Inverse association between hypertension treatment and COVID-19 prevalence in Japan

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

Both angiotensin-converting enzyme (ACE) inhibitors and AT-1 receptor antagonists reduce the effects of angiotensin II, however they may have different clinical effects. This is because the ACE inhibitors, but not the AT-1 receptor antagonists, increase the levels of substance P, bradykinin and tissue plasminogen activator. The AT-1 receptor antagonists, but not the ACE inhibitors, are capable of inhibiting the effects of angiotensin II produced by enzymes other than ACE. On the basis of the present clinical trial evidence, AT-1 receptor antagonists, rather than the ACE inhibitors, should be used to treat hypertension associated with left ventricular (LV) hypertrophy. Both groups of drugs are useful when hypertension is not complicated by LV hypertrophy, and in diabetes. In the treatment of diabetes with or without hypertension, there is good clinical support for the use of either an ACE inhibitor or an AT-1 receptor antagonist. ACE inhibitors are recommended in the treatment of renal disease that is not associated with diabetes, after myocardial infarction when left ventricular dysfunction is present, and in heart failure. As the incidence of cough is much lower with the AT-1 receptor antagonists, these can be substituted for ACE inhibitors in patients with hypertension or heart failure who have persistent cough. Preliminary studies suggest that combining an AT-1 receptor antagonist with an ACE inhibitor may be more effective than an ACE inhibitor alone in the treatment of hypertension, diabetes with hypertension, renal disease without diabetes and heart failure. However, further trials are required before combination therapy can be recommended in these conditions.

HomeHypertensionVol. 76, No. 5Plasma Angiotensin Peptide Profiling and ACE (Angiotensin-Converting Enzyme)-2 Activity in COVID-19 Patients Treated With Pharmacological Blockers of the Renin-Angiotensin System Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBPlasma Angiotensin Peptide Profiling and ACE (Angiotensin-Converting Enzyme)-2 Activity in COVID-19 Patients Treated With Pharmacological Blockers of the Renin-Angiotensin System Ulrich Kintscher, Anna Slagman, Oliver Domenig, Robert Röhle, Frank Konietschke, Marko Poglitsch and Martin Möckel Ulrich KintscherUlrich Kintscher Correspondence to Ulrich Kintscher, Charité–Universitätsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Hessische Strasse 3-4, 10115 Berlin, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7386-0990 From the Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (U.K., A.S., M.M., R.R., F.K.) Institute of Pharmacology, Center for Cardiovascular Research, Germany (U.K.) DZHK (German Centre for Cardiovascular Research), Partner Site Berlin (U.K.) , Anna SlagmanAnna Slagman From the Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (U.K., A.S., M.M., R.R., F.K.) Department of Emergency and Acute Medicine, Campus Mitte and Campus Virchow Clinic (A.S., M.M.) , Oliver DomenigOliver Domenig Attoquant Diagnostics, Vienna, Austria (O.D., M.P.). , Robert RöhleRobert Röhle https://orcid.org/0000-0002-8130-6524 From the Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (U.K., A.S., M.M., R.R., F.K.) Institute of Biometry and Clinical Epidemiology, Coordinating Center for Clinical Studies (R.R.) Berlin Institute of Health, Germany (R.R., F.K.) , Frank KonietschkeFrank Konietschke From the Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (U.K., A.S., M.M., R.R., F.K.) Institute of Biometry and Clinical Epidemiology (F.K.) Berlin Institute of Health, Germany (R.R., F.K.) , Marko PoglitschMarko Poglitsch Attoquant Diagnostics, Vienna, Austria (O.D., M.P.). and Martin MöckelMartin Möckel https://orcid.org/0000-0002-7691-3709 From the Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (U.K., A.S., M.M., R.R., F.K.) Department of Emergency and Acute Medicine, Campus Mitte and Campus Virchow Clinic (A.S., M.M.) Originally published27 Aug 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15841Hypertension. 2020;76:e34–e36Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 27, 2020: Ahead of Print Pharmacological blockade of the renin-angiotensin system (RAS) with ACE (angiotensin-converting enzyme) inhibitors or angiotensin type 1 receptor blockers (ARB) reduces morbidity and mortality in various cardiovascular diseases. One of the key RAS-modulating enzymes, ACE2, has recently gained increasing attention because it converts not only angiotensin (Ang) II to the alternative RAS metabolite Ang-(1–7) but also functions as the cellular entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2.1 At the beginning of the SARS-CoV-2 pandemic, some investigators suggested that because ACE inhibitor or ARB may lead to upregulation of ACE2 expression/activity, use of these agents in coronavirus disease 2019 (COVID-19) patients might be associated with worsened outcomes.1 Meanwhile, several observational studies have shown that neither the risk of COVID-19 nor its severity is negatively affected by ACE inhibitor or ARB.2,3 However, it remains unclear how RAS activity, particularly ACE2, is regulated in COVID-19 and how this is altered by ACE inhibitor/ARB therapy. In this study, we analyzed distinct RAS components in plasma from patients with COVID-19 ±ACE inhibitor/ARB therapy using liquid chromatography-mass spectrometry/mass spectrometry.The study was approved by the Charité-Universitäts-medizin, Berlin, Germany, Institutional Ethics Committee (EA2/204/19, Amendment 1) and registered in the German Registry for Clinical Studies (DRKS00019207). Surplus plasma samples were collected at the time of admission to the emergency room from 6 different patient groups (total, n=58 [women, 21]): SARS-CoV-2 negative control group (control, n=9 [4]), SARS-CoV-2 negative with ACE inhibitor (control-ACE inhibitor, n=10 [2]), SARS-CoV-2 negative with ARBs (control-ARB, n=8 [5]), COVID-19 without ACE inhibitor/ARB (COVID, n=12 [5]), COVID-19 with ACE inhibitor (COVID-ACE inhibitor, n=10 [2]), and COVID-19 with ARBs (COVID-ARB, n=9 [3]). Equilibrium levels of Ang-peptides (Ang I, Ang II, Ang-[1–7], and Ang-[1–5]) were measured using liquid chromatography-mass spectrometry/mass spectrometry technology (Attoquant Diagnostics).4 Ang-based markers for ACE (Ang II/Ang I) and plasma renin activity (Ang I+Ang II) were calculated from Ang-peptide levels. ACE2 activity was assayed by a classical kinetic approach applying its natural substrate (ex vivo spiked Ang II) and measuring the turnover to Ang-(1–7)±ACE2 inhibitor MLN-4760. The inhibitor-sensitive ACE2-specific turnover was converted to an ACE2 concentration using a calibration curve of recombinant human ACE2. Ang-peptide concentrations/ratios, ACE2 activity, and age between groups were compared using the Kruskal-Wallis test. In case of a significant result, the Dunn-Test for pairwise comparisons using Bonferroni correction was applied. A P of <0.05 was considered statistically significant, although results have to be considered exploratory.Patient CharacteristicsAge (years, mean±SD): control, 44.8±19.7; control-ACE inhibitor, 63.6±17.8; control-ARB, 73.1±11.4 (P=0.02 versus control); COVID, 50±15.1; COVID-ACE inhibitor, 61.4±20.9; COVID-ARB, 74.2±10.1 (P=0.02 versus COVID); COVID severity (n/group), as defined previously,3 severe (intensive care unit admission, mechanical ventilation, and death): COVID (2), COVID-ACE inhibitor (1), COVID-ARB (1); acute renal failure ([n/group] control-ARB [2], COVID [1], COVID-ARB [1]); diuretic use (n/group): control (0), control-ACE inhibitor (4), control-ARB (6), COVID (0), COVID-ACE inhibitor (1), and COVID-ARB (3). Coexisting conditions are outlined in the Figure (A).ResultsAng-peptide equilibrium concentrations did not significantly differ between the control and COVID groups without ACE inhibitor/ARB treatment (Figure [B], left). More importantly, Ang I+II, Ang II/Ang I, and ACE2 activity were not significantly different between both groups (Figure [C]). These data suggest that patients with COVID-19 are not those with increased RAS activity levels and that particularly COVID-19–induced alternative RAS activation, potentially mediated through circulating ACE2, is not a typical feature in our patient cohort.Download figureDownload PowerPointFigure. Patient characteristics, Ang (angiotensin) peptide profiles, and ACE (angiotensin-converting enzyme)-2 levels. A, The presence of cardiovascular disease (hypertension, coronary artery disease, and chronic heart failure) and type 2 diabetes mellitus depicted as percentage of patients in each group. B, Plasma Ang-peptide concentrations and renin-angiotensin system (RAS) enzymatic cascade are depicted as RAS Fingerprints. The concentration of indicated Ang metabolites is reflected by the size of the corresponding sphere. Blue arrows indicate enzymes that are known to carry out metabolic conversions between connected Ang metabolites. Numbers represent median concentrations (pmol/L) and interquartile ranges in parentheses. C, Ang-based markers for plasma renin activity: Ang I+Ang II and ACE: Ang II/Ang I were calculated from Ang-peptide levels. ACE2 activity was measured as described above. Data are shown as dot plots and median. Significant P values within each group (control and coronavirus disease 2019 [COVID]) are indicated. control: severe acute respiratory syndrome coronavirus 2 negative control group without ACE inhibitor/angiotensin type 1 receptor blocker (ARB) therapy; control+ACE inhibitor: severe acute respiratory syndrome coronavirus 2 negative control group with ACE inhibitor therapy; control+ARB: severe acute respiratory syndrome coronavirus 2 negative control group with ARB therapy; COVID: patients with COVID-19 without ACE inhibitor/ARB; COVID+ACE inhibitor: patients with COVID-19 with ACE inhibitor therapy; COVID+ARB: patients with COVID-19 with ARB therapy. ACEi indicates ACE inhibitor; and CTRL, control.Comparison of all groups, including ACE inhibitor/ARB treatment groups, revealed no significant differences of Ang I+II levels between the groups (Figure [C], upper left). Ang I+II is a reliable marker for plasma renin activity and did not change significantly, despite the use of ACE inhibitor/ARB, while median values were clearly increased in patients on ACE inhibitor/ARB. This is consistent with previous observations demonstrating a broad spectrum of intensity in compensatory renin secretion in patients treated with ACE inhibitor or ARB.4 As expected, patients in the control-ACE inhibitor and COVID-ACE inhibitor group showed increased Ang I and markedly suppressed Ang II levels (Figure [B]), resulting in a significant reduction of the Ang II/Ang I ratio (Figure [C], lower left). Ang-(1–5) levels did not significantly differ between groups, whereas Ang-(1–7) was significantly increased in the COVID-ACE inhibitor group versus COVID without ACE inhibitor/ARB (P=0.01) and versus COVID-ARB (P=0.045). ACE2 activity was significantly higher in patients with COVID-19 treated with ACE inhibitor compared with patients with COVID-19 without ACE inhibitor/ARB (Figure [C], right). ACE2 activity was also increased in the control-ACE inhibitor and control-ARB group but did not reach statistical significance (Figure [C], right). ARB treatment in COVID-19 did not significantly affect ACE2 activity (Figure [C], right).The main findings of this study are as follows: (1) patients with COVID-19 are not characterized by major changes in RAS activity in plasma including ACE2 activity, (2) ACE inhibitor therapy significantly suppressed Ang II/Ang I ratios, the Ang-based marker for ACE, in COVID-19 and in non–patients with COVID-19, and (3) plasma ACE2 activity is increased in patients with COVID-19 treated with ACE inhibitor. These data are consistent with previously published results in SARS-CoV-2–negative patients treated with ACE inhibitor or ARB demonstrating an Ang II/Ang I suppression and a more profound increase of Ang-(1–7) under ACE inhibitor compared with ARBs.4 The data published so far on plasma ACE2 activity and Ang-(1–7) levels in patients without COVID treated with ACE inhibitor or ARBs are controversial.1 Some studies showed an increase in circulating ACE2 activity and Ang-(1–7) levels that cannot be proven by other studies.1 In addition, increased ACE2 activity has been identified in multiple cardiovascular diseases such as hypertension, coronary artery disease, and chronic heart failure, which are usually treated with ACE inhibitor.1 Whether the ACE inhibitor treatment in our study plays a role in ACE2 upregulation or whether these changes are mediated by the increased presence of cardiovascular disease in this group requires further investigation. Furthermore, the clinical significance of the elevated ACE2 activity in patients with COVID-19 treated with ACE inhibitor is currently not completely understood. Whether plasma ACE2 level may be a reliable marker of the full-length membrane bound form1 and whether ACE2 serves as a marker for disease severity or endothelial regeneration in the lung5 need to be clarified in future studies. Some of the major limitations of this study include small sample sizes, lack of a power analysis, lack of any data on blood pressure when the plasma samples were obtained, and lack of any data on duration of illness. Finally, it should be emphasized that the majority of the study patients were not experiencing severe COVID-19. However, we provide for the first time a snapshot of distinct systemic RAS components in patients with COVID-19 under ACE inhibitor/ARB therapy that helps to understand the clinical data on a molecular pharmacological level.AcknowledgmentsWe thank Fabian Holert, Jana Eberst, and Beata Hoeft for the support with sample preparation/handling and clinical data collection.Sources of FundingThis study was supported by institutional funding from the Charité–Universitätsmedizin Berlin, Germany. U. Kintscher is supported by the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research); BER 5.4 PR, the Deutsche Forschungsgemeinschaft (KI 712/10-1), the BMBF/BfR1328-564 m, and the Einstein Foundation/Foundation Charité (EVF-BIH-2018-440).DisclosuresO. Domenig and M. Poglitsch are employees of Attoquant Diagnostics, Vienna, Austria. U. Kintscher received research grants/speaker honoraria from Bayer. U. Kintscher received speaker honoraria from Berlin Chemie, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Sanofi, and Servier and participated in advisory boards of Berlin Chemie, Boehringer Ingelheim, Novartis, and Sanofi. M. Möckel received research grants/speaker honoraria from Roche Diagnostics and BRAHMS ThermoFisher; M. Möckel received speaker honoraria from Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Bristol Myers Squibb and participated in advisory boards of Daiichi Sankyo and Boehringer Ingelheim. The other authors report no conflicts.FootnotesCorrespondence to Ulrich Kintscher, Charité–Universitätsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Hessische Strasse 3-4, 10115 Berlin, Germany. Email ulrich.kintscher@charite.de

R enin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II

The role of the brain as a target for angiotensin converting enzyme (ACE) inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibitors may modulate other central neuropeptide systems such as the central vasopressin system, we studied the effects of chronic treatment with the ACE inhibitor, quinapril, on ACE activity and on central vasopressin content in specific brain areas in rats. 22 rats were chronically treated with quinapril (6 mg.kg-1 BW per gavage daily for 6 weeks; untreated controls, n = 14). ACE density in various brain regions was assessed by in vitro autoradiography using the specific ACE inhibitor, 125I-351A. Vasopressin content was determined in 19 brain areas (micropunch technique) known to be involved in cardiovascular regulation. Following chronic quinapril treatment ACE was significantly decreased in the thalamus (-38%), hypothalamus (-37%), hypophysis (-35%), cerebellum (-36%) choroid plexus (-20%), and locus coeruleus (-35%). Additionally, a marked reduction in serum ACE activity (-97%) was observed. Plasma levels of vasopressin were significantly decreased after quinapril treatment (0.97[s.e.m. 0.11] vs. 1.63[0.24] pg.ml-1 in controls, P < 0.05). Vasopressin content was significantly reduced in 9 of 19 specific brain areas. Regarding the hypothalamic vasopressin-producing nuclei, vasopressin was decreased in the paraventricular (292[197] vs. 2379[585] pg.mg-1 crotein in controls; P < 0.001) and supraoptic nuclei (13618[1979] vs. 24525[3894] pg.mg-1 protein; P < 0.05), but not in the suprachiasmatic nucleus. Vasopressin content was significantly reduced in brain areas connected by vasopressinergic fibres originating in the hypothalamic paraventricular nucleus: namely central gray, subcommissural organ, organum vasculosum laminae terminalis, dorsal raphe nucleus, and locus coerules. Vasopressin content was also significantly reduced in the median eminence (5887[1834] vs. 28321[4969] pg.mg-1 protein, P < 0.001), where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. Autoradiographic studies in vitro indicate that orally administered quinapril suppresses central ACE activity after chronic treatment. ACE inhibition by quinapril strongly influences vasopressin content in important brain areas which are involved in central cardiovascular regulation. Therefore, central modulatory effects of ACE inhibitors may also contribute to overall therapeutic efficacy.

[Figure: see text].

There are now numerous angiotensin converting enzyme (ACE) inhibitors under development, clinical trial or in clinical use for cardiovascular disease, a situation analagous to the beta blockers. They currently vary in their chemical and physical structure, whether they contain a sulphydril group or are pro-drugs, and in their pharmacokinetics. Whether these differences will convey any special or particular clinical advantages to individual ACE inhibitors has yet to be established. Further research is necessary to determine whether tissue ACEs are merely isoenzymes or whether they differ in their functional properties. Different bioavailability in tissues of the individual ACE inhibitors could confer differing pharmacodynamic properties. ACE inhibitors have been a major advance in the treatment of hypertension and heart failure. In heart failure they have been shown to improve the haemodynamics, to improve symptoms, and most recently, to prolong survival. In hypertension, ACE inhibitors have some physiological advantages over current antihypertensive agents. They have several favourable cardiovascular effects without metabolic disadvantages which provide a theoretical basis for cardio-protection in hypertensive patients.

Cardiac hypertrophy is a morphological adaptive increase in myocardial mass in response to chronic work overload and is a common clinical finding affecting 23% of men and 33% of women over the age of 59 years [1]. Pressure or volume overload on the myocardium results in an increase in myocardial wall stress and hypertrophy may be seen as an attempt to normalise wall stress and oxygen demand. Although initially protective, the increased myocardial mass requires an increase in coronary blood flow to maintain function; indeed, ventricular hypertrophy may be associated with myocardial ischaemia even with angiographically normal coronary arteries [2–4]. Left ventricular hypertrophy (LVH) significantly increases the risk of myocardial infarction, congestive heart failure and sudden cardiac death [5–7]. It is also associated with a greater prevalence of cardiac arrhythmias [8] and is an important risk factor for cardiac morbidity and mortality [9–10]. Understanding the potential mechanisms for these adverse effects has been the focus of much interest in recent years.

1. The present study was designed to test the hypothesis that beneficial effects of angiotensin converting enzyme (ACE)inhibitors are independent of a fall in blood pressure in rat experimental heart failure following coronary ligation. 2. The animals were assigned randomly to six groups; sham operation, controls subjected to coronary ligation (control), coronary ligation plus chronic treatment with ACE inhibitors at non- and hypotensive doses; perindopril (0.2 or 2 mg kg-1 day-1) or enalapril (2 or 20 mg kg-1 day-1) for three weeks starting one week after the ligation. 3. Systemic blood pressure was measured every week during the experiments. At the end of the treatments, cardiac function and heart weight (an index of myocardial hypertrophy) were determined. In the other animals, ACE activities in plasma and tissues including heart, kidney, lung and blood vessels were measured. 4. In the controls, cardiac ACE activity, weight of right ventricle and left ventricular end-diastolic pressure (LVEDP) were higher compared to those in the sham-operated animals four weeks after the coronary ligation. However, ACE activities were not changed in plasma, kidney, lung and aorta by ligation of the coronary artery. 5. The chronic treatment with perindopril at a dose of 0.2 mg kg-1 day-1 inhibited the increase in ACE activity in cardiac tissue and suppressed the right ventricular hypertrophy without affecting systemic haemodynamics. In contrast, enalapril at a dose of 20 mg kg-1 day-1, but not 2 mg kg-1 day-1, prevented the development of the right ventricular hypertrophy. Enalapril at 20 mg kg-1 day-1 also lowered systemic blood pressure. 6. There is no significant correlation between systemic blood pressure and right ventricular hypertrophy at the end of the treatment with perindopril (r = 0.06) or enalapril (r = 0.1).7. These findings demonstrate that perindopril, an ACE inhibitor, prevents cardiac hypertrophy without affecting systemic blood pressure in the rat with heart failure after coronary ligation, and suggest that selective augmentation of ACE activity in cardiac tissue is involved in the progression of hypertrophy in this model.

Neutral endopeptidase inhibition: the potential of a new therapeutic approach in cardiovascular disease evolves.

The most important factor that prevents the progression of renal damage in diabetes mellitus, beside the improvement of blood glucose control, is tight BP control. The tenet of tight BP control may be defined as the lowest BP level one can accomplish using antihypertensive therapy that is at the same time compatible with the absence of untoward side effects. In fact, both the Framingham Heart Study in nondiabetic normal subjects and the United Kingdom Prospective Diabetes Study in type 2 diabetic patients showed that systolic values as low as 108 to 111 mmHg and diastolic values as low as 70 to 71 mmHg are significantly associated with decreased cardiovascular mortality and morbidity. However, 45 to 50% of the patients with type 2 diabetes mellitus and hypertension have systolic BP levels above 140 mmHg during antihypertensive therapy, particularly when using monotherapy. Thus the issue regarding the choice of which drugs one should use to treat hypertension became critical from a clinical point of view. Pharmaceutical compounds, which inhibit the renin-angiotensin system, have become the first-choice treatment in patients with diabetes mellitus and incipient and advanced renal complications. The present brief review analyzes the effects of calcium channel blockers (CCB) on cardiovascular and renal complications in diabetes mellitus. The review discussed those studies that directly and blindly compared CCB with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin II AT(1) receptor blockers (ARB). Furthermore, size of the population recruited in each trial was used as a criterion of priority in the selection of the reports from the available literature. From the point of view of cardiovascular complications, the results of these studies showed a slightly better benefit of CCB on stroke, whereas ACE inhibitors better prevented the occurrence of myocardial infarction and congestive heart failure. On the other hand, recent observations demonstrated that also ACE inhibitors and ARB are effective in the primary and secondary prevention of stroke, although these studies did not directly compare these compounds with CCB. With regard to the outcome of renal complications, both ARB and ACE inhibitors more effectively prevented the progression of renal damage among the patients with overt nephropathy than CCB. On the contrary, both CCB and ACE inhibitors were equally effective on blunting the decay of GFR in diabetic patients who do not have overt proteinuria. However, ACE inhibitors and ARB more markedly decreased the rate of albumin excretion rate in the range of both microalbuminuria and macroalbuminuria. Recent advances in the understanding of the pathogenesis of abnormalities of albumin excretion rate and of atherosclerosis are also discussed. Both mechanical stress, mainly secondary to systolic hypertension, and elevated circulating and tissue levels of angiotensin II, partially independent from each other, cause excessive generation of superoxide compounds. This chain reaction of events in turn leads to disorders of structural components of glomerular filter and to damage of the vascular wall. Systolic BP control (<130 mmHg) is not adequately accomplished in the majority of the patients treated only with ACE inhibitors and ARB, even in association with diuretics. Poor BP control may lead to excessive systemic mechanical stress at the vascular level despite satisfactory inhibition of angiotensin II effects. In conclusion, one can suggest that CCB are useful and often indispensable pharmaceutical compounds, beside ACE inhibitors and ARB, to accomplish tight BP control (<130/85 mmHg), a target that is unlikely to be successfully maintained in the overall population of type 2 diabetic patients only by ACE inhibitors or ARB, as monotherapy. However, ACE inhibitors and ARB might be considered first-choice drugs in the treatment of hypertension in diabetes mellitus, mainly because of a better renoprotection.

Introduction: Small-cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival at five years for patients with SCLC is estimated to be five to ten percent. Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) have been reported to decrease the risk of lung cancer. The aim of this retrospective study was to investigate the association between ACE inhibitors and ARBs and cancerrelated mortality in patients with SCLC. Methods: In this study, we retrospectively reviewed the charts of 360 patients diagnosed with SCLC in our institution between 1995 and 2004. 199 patients with advanced SCLC, deceased at the time of this report, and for whom the cause of death was known, were identified. Within this group, cancer-related mortality in patients who were on ACE inhibitors and/or ARBs was compared to that of patients not on these medications. Results: Out of 199 patients, 58 (29%) were on ACE inhibitors and/or ARBs, 141 (71%) were not. In ACE inhibitor and/or ARB users, cancer was the cause of death in 34 patients. In patients not on ACE inhibitors and/or ARBs, 103 died from cancer. Patients on ACE inhibitors and/or ARBs had a 14% decrease in cancer-related mortality compared to patients who were not on these medications (59% versus 73% respectively, P= 0.046). Conclusion: Our data support the fact that ACE inhibitors and ARBs may be associated with a decrease in cancer-related mortality in patients with SCLC. This could be related to their inhibitory effects on angiogenesis and tumor growth, by blocking angiotensin II and increasing the levels of angiotensin (1–7). However, prospective studies are needed to establish the effect of ACE inhibitors and ARBs on cancer-related mortality in patients with SCLC. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B93.

To clarify the mechanisms by which angiotensin-converting enzyme (ACE) inhibitors lower blood pressure or inhibit cardiac hypertrophy, we analyzed the correlations among tissue ACE activities, blood pressure and cardiac hypertrophy. In spontaneously hypertensive rats (SHR), blood pressure, heart weight and ACE activities in plasma and various tissues were measured 3, 24 and 48 h after repeated daily treatment for 2 weeks with the ACE inhibitors trandolapril, perindopril, temocapril and enalapril. For all four ACE inhibitors, blood pressure and ACE activities in the plasma, aorta and kidney were significantly reduced 3 h after the last treatment. Although hypotensive effects were maintained at 24 h, ACE activities in plasma were not suppressed by temocapril and enalapril. Even at 3 h, enalapril could not suppress ACE activity in the brain, and temocapril and enalapril could not inhibit ACE activities in the heart. Significant correlations between ACE activity in the aorta and blood pressure were observed for all four ACE inhibitors, while the ACE activities in the heart and brain were not correlated with changes in blood pressure. Significant decreases in the ratio of heart weight to body weight were observed in SHR treated with trandolapril and perindopril, whereas they were not observed with temocapril and enalapril. The ratio of heart weight to body weight was significantly correlated with ACE activity in the heart. ACE activities in vascular tissues and the heart may be important targets in terms of the ability of ACE inhibitors to lower blood pressure or inhibit cardiac hypertrophy, respectively.

61-Year-Old Man With Nausea and Vomiting

The effects of angiotensin converting enzyme (ACE) inhibitors result from the inhibition of the ACE (kininase II) to ultimately influence both the renin–angiotensin system and the degradation of the bradykinin (BK) metabolism. ACE inhibitors block the degradation of BK and substance P by ACE. In addition, an active metabolite of BK (Des-Arg9-BK) is catalysed by kininase I and its degradation is controlled in part by the conversion enzyme. These molecules have been associated with increased plasma extravasation associated with ACE inhibitors. ACE inhibitors are the leading cause of drug-induced Angioedema (AE). Symptoms of AE mainly occur after the first month of treatment by ACE. However, very late onset cases, sometimes after several years of stable therapy, are also described in the literature. It has been observed that patients previously stable under ACE inhibitor will most likely develop AE soon after the addition of another medication, including the combination of aspirin or non-steroid anti-inflammatory drugs with ACE inhibitor which has proved to be the most common cause, accounting for close to 50% of all AE cases related to ACE inhibitors. This side effect of ACE inhibitors, sometimes very late and rare, deserves to be recalled