Chronic Angiotensin-converting Enzyme Research Articles

Chronic angiotensin converting enzyme inhibition attenuates frailty and protects against atrial fibrillation in aging mice

BackgroundAging is a major risk factor for atrial fibrillation (AF); however, not all individuals age at the same rate. Frailty, which is a measure of susceptibility to adverse health outcomes, can be quantified using a frailty index (FI). ObjectiveTo determine the effects of angiotensin converting enzyme (ACE) inhibitors on AF and atrial remodeling in aging and frail mice. MethodsAging mice were treated with the ACE inhibitor enalapril for 6 months beginning at 16.5 months of age and frailty was quantified. AF susceptibility as well as atrial structure and function were assessed using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, patch-clamping in isolated atrial myocytes, and histology and molecular biology in atrial tissues. ResultsEnalapril attenuated frailty in aging mice with larger effects in females. AF susceptibility was increased in aging mice, but attenuated by enalapril. AF susceptibility and duration also increased as a function of FI score. P wave duration was increased and atrial conduction velocity was reduced in aging mice and improved after enalapril treatment. Furthermore, P wave duration and atrial conduction velocity were strongly correlated with FI score. Atrial action potential upstroke velocity (Vmax) and Na+ current (INa) were reduced while atrial fibrosis was increased in aging mice. Action potential Vmax, INa, and fibrosis were improved by enalapril and also correlated with FI scores. ConclusionsACE inhibition with enalapril attenuates frailty and reduces AF susceptibility in aging mice by attenuating atrial electrical and structural remodeling.

ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock

BackgroundAngiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock.MethodsIn a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h.ResultsWe included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6–10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: − 2.2 mmHg [95% CI − 7.0–2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: − 6.0 mmHg [95% CI − 11.5 to − 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients.ConclusionsIn vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock.Trial Registration ClinicalTrials.Gov Identifier: NCT 02338843 (Registered January 14th 2015).

Ventricular arrhythmia susceptibility in a new porcine model of heart failure (HF) with reduced ejection fraction

Abstract Introduction Sudden death secondary to ventricular arrhythmias is common in HF patients, with no effective treatment available outside of implantable cardiac defibrillators. While animal models are essential for the discovery of anti-arrhythmic drugs, no reliable large animal HF models with associated ventricular arrhythmias have been described so far. Objectives We aimed at evaluating ventricular remodeling and arrhythmia susceptibility in an HF pig model with reduced ejection fraction (EF) following myocardial infarction (MI). Methods MI was induced in 53 male Göttingen minipigs (12–15 months, 20–25 kg) by coronary embolization in mid-left anterior descending and mid-left circumflex coronary arteries using endovascular coils. Seven other pigs underwent sham operation and were used as control. Two weeks after surgery, cardiac function was assessed by echocardiography, and animals were included based on EF&amp;lt;50% (n=15/53), assigned either to 12 weeks of vehicle (n=9) or perindopril (n=6, 1 mg/kg/d, per os) group. At the end of the study, their left ventricular (LV) electrical remodeling was studied by echocardiography/electrocardiography and a programmed-electrical stimulation protocol was performed to evaluate the susceptibility to develop ventricular arrhythmias. Results At the end of the study, animals in the vehicle group had a significant LV remodeling associated with a reduced EF (p&amp;lt;0.05 vs. sham, see table). This remodeling was associated with cardio-pulmonary congestion, significant increases in LV end-diastolic pressure, left atrial volume, and lung mass (all p&amp;lt;0.05 vs. sham, see table), fully prevented by perindopril treatment. They had also an electrical remodeling as evidenced by an increase in PR, QRS, and QTc intervals, as well as LV effective refractory period (+18%, 14%, 33%, and 13%, respectively, p&amp;lt;0.05, compared to sham animals). Electrical changes were mitigated by perindopril treatment (p=NS vs. sham). LV mechanical dispersion measured with speckle-tracking echocardiography was significantly increased in vehicle group (58±5 vs. 22±1 ms in sham group, respectively) as well as in perindopril group. Programmed-electrical stimulations induced in 6/8 vehicle animals either non-sustained (n=3) or sustained (n=2) ventricular tachycardia, or ventricular fibrillation (n=1). In sham group only 1/7 animal had a ventricular fibrillation. No inducible ventricular arrhythmia was observed in animals treated with Perindopril. Conclusion In this new pig model of congestive HF with reduced EF, LV remodeling was associated with electrical remodeling and susceptibility to develop arrhythmias. Chronic angiotensin-converting enzyme inhibitor treatment prevented congestion, mitigated electrical remodeling, and suppressed arrhythmia susceptibility. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Servier Research Institute - CardioVascular &amp; Metabolic Diseases Center for Therapeutic Innovation Table 1

Effects of Trandolapril on Structural, Contractile and Electrophysiological Remodeling in Experimental Volume Overload Heart Failure.

Chronic volume overload induces multiple cardiac remodeling processes that finally result in eccentric cardiac hypertrophy and heart failure. We have hypothesized that chronic angiotensin-converting enzyme (ACE) inhibition by trandolapril might affect various remodeling processes differentially, thus allowing their dissociation. Cardiac remodeling due to chronic volume overload and the effects of trandolapril were investigated in rats with an aortocaval fistula (ACF rats). The aortocaval shunt was created using a needle technique and progression of cardiac remodeling to heart failure was followed for 24 weeks. In ACF rats, pronounced eccentric cardiac hypertrophy and contractile and proarrhythmic electrical remodeling were associated with increased mortality. Trandolapril substantially reduced the electrical proarrhythmic remodeling and mortality, whereas the effect on cardiac hypertrophy was less pronounced and significant eccentric hypertrophy was preserved. Effective suppression of electrical proarrhythmic remodeling and mortality but not hypertrophy indicates that the beneficial therapeutic effects of ACE inhibitor trandolapril in volume overload heart failure might be dissociated from pure antihypertrophic effects.

Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula.

The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/l in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.

Inhibition of soluble epoxide hydrolase counteracts the development of renal dysfunction and progression of congestive heart failure in Ren-2 transgenic hypertensive rats with aorto-caval fistula.

The detailed mechanisms determining the course of congestive heart failure (CHF) in hypertensive subjects with associated renal dysfunction remain unclear. In Ren-2 transgenic rats (TGR), a model of angiotensin II (ANG II)-dependent hypertension, CHF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). In these rats we investigated the putative pathophysiological contribution of epoxyeicosatrienoic acids (EETs) and compared it with the role of the renin-angiotensin system (RAS). We found that untreated ACF TGR exhibited marked intrarenal and myocardial deficiency of EETs and impairment of renal function. Chronic treatment of these rats with cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/L in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs, markedly improved survival rate, and increased renal blood flow, glomerular filtration rate and fractional sodium excretion, without altering RAS activity. Chronic angiotensin-converting enzyme inhibition (ACEi) with trandolapril, (6 mg/L in drinking water) improved survival rate even more, and also inhibited the development of renal dysfunction; these beneficial actions were associated with significant suppression of the vasoconstrictor/sodium retaining axis and further activation of the vasodilatory/natriuretic axis of the systemic and intrarenal RAS, without modifying tissue availability of biologically active fatty acid epoxides. In conclusion, these findings strongly suggest that chronic sEH inhibition and chronic treatment with ACEi, each of them altering a different vasoactive system, delay or even prevent the onset of decompensation of CHF in ACF TGR, probably by preventing the development of renal dysfunction.

Effect of angiotensin converting enzyme inhibitors on periprocedural myocardial infarction in patients with metabolic syndrome.

Metabolic syndrome (MetS) has been reported as a risk factor for cardiovascular events. The aim of the present study is to investigate the association between chronic angiotensin-converting enzyme inhibitors (ACE-I) therapy and the rate of periprocedural myocardial infarction (PMI) after elective coronary stenting among patients with MetS. The inclusion criteria were MetS and plan for elective percutaneous coronary intervention. To assess the effect of ACE-I treatment on the incidence of PMI, measurements of cardiac biomarkers (CK-MB mass and troponin I) were performed at baseline and 24 h after the procedure. A total of 459 patients fulfilling the inclusion criteria were recruited to chronic ACE-I treatment and ACE-I naive groups in a 2/1 ratio. Baseline troponin I and CK-MB levels were similar in both treatment groups, whereas they were significantly lower in ACE-I group 24 h after the procedure. Univariate analysis identified body mass index (BMI), LDL cholesterol, nitrate and ACE-I use as significant factors for the development of PMI. Multivariate regression model revealed that body mass index increased and use of nitrate and ACE-I decreased the probability of PMI independent from confounding factors (OR 1.14, 95% CI 1.05-1.23, p = 0.002 for BMI; OR 0.26, 95% CI 0.14-0.48, p = 0.01 for nitrate use, OR 0.51, 95% CI 0.27-0.93, p = 0.03 for ACE-I use). This prospective observational cohort trial demonstrated that chronic ACE-I therapy was an independent predictor for reduced PMI among patients with MetS who underwent elective coronary intervention.

Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat.

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca(2+)-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr(17)-PLB-phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2-voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20%, and by 31%, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34%, P < 0.05) and under beta-adrenergic stimulation (by 73%, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca(2+)/calmodulin-dependent phosphorylation of PLB at Thr(17). Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.

Management of Hypotension Associated With Angiotensin-Axis Blockade and General Anesthesia Administration

YPOTENSION, SOMETIMES REFRACTORY, is a well-recognized phenomenon associated with the administration of general anesthesia in patients who have angiotensin-axis blockade (AAB) because of the administration of either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs). 1 Hypotension in such patients usually occurs within 30 minutes of the induction of anesthesia2,3 and is more frequent in patients also receiving diuretics. 4 There is an ongoing debate as to whether ACEIs and ARBs should be discontinued before surgery. 2,3,5-9 Although omitting these agents before general anesthesia may avoid hypotension,3,8,10 some argue that their discontinuation is not required because the associated hypotension is easily treatable 6,11 and subsequent hypertension may occur perioperatively requiring antihypertensive therapy. 9 Furthermore, the discontinuation of ACEIs and ARBs might remove the potential beneficial effect of AAB on myocardial protection 9,12-14 Adding to this debate, preoperative therapy with ACEIs in cardiac surgery 5 and ACEIs and ARBs in vascular surgery 15 have been found to be associated with an increased risk of mortality. In contrast, in cardiac surgery, ACEIs may confer renal protection16 ; and in

Angiotensin-Converting Enzyme Inhibitors

KEY POINTS AND RECOMMENDATIONS: • In addition to hypertension, angiotensin-converting enzyme inhibitors are indicated for treatment of patients at high risk for coronary artery disease, after myocardial infarction, with dilated cardiomypathy, or with chronic kidney disease. • The most familiar angiotensin-converting enzyme subtype, angiotensin-converting enzyme-1 (kininase II), cleaves the vasoconstrictor octapeptide angiotensin II from its inactive decapeptide precursor, angiotensin I, while simultaneously inactivating the vasodilator bradykinin. • Biochemical pathways within and around the renin-angiotensin system are highly species-specific; there is little evidence that "angiotensin-converting enzyme bypass pathways" have major clinical implications in humans. • Dietary sodium loading can diminish or abolish the antihypertensive effect of an angiotensin-converting enzyme inhibitor, while salt restriction or concomitant diuretic therapy enhances it. • Dose-response curves with angiotensin-converting enzyme inhibitors are quite flat but their peak effects vary in different individuals. • Increased serum creatinine (decreased glomerular filtration rate) during acute or chronic angiotensin-converting enzyme inhibition identifies individuals likely to experience long-term renal protective benefits. • Angiotensin-converting enzyme inhibitors are contraindicated in pregnancy due to fetal toxicity. • Use of angiotensin-converting enzymes can be limited by idiosyncratic reactions (cough or angioedema), hyperkalemia (usually in cardiac or renal failure or with combined renin-angiotensin blockade) or hypotension (usually with severe volume-depletion or cardiac failure).

Angiotensin-converting enzyme inhibition augments the expression of rat elastase-2, an angiotensin II-forming enzyme

Mounting evidence suggest that tissue levels of angiotensin (ANG) II are maintained in animals submitted to chronic angiotensin-converting enzyme (ACE) inhibitor treatment. We examined the expression levels of transcripts for elastase-2, a chymostatin-sensitive serine protease identified as the alternative pathway for ANG II generation from ANG I in the rat vascular tissue and the relative role of ACE-dependent and -independent pathways in generating ANG II in the rat isolated carotid artery rings of spontaneously hypertensive rats (SHR) and Wistar normotensive rats (WNR) treated with enalapril for 7 days. Enalapril treatment decreased blood pressure of SHR only and resulted in significantly more elastase-2 mRNA expression in carotid artery of both enalapril-treated WNR and SHR. Captopril induced a comparable rightward shift of concentration-response curves to ANG I in vehicle and enalapril-treated rats, although this effect was of lesser magnitude in SHR group. Chymostatin induced a rightward shift of the dose response to ANG I in vehicle-treated and a decrease in maximal effect of 22% in enalapril-treated WNR group. Maximal response induced by ANG I was remarkably reduced by chymostatin in enalapril-treated SHR carotid artery (by 80%) compared with controls (by 23%). Our data show that chronic ACE inhibition was associated with augmented functional role of non-ACE pathway in generating ANG II and increased elastase-2 gene expression, suggesting that this protease may contribute as an alternative pathway for ANG II generation when ACE is inhibited in the rat vascular tissue.

Update in Nephrology

This Update features articles on chronic kidney diseases, lupus nephritis, angiotensin-receptor blockers and angiotensin-converting enzyme inhibitors, and end-stage renal disease.

Chronic angiotensin-converting enzyme inhibition up-regulates mouse kidney growth arrest specific-6 protein and the AXL subfamily of receptor tyrosine kinases

Growth arrest specific-6 (GAS-6), a vitamin K-dependent protein, is a potential mediator in progressive and chronic renal disease, specifically as a mediator of abnormal mesangial cell proliferation. Nitric oxide and angiotensin II affect mesangial cell proliferation. However, an association between nitric oxide synthase or angiotensin II on GAS-6 expression in the kidney has not previously been examined. Thus, our aim was to examine the effects of antihypertensive angiotensin-converting enzyme inhibitors and chronic nitric oxide synthase inhibition on the kidney expression of GAS-6 and its receptors AXL, MER and RSE. Four groups of adult male C57BL/6J mice were studied: group 1, untreated controls (tap water for six weeks); group 2, treated orally with a nitric oxide synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 0.325 mg/ml for six weeks); group 3, treated orally with captopril (0.6875 mg/ml for six weeks); group 4, co-treated orally with L-NAME and captopril (same doses for six weeks). At the end of the study, kidneys were placed in fixative and processed to paraffin for immunohistochemical staining. GAS-6 and its receptors were not present in control and L-NAME-treated mice. Positive GAS-6 staining was detectable only in those mice receiving some form of chronic dosing with captopril, whether they were treated with captopril only or with captopril and L-NAME. Immunohistochemical detection across cases for MER and RSE was rare, whereas AXL-positive staining in the kidney mirrored GAS-6 staining/expression. The staining of GAS6 and AXL was predominantly localised to the renal tubular cells. These findings suggest that GAS-6 may not be a final common pathway for nitric oxide synthase inhibition-induced renal disease. Renal tubular GAS-6 expression following captopril treatment was unexpected and could be beneficial in preventing tubular atrophy following the onset of persistent systemic hypertension.

The vasopressin and copeptin response in patients with vasodilatory shock after cardiac surgery: a prospective, controlled study

To evaluate arginine vasopressin (AVP) and copeptin plasma concentrations in patients with vasodilatory shock after cardiac surgery. Prospective, controlled, clinical study. Surgical intensive care unit and cardiac surgery ward in a tertiary university teaching hospital. Thirty-three critically ill patients with vasodilatory shock after cardiac surgery and ten control patients undergoing uncomplicated aorto-coronary bypass surgery. Hemodynamic, laboratory and clinical data were recorded daily in all patients during the first 7 days after cardiac surgery. At the same time, points blood was withdrawn to determine plasma concentrations of AVP (radioimmunoassay) and copeptin (immunoluminometric assy). Standard tests, a mixed effects model and regression analyses were used for statistical analysis. The course of AVP was significantly different between groups (P < 0.001). While AVP concentrations were lower in the study group on the first postoperative day, they were higher than that in the control group from postoperative day 3 on. There was no difference in the postoperative AVP response between study patients with or without chronic angiotensin-converting enzyme inhibitor therapy. Except during continuous veno-venous hemofiltration, AVP and copeptin correlated significantly with each other (P < 0.001; r = 0.749). The AVP response to cardiac surgery is significantly different between patients with vasodilatory shock and patients undergoing uncomplicated aorto-coronary bypass surgery. Although no causative relationship between AVP concentrations and cardiovascular instability can be drawn from these results, our data support the hypothesis that inadequately low AVP plasma levels contribute to the failure to restore vascular tone in vasodilatory shock after cardiac surgery.

The effect of withdrawal of ACE inhibitors or angiotensin receptor blockers prior to coronary angiography on the incidence of contrast-induced nephropathy

The effect of continuing or discontinuing chronic angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy prior to coronary angiography on the incidence of contrast-induced nephropathy (CIN) is not clear. We undertook a randomized trial to evaluate the effect of withdrawing ACEIs or ARBs 24 h prior to coronary angiography on the incidence of CIN associated with coronary angiography. A total of 220 patients with chronic kidney disease (CKD) stages 3-4 (glomerular filtration rate 15-60 ml/min/1.73 m2) on ACEI or ARB therapy were randomized before angiography to either ACEI/ARB continuation group or discontinuation group. A third group of patients with CKD stages 3-4 but not on angiotensin blockade therapy were also followed. The primary outcome measure was the incidence of CIN defined by a rise in serum creatinine by 25% or 0.5 mg/dl (44 micromol/l) from baseline. There was no statistically significant difference in the incidence of CIN between the three groups (P=0.66). The incidences were 6.2%, 3.7%, and 6.3% for the continuation, discontinuation, and angiotensin blockade naïve group, respectively. There was also no significant difference found between the groups in mean serum creatinine and glomerular filtration rate values at baseline and post contrast administration. Withholding ACEIs and ARBs 24 h before coronary angiography does not appear to influence the incidence of CIN in stable patients with CKD stages 3-4.

Chronic Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Therapy Combined With Diuretic Therapy is Associated With Increased Episodes of Hypotension in Noncardiac Surgery

Chronic angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) therapy has been reported to result in intraoperative hypotension in patients undergoing general anesthesia. This study evaluated the association between ACE-I/ARB therapy and the hemodynamics of patients undergoing noncardiac surgery using a large patient dataset. A prospective, observational study performed at a single tertiary care hospital. All adult patients undergoing noncardiac surgery. None. Propensity score matching for the likelihood of chronic ACE-I/ARB therapy was used to create 2 patient cohorts with similar cardiovascular and pulmonary comorbidities. The number of periods of absolute and relative hypotension, vasopressor requirements, and postoperative myocardial infarction and renal failure rates were compared among patients with and without ACE-I/ARB therapy. A total of 65,043 noncardiac cases between 2003 and 2006 were included. Two-digit propensity score matching resulted in a study population of 12,381 operative cases with very similar cardiovascular comorbidities between the ACE-I/ARB and control cohort. Patients with chronic ACE-I/ARB and diuretic therapy showed more periods with a mean arterial pressure <70 mmHg, periods with a 40% decrease in systolic blood pressure, periods with a 50% decrease in systolic blood pressure, and vasopressor boluses when compared with patients with diuretic therapy alone. There were no statistically significant differences in the rates of postoperative myocardial infarction or renal failure between patients with and without ACE-I/ARB therapy. Chronic diuretic therapy is associated with more frequent hypotension in ACE-I/ARB-treated patients undergoing noncardiac surgery.

Effect of Perindopril on Renal Medullary Blood Flow: Comparison With Other Antihypertensive Treatments

Early and chronic angiotensin-converting enzyme (ACE) inhibition in Lyfon hypertensive (LH) rats improves their blunted vasodilator response of renal medullary blood flow (MBF) to angiotensin II (AngII). This study examined the specificity of this effect and the possible involvement of nitric oxide (NO). The renal response to AngII (from 7.5 to 480 ng/kg, IV) and acetylcholine (Ach, from 3 to 192 microg/kg, IV) were examined in 12-week-old anesthetized LH rats treated orally from 3 weeks of age with perindopril (1.5 mg/kg/d), nifedipine (50 mg/kg/d), or a triple therapy with hydralazine, hydrochlorothiazide, and reserpine (75, 15, and 0.75 mg/kg/d, respectively). After 9 weeks of therapy, perindopril lowered systolic blood pressure to 113 +/- 3 mm Hg, nifedipine to 144 +/- 4 mm Hg, and triple therapy to 133 +/- 2 mm Hg compared with 160 +/- 3 mm Hg in untreated LH rats. Despite a significant reduction in blood pressure, only the treatment with perindopril significantly increased the vasodilator response of MBF to AngII. However, the vasodilator response of MBF to Ach was similar among the groups. In conclusion, a renal medullary protection is conferred in LH rats by ACE inhibition, an effect that is not obtained with other antihypertensive treatments and is not explained by Ach-induced NO release.

Chocolate-induced prolonged angiooedema in an elderly patient

This report presents a 93-year-old woman with prolonged angioedema associated with diabetic chocolate and chronic angiotensin-converting enzyme inhibitor use.

Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats

In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade. From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age. High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta. As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

Cardiovascular expression of inflammatory signaling molecules, the kinin B 1 receptor and COX2, in the rabbit: Effects of LPS, anti-inflammatory and anti-hypertensive drugs

We first aimed to test the effect of anti-inflammatory drugs, etanercept and dexamethasone sodium phosphate (DSP), on the expression of inducible inflammatory signaling molecules (the bradykinin [BK] B 1 receptor [B 1R], cyclooxygenase [COX]-2) in lipopolysaccharide (LPS)-treated rabbits. Preliminary experiments mostly based on a novel cellular model, rabbit dermis fibroblasts, showed that etanercept inhibited TNF-α-induced B 1R expression ([ 3H]Lys-des-Arg 9-BK binding), but that DSP also inhibited cytokine-induced B 1R upregulation with less selectivity. LPS (100 μg/kg i.v.) induced the expression of the B 1R (aortic contractility ex vivo, mRNA in hearts) and COX2 (immunoblots, heart extracts). However, the function of the BK B 2 receptor was unchanged (jugular vein contractility ex vivo). DSP pre-treatment profoundly reduced the induction of the B 1R and COX2 whereas etanercept significantly inhibited only COX2 expression. The second aim was to verify whether chronic angiotensin converting enzyme (ACE) blockade in rabbits would induce B 1R expression, as reported in other species. 14-Day enalapril oral dosing, but not treatment with the angiotensin receptor antagonist losartan, significantly increased aortic contractions mediated by B 1Rs, however much less than LPS. Enalapril treatment did not increase COX2 expression but increased the ex vivo relaxation of the mesenteric artery mediated by endogenous prostaglandins. Chronic ACE inhibition recruits inflammatory signaling systems.