles et al compared in a randomized, crossover study the effect of 1-week treatment with an ACE inhibitor, enalapril, an AT1 receptor antagonist, eprosartan, and their combination on renal hemodynamics in human essential hypertension6.Delles C. Jacobi J. John S. et al.Effects of enalapril and eprosartan alone or in combination on the renal vascular nitric oxide system in human essential hypertension.Kidney Int. 2002; 61: 1462-1468Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar. Neither drug alone had a clear-cut effect on renal plasma flow over the observation period, whereas an increase in RPF was found with combination therapy. Renal vascular resistance was reduced by each treatment alone, however, the most prominent effect was observed with the combination therapy. Glomerular filtration rate (GFR) was not affected by any treatment. Of note, the effects of enalapril, eprosartan, and combination therapy on renal hemodynamics were independent of blood pressure changes, as documented by the lack of significant correlations between blood pressure changes and changes in renal plasma flow. These findings are consistent with previous work by other investigators who found additive effects of ACE inhibitor and AT1 receptor antagonist combination therapy on cardiac output and ejection fraction in patients with heart failure and on proteinuria in patients with nephropathy, which were independent of blood pressure7.Russo D. Minutolo R. Pisani A. et al.Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.Am J Kidney Dis. 2001; 38: 18-25Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar. Following this line of investigation, preliminary data in patients with chronic nephropathies document that doses of ACE inhibitors and AT1 receptor antagonist higher than the maximum recommended doses for blood pressure control further reduced urinary protein excretion as compared to conventional doses, without significant changes in blood pressure (abstract; Weinberg SM et al, J Am Soc Nephrol 11:79A, 2000). However, one must be cautious in assuming that the renal effects of ACE inhibitors and AT1 receptor antagonist and their combination are independent of systemic hemodynamics, as several important limitations make the study by Delles et al6.Delles C. Jacobi J. John S. et al.Effects of enalapril and eprosartan alone or in combination on the renal vascular nitric oxide system in human essential hypertension.Kidney Int. 2002; 61: 1462-1468Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar far from conclusive. First, it is likely that 1-week therapy is not long enough to fully disclose the systemic and renal effects of ACE inhibitors and AT1 receptor antagonists. It should be noted that the maximum antihypertensive effect of both ACE inhibitors and AT1 receptor antagonists may be observed after at least 6 weeks of therapy4.Taal M.W. Brenner B.M. Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists.Kidney Int. 2000; 57: 1803-1817Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar. Thus, an assessment of the full response to treatment should be delayed until after 6 weeks. In a previous study in which 20 patients with essential hypertension and normal serum creatinine concentrations were randomized to receive either enalapril or the AT1 receptor antagonist, irbesartan, for 12 weeks, both treatments were equally effective in lowering mean blood pressure and both resulted in decreases in renal vascular resistance and increases in RPF with no average change in GFR4.Taal M.W. Brenner B.M. Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists.Kidney Int. 2000; 57: 1803-1817Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar. Another limitation of the study by Delles et al6.Delles C. Jacobi J. John S. et al.Effects of enalapril and eprosartan alone or in combination on the renal vascular nitric oxide system in human essential hypertension.Kidney Int. 2002; 61: 1462-1468Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar is that their patients were not kept on a control of sodium intake during the study period. This is a crucial point since it is well-known that oral salt intake considerably influences renal hemodynamics and renal response to RAS inhibition. During low, but not high, sodium intake, activation of the intrarenal RAS system occurs that may potentiate the efficacy of ACE inhibitors. In patients with chronic nephropathies, treatment with the ACE inhibitor, lisinopril, associated with a low-salt diet, provided a higher renoprotective effect than the same ACE inhibitor but with a high-salt diet. Delles et al6.Delles C. Jacobi J. John S. et al.Effects of enalapril and eprosartan alone or in combination on the renal vascular nitric oxide system in human essential hypertension.Kidney Int. 2002; 61: 1462-1468Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar also investigated the mechamisms by which enalapril and eprosartan influence renal hemodynamics in essential hypertension, moving from the hypothesis that drug association may improve the function of renal vascular endothelium, particularly its capacity to produce the potent vasodilator nitric oxide. There are a number of mechanisms by which ACE inhibitors and AT1 receptor antagonists augment nitric oxide activity. ACE, also termed kininase II, is responsible for the breakdown of bradykinin, which is a potent stimulator of nitric oxide synthase. ACE inhibition, therefore, results in elevated bradykinin levels and increased nitric oxide synthesis. Incubation of human cultured endothelial cells with the ACE inhibitor, ramiprilat, increased nitric oxide formation, which was prevented by pretreatment with a selective B2 kinin receptor antagonist. In normotensive subjects, a single oral dose of enalapril significantly increased the nitric oxide release rate from the lung, as evaluated by measuring nitric oxide concentration in the exhaled air, however, the same treatment had no effect on nitric oxide production in hypertensive patients8.Sumino H. Nakamura T. Kanda T. et al.Effect of enalapril on exhaled nitric oxide in normotensive and hypertensive subjects.Hypertension. 2000; 36: 934-940Crossref PubMed Scopus (19) Google Scholar. ACE inhibitors, besides stimulating nitric oxide synthesis, also induced the expression of the endothelial constitutive isoform of nitric oxide synthase (ecNOS), as documented by increased ecNOS expression in cultured bovine aortic endothelial cells incubated with ramiprilat, and by increased miocardial ecNOS expression in deoxycorticosterone acetate (DOCA)-salt hypertensive rats treated with the ACE inhibitor, quinalapril, as compared with rats receiving vehicle9.Linz W. Wohlfart P. Scholkens B.A. et al.Interactions among ACE, kinins and NO.Cardiovascular Res. 1999; 43: 549-561Crossref PubMed Scopus (140) Google Scholar. Finally, ACE inhibitors exert an antioxidant action and increase the activity of endothelial superoxide dismutase (ecSOD) in arterial vessels, which may prevent nitric oxide degradation by reactive oxygen species. AT1 receptor antagonist have been shown to stimulate nitric oxide production and activity as well. Comparative studies in DOCA-salt hypertensive rats, in patients with coronary artery disease10.Hornig B. Landmesser U. Kohler C. et al.Comparative effect of ACE inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: Role of superoxide dismutase.Circulation. 2001; 103: 799-805Crossref PubMed Scopus (311) Google Scholar, and in healthy subjects documented that ACE inhibitors and AT1 receptor antagonists had the same stimulating effects on nitric oxide synthesis, ecNOS, and ecSOD expression in vascular endothelium. AT1 receptor antagonists, on the other hand, have no effect on bradykinin levels. However, blockade of AT1 receptors in the presence of elevated Ang II levels results in stimulation of subtype 2 (AT2) receptors that are known to mediate Ang II-induced production of nitric oxide. In a rat model of cardiac failure, the importance of AT2 receptor stimulation has been demonstrated by the observation that administration of an AT2 receptor antagonist blocks the cardioprotective effect of AT1 receptor antagonist. Thus, combined administration of ACE inhibitors and AT1 receptor antagonist, by indirect nitric oxide synthesis stimulation via bradykinin and by direct nitric oxide synthesis stimulation via the AT2 receptors, may exert a synergistic effect on endothelial-dependent vasodilatation. However, very little data are available in vivo in human subjects on the effects of the two classes of drugs on renal vascular nitric oxide. In their report Delles et al6.Delles C. Jacobi J. John S. et al.Effects of enalapril and eprosartan alone or in combination on the renal vascular nitric oxide system in human essential hypertension.Kidney Int. 2002; 61: 1462-1468Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar examined the effect of L-NMMA, a competitive inhibitor of nitric oxide synthase, on renal hemodynamic parameters. They found that in patients with essential hypertension, administration of L-NMMA decreased RPF by approximately the same percentage independent of whether they were taking placebo, enalapril, eprosartan, or their combination. These results at first glance rule out any change in renal endothelial nitric oxide production induced by enalapril, eprosartan, or their combination. However, to focus more on the individual subject's RPF reaction to study medication and to L-NMMA administration, the authors calculated correlation coefficients between the increase in RPF induced by enalapril, eprosartan, or the combination and response of RPF to nitric oxide synthase inhibition with L-NMMA at the end of each treatment. With this approach, they found that after 1-week treatment with either eprosartan or the combination of eprosartan and enalapril, the greater was the increase in RPF, the more marked was the renal vasoconstriction induced by L-NMMA. In contrast, no correlation between the increase in RPF and the L-NMMA induced decrease in RPF was found at the end of enalapril treatment. These results would suggest that the improvement of RPF by eprosartan alone or in combination with enalapril is at least in part dependent on increased renal nitric oxide vascular release. However, the fact that mean RPF changes after L-NMMA were not different among the treatment groups makes the authors conclusion somewhat doubtful. In summary, this preliminary study suggests that adding an AT1 receptor antagonists may help maximize the beneficial effect of ACE inhibitor on renal hemodynamics and renal endothelial function. Prospective trials and more direct evaluations of renal nitric oxide production will tell whether combined therapy is actually more renoprotective than each drug alone and whether increase of renal vascular nitric oxide activity has actually a role in the renoprotective effect.