Angiotensin-converting Enzyme Inhibitor Fosinopril Research Articles

Babesia BdFE1 esterase is required for the anti-parasitic activity of the ACE inhibitor fosinopril

Effective and safe therapies for the treatment of diseases caused by intraerythrocytic parasites are impeded by the rapid emergence of drug resistance and the lack of novel drug targets. One such disease is human babesiosis, which is a rapidly emerging tick-borne illness caused by Babesia parasites. In this study, we identified fosinopril, a phosphonate-containing, FDA-approved angiotensin converting enzyme (ACE) inhibitor commonly used as a prodrug for hypertension and heart failure, as a potent inhibitor of Babesia duncani parasite development within human erythrocytes. Cell biological and mass spectrometry analyses revealed that the conversion of fosinopril to its active diacid molecule, fosinoprilat, is essential for its antiparasitic activity. We show that this conversion is mediated by a parasite-encoded esterase, BdFE1, which is highly conserved among apicomplexan parasites. Parasites carrying the L238H mutation in the active site of BdFE1 failed to convert the prodrug to its active moiety and became resistant to the drug. Our data set the stage for the development of this class of drugs for the therapy of vector-borne parasitic diseases.

Possibilities of using fosinopril in treatment of patients with chronic kidney disease in combination with cardiovascular diseases and diabetes mellitus

Chronic kidney disease is one of the most common diseases in general medical practice, due to their secondary damage to the kidneys in arterial hypertension, chronic heart failure, and diabetes mellitus. The coexistence of hypertension and diabetes increases the likelihood of developing chronic kidney failure tenfold. In turn, chronic kidney disease is an important independent risk factor for the development of cardiovascular complications, including fatal ones, due to the direct relationship of the pathogenetic mechanisms of cardiorenal relationships. Approaches to the treatment of chronic kidney disease should be aimed both at preventing the risks of developing renal dysfunction, and at treating existing pathology. The multifactorial nature of the disease and the complex etiopathogenetic relationships determine the need to optimize existing approaches to the treatment of chronic kidney disease in multimorbidity patients with concomitance cardiovascular diseases and diabetes mellitus. This is also due to the fact that, unlike other target organs, compensation for background disease does not always prevent further deterioration of kidney function. According to the recommendations of the main scientific communities, in such cases, it is advisable to start therapy with the most effective angiotensin-converting enzyme inhibitors that combine nephro-and cardioprotective effects and have a dual route of elimination from the body, which is especially important in multimorbidity, the aim to prevent polypharmacy, reduce the risk of drug interactions and, consequently, side effects. This article reviews the literature data indicating the high efficacy and safety of the angiotensin converting enzyme inhibitor fosinopril in patients with chronic kidney disease in combination with cardiovascular diseases and diabetes mellitus.

P0965CAN EMPAGLIFLOZIN BE A CANDIDATE FOR THE ROLE OF A UNIVERSAL CARDIO- AND NEPHROPROTECTIVE DRUG IN CHRONIC HEART FAILURE WITHOUT DIABETES MELLITUS?

Abstract Background and Aims The multi-system nature of chronic heart failure (CHF) requires therapeutic approaches and medications that can have pleiotropic effects. For example, it is desirable that drugs for the treatment of CHF have direct cardio- and nephroprotective effects. These conditions are largely met by angiotensin converting enzyme (ACE) inhibitors and, possibly, inhibitors of the membrane sodium/glucose cotransporter (SGLT-2) inhibitors. The study aimed to investigate the effects of the SGLT2 inhibitor empagliflozin on CHF in normoglycemic rats. The effects of empagliflozin were compared with the standard medications for CHF - ACE inhibitor fosinopril, which has cardio - and nephroprotective effects in CHF. Method Myocardial infarction (MI) was induced in male Wistar rats via permanent ligation of the left descending coronary artery. One-month post MI 30 animals were randomized into 3 groups (n=10): vehicle-treated, empagliflozin (1.0 mg/kg) and fosinopril (10 mg/kg). One month after surgery all medications administered per os daily for 3 months. Echocardiography, 24-hour urine volume test, albuminuria, proteinuria or miRNA-21 expression in urine and treadmill exercise tests (0.7 m/sec and the slope angle 15°) were performed at the beginning and at the end of the study. Results At the finish of the study (4 months after MI - 3 months on treatment) all empagliflozin treated animals survived, one animal died in vehicle group and 3 animals in the fosinopril group. In vehicle group sizes of the left ventricle (LV) increased and the ejection fraction (EF) decreased in comparison with the initial values. Rats of fosinopril group confirm well known beneficial effect ACE inhibitors on cardiac remodeling and function; LV sizes and EF didn’t change except 2 atrial dimensions enlargement. Treatment with empagliflozin slowed the progression of left ventricular dysfunction: LV sizes and EF didn’t change and the minute volume significantly increased (from 52,0±15,5 ml/min to 61,2±21,2 ml/min) as compared to baseline. Moreover, empagliflozin exhibited maximal physical exercise tolerance in comparison with all groups (289 ± 27 sec versus 183 ± 61 sec in fosinopril group, p=0,0035 for multiple comparisons). Recently, using this model of CHF in the normoglycemic rats we have found that SGLT2 inhibition for 3 months increased the tolerance to physical exercise. This effect was associated with an improvement of cardiac function as demonstrated by increased stroke volume, minute volume and LV ejection fraction as well as with the improvement of renal function. In rats of empagliflozin group 24-hour urine volume (9.8±0.92 ml) was slightly but not significantly higher than in the vehicle (6.9±1.25 ml) and in the fosinopril group (7.39±0.53 ml); p=0,09 for multiple comparisons. So, it could be suggested that other mechanisms apart from SGLT2 inhibition in kidneys and decrease of the volume overload are involved in protective action of empagliflozin. In any case, due to increased water and sodium excretion empagliflozin treatment can lead to decreased cardiac preload. There were no significant differences in levels of albuminuria and proteinuria or miRNA-21 expression in urine in groups with and without empagliflozin. Conclusion Sodium-glucose co-transporter 2 inhibitor empagliflozin reduced progression of left ventricular dysfunction and improved tolerance of physical exercise in normoglycemic rats with HF. Empagliflozin treatment compared with fosinopril was superior in respect of physical tolerance and not inferior in terms of nephroprotective action. Taking into account the obtained results one can be considered empagliflozin as a potential universal cardionephroprotector.

Выбор оптимального блокатора ренин- ангиотензин-альдостероновой системы у больных с сочетанием артериальной гипертонии и хронической обструктивной болезни легких

to compare hypotensive and pleiotropic effects of angiotensin II receptor blocker (ARB) azilsartan medoxomil (AM) and angiotensin converting enzyme inhibitor (ACEI) fosinopril in patients with concomitant arterial hypertension (AH) and chronic obstructive pulmonary disease (COPD). We included in this open study 49 patients with concomitant stage I-II AH and COPD. Initially all patients received hydrochlorothiazide (12.5 mg/day) and various ACEI but target blood pressure levels were not achieved, and these ACEI were withdrawn. By method of closed envelopes, the patients were divided into 2 groups. Patients of group 1 were given ARB АМ, of group 2 - ACEI fosinopril. Methods of investigation were repetitive 24‑hour ambulatory blood pressure monitoring (ABPM), spirometry, measurement of mean pulmonary artery pressure (mPAP), study of endothelial function by instrumental and laboratory methods. After 4 weeks of treatment with AM target BP level (.

ACE inhibitor effects of brachial artery structure and function in patients with arterial hypertension

Aim. To investigate the effects of an angiotensin-converting enzyme (ACE) inhibitor fosinopril on the structural and functional parameters of brachial arteries (BA) in patients with essential arterial hypertension (EAH). Material and methods. The study included 32 EAH patients: 15 men and 17 women aged 27-59 years (mean age 45,6±11,7 years). BA ultrasound and echocardiography (EchoCG) were performed with the use of the Vivid 7 Dimension device (USA). The following parameters of BA remodelling were analysed: intima-media thickness (IMT), lumen diameter (D), and wall-to-lumen (W/L) ratio. BA endotheliumdependent vasodilatation (EDVD) was assessed in the reactive hyperemia test. Central hemodynamic parameters were also assessed. Results. In EAH patients, the six-month fosinopril treatment was associated with BA IMT reduction, but not with substantial intraluminal diameter changes, or increased endothelium-dependent vasodilatation. Conclusion. Among EAH patients, an ACE inhibitor fosinopril demonstrated a marked improvement in BA structural and functional parameters.

Abstract 5963: Prevention of Tilt-Table Induced Vasovagal Response by Angiotensin-Converting Enzyme Inhibition

The use of various pharmacologic agents has been proposed for the preventive treatment of vasovagal syncopal episodes, with conflicting efficacy results from various studies. Angiotensin-converting enzyme inhibitors (ACEIs), although reported in small studies to have a beneficial effect in patients with vasovagal syncope, have not been generally accepted as part of conventional treatment in such patients. Our population consisted of 125 consecutive patients (60 male, mean age 40±15 years), with a positive head-up tilt-table testing (HUTTT) (cardioinhibitory or vasodepressive or mixed response), who were randomized to receive either the ACEI fosinopril (N=63), at a dose of 10 mg qd, or placebo (N=62), for 30 days. They were then submitted to a new HUTTT (80 degrees, before and after infusion of isoproterenol, at a max. rate of 5 mcg/min). Before randomization, the patients were stratified according to the use of other vasoactive agents. Physicians performing the HUTTT were blinded as to each patient’s randomization group. Twenty-eight (44%) of fosinopril-treated patients were positive in the second HUTTT versus 52 (84%) in the placebo group (p=0.015). In a multivariate analysis, entering, apart from the treatment group, patient age, gender, smoking habit, hypertension, the use of beta-blocking agents and various demographic factors, with a negative result in the second HUTTT as the dependent variable, female gender, younger age and the use of fosinopril were independently associated with a negative repeat HUTTT. The present study reports a potential preventive effect of ACEIs in vasovagal syncope and indicates that younger, female patients, taking fosinopril were more likely to have a negative repeat HUTTT. The observed effect may be related to the ability of ACEIs to reduce cardiac wall tension, thus decreasing the activation of C-mechanoreceptors, as well as to their potential to inhibit angiotensin-related catecholamine release.

Effects of Blocking the Renin-Angiotensin System on Expression and Translocation of Protein Kinase C Isoforms in the Kidney of Diabetic Rats

Background: High glucose and angiotensin II (Ang II) can activate protein kinase C (PKC) in diabetes mellitus. However, it is not clear which isoform of PKC is activated by glucose or Ang II. Our study focused on the effects of angiotensin blockade, using the angiotensin-converting enzyme inhibitor fosinopril, the Ang II receptor blocker irbesartan and their combination, on the expression and translocation of PKC isoforms α and βII in the renal cortex and medulla in diabetes. Methods: Hyperglycemia was induced with streptozotocin and diabetic rats were randomized to 4 groups: diabetic control, irbesartan group (40 mg/kg daily), fosinopril group (40 mg/kg daily) and combination group (irbesartan plus fosinopril, 20 mg/kg daily, respectively); age-matched normal rats served as normal control. After 4 weeks, expression and translocation of PKC-α and -βII in the renal cortex and medulla were assessed by immunohistochemistry and Western immunoblotting. Results: The expression of PKC-α in the membrane and cytosol fractions from the renal cortex was significantly higher in diabetic rats (276.83 ± 32.44% in membrane, 149.04 ± 23.42% in cytosol) than that in normal ones. The expression of PKC-βII in the renal cortex of diabetic rats decreased significantly in the membrane (50.00 ± 11.68%, p < 0.05) and remained unchanged in the cytosol (94.51 ± 11.69%, p > 0.05) compared with normal controls. Treatment with irbesartan, fosinopril and their combination partially corrected the abnormalities mentioned above. For the expression of PKC-α and -βII in the medulla, no difference was detected among the 5 groups. Conclusion: The renin-angiotensin system was implicated in the pathogenesis of diabetic nephropathy by regulating the activation of PKC isoforms.

Treating Microalbuminuria-Cosmetic Exercises with Urine Chemistry or Effective Reduction of Clinical Events?: Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects with Microalbuminuria. Circulation 110: 2809-2816, 2004.

Treating Microalbuminuria-Cosmetic Exercises with Urine Chemistry or Effective Reduction of Clinical Events?: Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects with Microalbuminuria. Circulation 110: 2809-2816, 2004.

Cardiorenal Protective Effects of Vasopeptidase Inhibition with Omapatrilat in Hypertensive Transgenic (mREN‐2)27 Rats

Vasopeptidase inhibitors simultaneously inhibit both angiotensin‐converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren‐2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren‐2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren‐2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 ± 3 mmHg; fosinopril 10 mg/kg/day, 130 ± 4 mmHg; omapatrilat 10 mg/kg/day, 110 ± 3 mmHg; omapatrilat 40 mg/kg/day, 91 ± 3 mmHg). Omapatrilat dose‐dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren‐2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension.

Effect of dual angiotensin converting enzyme/neutral endopeptidase inhibition, angiotensin converting enzyme inhibition, or AT 1 antagonism on coronary microvasculature in spontaneously hypertensive rats

Microvascular remodeling contributes to increased cardiovascular risk in hypertension. The dual angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitor omapatrilat improves small artery remodeling in hypertension. The aim of the present study was to compare effects of omapatrilat to the ACE inhibitor fosinopril and the AT 1 antagonist irbesartan on the coronary microvasculature in spontaneously hypertensive rats (SHR). Ten-week-old SHR were treated for 10 weeks with omapatrilat (20 or 40 mg/kg/d), irbesartan (50 mg/kg/d), or fosinopril (20 mg/kg/d). Arterioles and capillaries were identified in the myocardium by immunolabeling. After 10 weeks, systolic blood pressure (BP) was significantly reduced in treated versus untreated SHR ( P < .01). Myocardial arteriolar density/mm 2 was higher ( P < .05) in untreated SHR versus Wistar-Kyoto (WKY), and was reduced by omapatrilat (at both high and low doses) and by fosinopril ( P < .01). Irbesartan decreased only subepicardial arteriolar density ( P < .05). Myocardial capillary density/mm 2 was decreased in untreated SHR versus WKY ( P < .01), associated with increase in cardiomyocyte cross-sectional area and cardiomyocyte-to-capillary ratio, and a decrease in myocyte density. Omapatrilat (at both high and low doses) resulted in increased capillary density, decreased myocyte hypertrophy and cardiomyocyte to capillary ratio, and increased myocyte density ( P < .01). Fosinopril and irbesartan reduced myocyte hypertrophy of SHR, but had no effect on capillary density. Dual ACE/NEP inhibition was more effective than ACE inhibition or AT 1 antagonism in improving microvascular and cardiomyocyte remodeling in the hypertensive heart. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

Short-term effect of fosinopril on left ventricular hypertrophy and diastolic function in patients with essential hypertension

to assess the effect of angiotensin-converting enzyme inhibitor fosinopril (FOS) on left ventricular (LV) diastolic function and LV mass in essential hypertension (EH) patients. 22 patients with EH (aged 44±9years) were treated 10 or 20 mg FOS daily for 8 weeks. The patients were examined by M-mode and Doppler echocardiography. LV mass index (LVMI), intraventicular septal thickness and posterior wall thickness in diastole, relative wall thickness (RWT), ejection fraction (EF), early filling velocity (E), late filling velocity (A), E/A ratio, time velocity integral of early filling (VTI E), time velocity integral of late filling, isovolumic relaxation time (IVRT), deceleration time were determined. Blood pressure (BP) was measured by 24-hour ambulatory monitoring. FOS 8-week treatment resulted in a significant fall of average 24-hour BP, average daytime BP, average nighttime BP. LVMI decreased from 129,9±10,5 to 113,9±7,5 g/m2 (p<0,05), RWT - from 0,40±0,01 to 0,36±0,01 (p<0,05). This reduction was associated with significant decreases in LV septal wall thickness (from 1,15±0,07 to 1,05±0,04 cm, p<0,05) without negative changes in LV systolic function (EF increased from 61,0±2,0 to 67,9±1,5 %, p<0,05). It was founded a modest relationship between reductions in BP and a decrease in LVMI. During treatment LV diastolic filling and relaxation were improved in EH patients with E/A<1: E (from 0,61±0,05 to 0,67±0,06 m/s, p<0,05), VTI E (from 0,087±0,01 to 0,099±0,01 m, p<0,05), E/A (from 0,92±0,1 to 1,05±0,1, p<0,05) and IVRT (from 100,0±4,2 to 94,2±3,9 ms, p<0,05). In spite of short period of treatment, FOS influence on LV mass and diastolic function in EH patients. These findings support the concept that nonhemodynamic mechanisms also participate in short-term therapeutic changes.

Pharmacodynamic effects of dual neutral endopeptidase–angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans

There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans. In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h). In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

Reversal of peripheral microvascular dysfunction during long-term treatment with the angiotensin converting enzyme inhibitor fosinopril in congestive heart failure

Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF) improves cardiac and peripheral hemodynamic function and exercise performance. However, studies on the effects of long-term treatment with an ACE inhibitor on the neurogenic and nonneurogenic regulation and structural microangiopathy of the peripheral microvasculature in CHF are lacking. Methods and Results: We investigated the effect of 12 weeks of treatment with the ACE inhibitor fosinopril on peripheral microvascular function in a double-blind, placebo-controlled study of 12 patients treated with fosinopril and 10 patients treated with placebo. All had moderate CHF. Microvascular blood flow and resistance were calculated after application of the local isotope washout method in relaxed and nonrelaxed calf vascular beds in the supine position and during head-up tilt. Skeletal muscle vascular resistance was reduced in the fosinopril group (46 ± 6 to 30 ± 1 mm Hg · mL −1 · 100 g · min ± standard error; P < .05) and differed compared with the effect of placebo ( P < .05) where no change was seen (37 ± 11 to 55 ± 13 mm Hg · mL −1 · 100 g · min; not significant [NS]). Also, skin minimal vascular resistance was reduced during fosinopril treatment (13 ± 0.6 to 11 ± 0.7 mm Hg · mL −1 · 100 g · min; ( P < .05) and differed compared with the effect of placebo ( P < .05) with absence of change (12 ± 1.6 to 14 ± 1.4 mm Hg · mL −1 · 100 g · min; NS). Conclusions: These results suggest that long-term ACE inhibitor treatment with fosinopril in patients with CHF improves hemodynamic status to as far as the peripheral microvascular level in both the relaxed and nonrelaxed microcirculation of the lower leg.

Pharmacokinetics of Fosinopril and Hydrochlorothiazide in Healthy Elderly and Young Men

Objective: This study evaluated the effect of advanced age on the single-dose and steady-state pharmacokinetics of the angiotensin converting enzyme inhibitor fosinopril along with the diuretic hydrochlorothiazide. Design and Setting: Open-label, multiple-dose study in a hospital-based clinical study unit. Study Participants: Twelve young (21 to 30 years) and 12 elderly (66 to 75 years) healthy men. Interventions: Participants received a combination tablet of fosinopril 20mg and hydrochlorothiazide (HCTZ) 12.5mg as a single daily dose for a total of 6 doses. Drug concentrations were measured on days 1 and 7 by radioimmunoassay (fosinoprilat, the active diacid) and by HPLC (HCTZ) for calculation of first-dose and steady-state pharmacokinetic parameters. Results: Fosinoprilat steady-state maximum serum concentration (Cmax) was somewhat higher in the elderly, but area under the serum concentration-time curve (AUC) and other pharmacokinetic parameters were similar in the young and elderly adults. As expected with age-related diminished renal function, HCTZ clearance was lower in the elderly, while its cumulative urinary excretion was similar in the two groups. Conclusion: Advanced age is not accompanied by a clinically meaningful change in the pharmacokinetic profiles of fosinopril and HCTZ and does not warrant dose adjustment based on advanced age alone. The favourable pharmacokinetic feature of fosinopril of having dual (renal and hepatic) and compensatory elimination pathways is preserved in the elderly during combination therapy with HCTZ.

Combination of fosinopril and pravastatin decreases platelet response to thrombin receptor agonist in monkeys.

Both angiotensin-converting enzyme (ACE) inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to decrease cardiovascular morbidity and mortality. Results from clinical trials have suggested that HMG-CoA reductase inhibition might exert a beneficial effect independent of its lipid-lowering effect, and ACE inhibition may exert a benefit independent of blood-pressure lowering. To test the hypothesis that such an effect might be mediated by alteration in platelet reactivity, we studied 55 monkeys receiving both, 1, or neither of the ACE inhibitor fosinopril and the HMG-CoA reductase inhibitor pravastatin. Platelet responsiveness to collagen and to the thrombin receptor agonist (TRA) SFLRRN-NH2 was determined by aggregometry. For each agonist, the maximum rate and extent of aggregation were measured for each dose, and the concentration required for half-maximal response (C50) was determined. Each drug, when given alone, slightly decreased the dose of agonist required to produce 50% response in the rate and extent of platelet aggregation relative to control. The combination of the 2 drugs, however, produced a significant increase in the dose of TRA required to produce 50% response in the rate and extent of aggregation relative to either drug alone or the control group. This was not true for collagen. The magnitude of the change relative to the control group, 47% for rate and 30% for extent of aggregation, could confer considerable protection by changing the threshold for thrombin-induced platelet aggregation and, thus, decrease thrombosis.

Relationships Among Diabetes, Microalbuminuria, and ACE Inhibition

Increasing worldwide rates of diabetes mellitus, combined with the significant micro- and macrovascular complications that accompany the disease, point to a heightened need to develop simple, rational strategies to protect against end-organ damage, particularly diabetic nephropathy. Although simple strategies do exist, i.e., early diagnosis of microalbuminuria (MAU) followed by nephroprotective therapy with angiotensin-converting enzyme (ACE) inhibitors, the use of these techniques should be increased. This is especially true for primary care physicians, who will continue to handle the majority of diabetic patients. To combat the underuse of this dual approach, this article reviews a stepwise approach to identifying early MAU so that therapeutic measures can be undertaken before the disorder progresses to diabetic nephropathy and, consequently, to end-stage renal disease in the majority of patients. Once a diagnosis of MAU is made, a variety of trials have demonstrated that ACE inhibitor therapy should be considered the standard therapy to retard worsening albuminuria and subsequent renal disease. ACE inhibitors can retard the progression of microalbuminuria and can lower the percentage of patients who progress to end-stage renal disease and death. Significant data indicate that ACE inhibitors should be used in MAU diabetics regardless of the level of blood pressure. In particular, the ACE inhibitor fosinopril may offer advantages because of its dual route of elimination, thus simplifying dosing in renally impaired patients. The newly developed angiotensin II receptor antagonists should be considered in patients intolerant to ACE inhibitors because of the similar effect on the interruption of the renin-angiotensin system.

Relationships among diabetes, microalbuminuria, and ACE inhibition.

Increasing worldwide rates of diabetes mellitus, combined with the significant micro- and macrovascular complications that accompany the disease, point to a heightened need to develop simple, rational strategies to protect against end-organ damage, particularly diabetic nephropathy. Although simple strategies do exist, i.e., early diagnosis of microalbuminuria (MAU) followed by nephroprotective therapy with angiotensin-converting enzyme (ACE) inhibitors, the use of these techniques should be increased. This is especially true for primary care physicians, who will continue to handle the majority of diabetic patients. To combat the underuse of this dual approach, this article reviews a stepwise approach to identifying early MAU so that therapeutic measures can be undertaken before the disorder progresses to diabetic nephropathy and, consequently, to end-stage renal disease in the majority of patients. Once a diagnosis of MAU is made, a variety of trials have demonstrated that ACE inhibitor therapy should be considered the standard therapy to retard worsening albuminuria and subsequent renal disease. ACE inhibitors can retard the progression of microalbuminuria and can lower the percentage of patients who progress to end-stage renal disease and death. Significant data indicate that ACE inhibitors should be used in MAU diabetics regardless of the level of blood pressure. In particular, the ACE inhibitor fosinopril may offer advantages because of its dual route of elimination, thus simplifying dosing in renally impaired patients. The newly developed angiotensin II receptor antagonists should be considered in patients intolerant to ACE inhibitors because of the similar effect on the interruption of the renin-angiotensin system.

Regulation of aortic wall structure by the renin-angiotensin system in Wistar rats.

The effects of long-term angiotensin-converting enzyme (ACE) inhibition, angiotensin II (AT1)-receptor blockade, calcium-entry blockade, or cyclosporin A treatment on rat aortic wall structure were investigated to determine the role of the renin-angiotensin system in the physiologic regulation of vascular structure in vivo. Groups of 15 Wistar rats were treated for 6 weeks either with the ACE inhibitors lisinopril or fosinopril or with the AT1-antagonists D 8731 or losartan (each 10 mg/kg/day) or with the calcium antagonist isradipine, 60 mg/kg/day, or cyclosporin A, 15 mg/kg/day, or a combination of cyclosporin with one of the vasodilators. Media thickness, vascular smooth-muscle cell density, and intima thickening were measured in histologic sections of the abdominal aorta. In addition, aortic contractility and heart weight were determined. Long-term ACE inhibition, AT1-receptor blockade, and calcium-entry blockade reduced aortic media thickness and increased media smooth-muscle cell density. Only ACE inhibition significantly reduced the extent of intima lesions. Media thickness correlated well with the maximal aortic contraction to phenylephrine and serotonin but not to angiotensin II. ACE inhibition and AT1-receptor blockade decreased heart weight, whereas calcium antagonism increased it. Cyclosporin treatment was without effect on any of these parameters. The data demonstrate a significant long-term influence of the renin-angiotensin system on aortic wall structure and function in Wistar rats.

An Effective Approach for Treating Elderly Patients With Isolated Systolic Hypertension: Results of an Italian Multicenter Study With Fosinopril

Cardiovascular diseases are the most common causes of mortality, and hypertension is the most common cardiovascular disease in all ages. The Systolic Hypertension in the Elderly Program (SHEP) trial has shown that the pharmacologic reduction of isolated systolic hypertension can significantly reduce the incidence of cardiovascular complications.The aim of the Italian multicenter study reported here is to compare the efficacy, safety, and tolerability of fosinopril, a novel angiotensin converting enzyme (ACE) inhibitor with a dual route of excretion, with chlorthalidone, the diuretic administered in the SHEP study, in 312 elderly patients with isolated systolic hypertension.Our results show that fosinopril and chlorthalidone produce identical and statistically significant reductions in systolic blood pressure (−23.9 ± 11.6 mm Hg and −23.7 ± 10.9 mm Hg, respectively) and, to a lesser extent, in diastolic blood pressure (−7.1 ± 3.1 mm Hg and −5.2 ± 2.3 mm Hg, respectively). Only chlorthalidone caused a statistically significant change in uric acid, total cholesterol, blood urea, and serum potassium concentrations. Fosinopril was also somewhat better tolerated than chlorthalidone.In conclusion, the novel ACE inhibitor fosinopril is an effective and well-tolerated antihypertensive agent for use in elderly patients with isolated systolic hypertension and appears to be a suitable alternative for the treatment of isolated systolic hypertension.

Prolonged effects of short-term fosinopril on blood pressure and vascular morphology and function in rats.

The aim of this study was to evaluate the delayed effects of an angiotensin converting enzyme (ACE) inhibitor on blood pressure and on structural and functional alterations in mesenteric small resistance arteries of spontaneously hypertensive rats (SHR). The ACE inhibitor fosinopril (25 mg/kg/day) was administered according to three different schedules: in one group of SHR from 4 to 8 weeks of age (n = 12), in a second group from 8 to 12 weeks of age (n = 15), and in a third group from 4 to 12 weeks of age (n = 12). Eighteen untreated SHR and 18 untreated Wistar-Kyoto rats served as controls. About half the animals in each group were killed at 13 weeks of age, and the remaining were killed at 38 weeks of age. After death, relative left ventricular mass (left ventricular weight/body weight) was calculated. Vascular morphology (media:lumen ratio) and function (responses to norepinephrine and acetylcholine) in mesenteric small resistance arteries were then assessed using a micromyographic technique. Short-term fosinopril, given either before or after the development of hypertension, persistently reduced (but did not normalize) systolic blood pressure, vascular structural alterations, and reactivity to norepinephrine in mesenteric resistance arteries in SHR. These favorable effects were maintained at least for 26 to 30 weeks after treatment withdrawal. The endothelium-dependent vasodilator response to acetylcholine was improved at 13 but not at 38 weeks of age, in treated SHR. Therefore, the vascular response to norepinephrine seems to be dependent mainly on the structure of the vessels, whereas endothelial function is probably more linked to the hemodynamic load.