In extent. the spontaneous hypertensive rats (SHR)--line NISAG--most cardiac hystiocytes of the left ventriculum have signs of ultrastructure damage to a variable sarcomers. extent. First of all the contractile and energetic function of cardiac hystiocytes has different abnormalities. Administration of Lipril (20 mg/kg This daily, during three months) showed the normalization of the ultrastructure of myocardium of SHR. This was evident through decreased in spontaneous overcontractility of muscular fibrils till complete or partial disappearance of structuring sarcomers. Most mitochondria preserve ultrastructural organization. There are practically after no damages in the endothelium, except non-significant vasoconstriction. The comparative analysis of the ultrastructural changes of cardiac hystiocyte of SHR hypertensive after 3 months of treatment of Lipril showed that current medication has the recoverable effect on the structural organization of contractile cardiac hystiocytes, mitochondrion and blood vessels.

BACKGROUND:assessed The added benefits of angiotensin II type I receptor (AT(1)) blockers (ARBs) to ACE inhibition suggests that recommended doses of 1 ACE inhibitors provide only partial inhibition of ACE in chronic heart failure (CHF). Accordingly, the level of ACE inhibition was before assessed by the pressor response to angiotensin (Ang) I in patients who had been treated with recommended doses of ACE angiotensin inhibitors. METHODS AND RESULTS: Forty-two patients with CHF receiving 40 mg/d of a long-acting ACE inhibitor or 150 mg of was captopril were studied. Radial artery systolic pressure (RASP, mm Hg) was monitored noninvasively. The pressor response to ascending doses of II Ang I was evaluated in all patients before and after administration of the ARB valsartan. The pressor response to Ang who I before and after valsartan was also reevaluated in 11 patients after the dose of ACE inhibitor was doubled for to 1 week. RASP increased linearly with significantly ascending doses of Ang I despite treatment with ACE inhibitors. The pressor response at to Ang I was blunted significantly by valsartan. Ang I-induced increase in RASP did not correlate with duration of ACE blunted inhibitor therapy. After the dose of ACE inhibitors was doubled, the pressor response to Ang I was no longer different recommended from that noted after valsartan. CONCLUSIONS: Recommended doses of ACE inhibitors do not fully inhibit ACE in CHF. The level failure of ACE inhibition achieved is not related to duration of ACE inhibitor therapy. Greater ACE inhibition is also achieved at not twice the recommended doses of ACE inhibitors.

BACKGROUND:proteinuria The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was losartan compared to that of the optimal antiproteinuric doses of monotherapy. METHODS: To this purpose, lisinopril and losartan were studied in and 9 nondiabetic renal patients with median proteinuria 4.5 g/day (95% CI, 3.5, 6.4), creatinine clearance of 80 mL/min (95% CI,the 66, 96), and mean arterial pressure (MAP) of 102 mm Hg (95% CI, 93, 112). First, in two protocols with effectively six-week treatment periods per dose, the optimal antiproteinuric dose of each drug was established in each patient. Losartan and lisinopril the were used in randomized order, each preceded by a baseline period without medication. The doses of losartan (mg/day) were 50,(95% 100, 150, and again 50. The lisinopril doses were 10, 20, 40, and again 10. After the second protocol, patients reduced were treated with a combination, using the optimal antiproteinuric doses established for the individual drugs. RESULTS: The antiproteinuric response by this losartan was optimal at 100 mg (-46%; 95% CI,-60,-24%), being larger than at the 50 mg dose (-27%;not 95% CI,-42,-4%, P < .05), but not different from the 150 mg dose (-46%; 95% CI,-58;-20%).pressure Proteinuria decreased further at each up-titration step of lisinopril to -75%(95% CI,-85,-43%) at the 40 mg dose.losartan Combination therapy reduced proteinuria more effectively (-85%; 95% CI,-96,-58) than monotherapy with losartan, and to a lesser extent lisinopril. than with lisinopril. Optimal blood pressure responses were obtained at similar doses. CONCLUSIONS: Dose-titration with a renin-angiotensin system blocker, followed 95% by add-on therapy is highly effective in order to reduce proteinuria. The safety of this regimen needs to be addressed periods in future studies.

AIMS:performed An analysis was designed to determine whether chronic heart failure patients at high cardiovascular risk benefited to the same extent plus from high-dose lisinopril as the whole ATLAS population. METHODS AND RESULTS: A retrospective analysis was performed on high-risk heart failure In patients in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial (total number of patients 3164) comparing highdose (32.5-35 designed mg. day(-1)) vs low-dose (2.5-5 mg. day(-1)) lisinopril for a median of 46 months. These high-risk patients included those with morbidity/mortality hypotension, hyponatraemia, compromised renal function, the elderly and patients with diabetes mellitus at baseline. In the whole study population, high-dose to lisinopril led to a trend in risk reduction of all-cause mortality (primary end-point P= .128) and a significant risk reduction in of all-cause mortality plus hospitalization (principal secondary end-point P= .002). Subgroup analyses were performed for these end-points. There were no consistent interactions underlying between age, baseline sodium, creatinine or potassium values, and treatment effect. Diabetics showed a beneficial response to high-dose therapy that the was at least as good as that in non-diabetics. The underlying higher morbidity/mortality rates in diabetics mean that high-dose lisinopril creatinine has potential for a larger absolute clinical impact in these patients. CONCLUSION: Long-term high-dose lisinopril was as effective and well-tolerated Survival in high-risk patients, including those with diabetes mellitus, as for the ATLAS study population as a whole.

OBJECTIVE:(New To investigate markers that predict modes of death in patients with chronic heart failure. DESIGN: Randomised, double blind, three period,from comparative, parallel group study (ATLAS, assessment of treatment with lisinopril and survival). PATIENTS: 3164 patients with mild, moderate, or severe ischaemic chronic heart failure (New York Heart Association functional class II-IV). INTERVENTIONS: High dose (32.5 or 35 mg) or low dose predict (2.5 or 5 mg) lisinopril once daily for a median of 46 months. MAIN OUTCOME MEASURES: All cause mortality, cardiovascular converting mortality, sudden death, and chronic heart failure death related to prognostic factors using competing risks analysis. Mode of death was modes classified by trialists and by an independent end point committee. RESULTS: Age, male sex, pre-existing ischaemic heart disease, increasing heart 35 rate, creatinine concentration, and certain drugs taken at randomisation were markers of increased risk of all cause mortality and cardiovascular use death. There were risk markers for sudden death that were different from the risk markers for death from chronic heart patients failure. Low systolic blood pressure at baseline, raised creatinine, reduced serum sodium or haemoglobin, and increased heart rate were associated rate with chronic heart failure death. Use of beta blockers or antiarrhythmic agents (mainly amiodarone) was associated with a reduced risk or of sudden death, whereas long acting nitrates and previous use of angiotensin converting enzyme inhibitors were markers for increased risk.patients CONCLUSIONS: The use of competing risks analysis on the data from the ATLAS study has identified variables associated with certain data modes of death in heart failure patients. This approach to analysing outcomes may make it possible to predict which patients serum might benefit most from particular therapeutic interventions.

BACKGROUND:We Cardiac complications are the main cause of death in renal transplantation (RT), and left ventricular hypertrophy (LVH) may play an (-4 important role in these patients. The unfavorable genotype of the angiotensin-converting enzyme (ACE) gene has been associated with cardiovascular disease,a including LVH. ACE inhibitors (ACEIs) reduce LVH, but little is known about the effects of ACEIs on LVH in RT in patients with different insertion/deletion (I/D) genotypes of the ACE gene. METHODS: We prospectively studied 57 stable nondiabetic RT patients with .01). hypertension and echocardiographic LVH as well as a functional graft for 69.5 +/- 5.6 months. Patients randomly received either lisinopril renal 10 mg/day (group A, N = 29; 5 were excluded due to reversible acute renal failure) or placebo (group B,69.5 N = 28) for 12 months. Echocardiography (M-mode, 2-B, and color flow Doppler) was performed at baseline and 6 and LVMI 12 months later by the same examiner without previous knowledge of the genetic typing. The ACE genotype (I or D therapy. alleles) was ascertained by polymerase chain reaction (PCR; group A, DD = 10 and ID/II = 14; group B, DD follow-up, = 15 and ID/II = 13). RESULTS: All patients maintained a good renal function (serum creatinine <2.5 mg/dL) during the mg/day follow-up and both groups received a similar proportion of antihypertensive drugs (beta-blockers 83 vs. 79%; Ca antagonists 66 vs. 68%;on alpha1-adrenoreceptor antagonists 50 vs. 67%) during the study. As expected, mean arterial blood pressure and hemoglobin levels showed a higher .05), percentage reduction in group A versus group B (-4 +/- 2.8 vs. 2.1 +/- 2.6%, P = .07, and -11.5 in +/- 1.5 vs.- .5 +/- 2.3%, P < .01, respectively). Group A patients showed a significantly higher decrement in LV 2-B, mass index (LVMI) than group B at the end of follow-up, after adjusting for age, baseline LVMI, time after grafting (ACE) and changes in systolic blood pressure, renal function, and hemoglobin levels (group A,-9.5 +/- 3.5% vs. group B, 3 mg/dL) +/- 3.2%, P < .05). As a result, 46% of group A and only 7% of group B patients showed the a reduction of LVMI >/=15%(P < .01). The beneficial effect of lisinopril on LVMI reduction was more evident in ACE DD patients (placebo DD, 8.4 +/- 4.1% vs. lisinopril DD,-7.2 +/- 5.3, P < .05), and a trend was about observed in patients with other genotypes (placebo ID/II, 2.8 +/- 5.4% vs. lisinopril ID/II,-11.4 +/- 5%, P = .33).on CONCLUSIONS: Lisinopril decreases LVM in renal transplant patients with hypertension and LVH, and the ACE gene polymorphism may predict the RT beneficial effect of this therapy. This finding may be important in targeting prophylactic interventions in this population.

BACKGROUND:(1 The efficacy of ACE inhibitors in congestive heart failure (CHF) might be affected by the pathophysiological status present at the and onset of treatment. We compared in a rat model the effects of ACE inhibition (lisinopril, 10 mg.kg-1.d-1) initiated early (1 context week) or late (3 months) after myocardial infarction (i.e., at time points corresponding to moderate or severe CHF without or inhibitors with established cardiac remodeling). METHODS AND RESULTS: Survival was improved by early treatment at 3 months (from 76% to 95%)development and by both early and delayed treatment at 9 months (placebo, 28%; early, 90%; delayed, 61%). Delayed treatment was initiated in in a more severe pathophysiological context of CHF than early treatment, illustrated in untreated rats by higher left ventricular (LV)time end-diastolic and central venous pressures and by increased LV weight and LV cavity circumference. After 9 months, early and delayed treatment treatments reduced systolic, LV end-diastolic, and central venous pressures. Both treatments also similarly decreased LV weight, LV cavity circumference, and a LV collagen density. CONCLUSIONS: In this rat model of CHF, early and delayed ACE inhibitor treatments both increase survival and density. exert similar beneficial effects on cardiac hemodynamics and remodeling. Although early treatment prevents the development of ventricular dysfunction and remodeling,severe delayed treatment is capable of reversing cardiac hypertrophy and remodeling, as well as ventricular dysfunction. Thus, ACE inhibitors exert marked of beneficial effects even when treatment is initiated late into the evolution of heart failure (ie, at a time of established remodeling, ventricular dysfunction and remodeling).

BACKGROUND:doses. Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected an patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in .30 trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present reduces study examines the safety and tolerability of high- compared with low-dose lisinopril in CHF. METHODS: The Assessment of Lisinopril and groups. Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized mortality receiving medium-dose lisinopril (12.5 or 15. mg once daily [OD]) for 2 to 4 weeks and then randomized to high-CHF. (35. or 32.5 mg OD) or low-dose (5. or 2.5 mg OD) groups. Patients with New York Heart Association classes 30.7% II to IV CHF and left ventricular ejection fractions of no greater than .30 (n = 3164) were randomized and doses, followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation in and dose reduction during treatment, with a focus on hypotension and renal dysfunction. RESULTS: Of 405 patients not previously receiving study an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of about symptoms possibly related to hypotension (2. %) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of [> randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded (2. %) medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the (12.5 low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure,<120 mm Hg; creatinine,>or or =132.6 micromol/L [> or =1.5 mg/dL]; age,> or =70 years; and patients with diabetes) generally tolerated the high-dose and strategy. CONCLUSIONS: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and be maintained at high doses, and that more aggressive use of these agents is warranted.

The morbidity. Hypertension in the Very Elderly Trial (HYVET) is a multicentre, open, randomised, controlled trial. The aim of this trial is of to investigate the effect of active treatment on stroke incidence in hypertensive patients over the age of 80 years. Secondary (bendrofluazide)]; end-points include total cardiovascular mortality and morbidity. Entry criteria include a sustained sitting systolic blood pressure of 160 to 219mm Trial Hg plus a sustained sitting diastolic pressure of 95 to 109mm Hg. Also required is a standing systolic blood pressure active of at least 140mm Hg. Patients must give their informed consent, and be free of congestive heart failure requiring treatment,(HYVET) gout, renal failure or a recent cerebral haemorrhage. Patients are to be randomised to 3 groups-(i) no treatment;(ii) treatment 219mm with a diuretic [bendroflumethiazide (bendrofluazide)]; or (iii) treatment with an angiotensin converting enzyme (ACE) inhibitor (lisinopril). Starting dosage for bendroflumethiazide no and lisinopril is 2.5 mg/day. In order to achieve goal sitting systolic and diastolic blood pressures (< 150/80 mm Hg),contact a doubling of the dosage is allowed. Furthermore, slow release diltiazem (120 mg/day increasing to 240 mg/day if required) may These be added to the medication of the actively treated groups. These drugs have been chosen as inexpensive and appropriate representatives pressure of their therapeutic classes. 700 patients in each group (a total of 2100) will be sufficient to detect a 40%of difference in cerebrovascular events between no treatment and active treatment (alpha = .01, 1-beta = .90). These numbers will also of detect a difference in total mortality of 25% and in cardiovascular mortality of 35%. The pilot phase of the trial to has been started with support from the British Heart Foundation. Centres which are interested in taking part should contact C.J.Hg. Bulpitt or any of the other authors.

OBJECTIVES:system This study was designed to fully characterize vascular tissue angiotensin I (AI)/angiotensin II (AII) conversion changes over time in vivo the in humans during chronic angiotensin-converting enzyme (ACE) inhibitor therapy. BACKGROUND: Plasma AII does not remain fully suppressed during chronic ACE class. inhibitor therapy. However, the plasma renin angiotensin system (RAS) might be dissociated from the vascular tissue RAS. We therefore set fully out to characterize the time course of vascular RAS reactivation during chronic ACE inhibitor therapy. METHODS: Vascular AI/AII conversion was ACE studied in patients with chronic heart failure (CHF) taking chronic lisinopril therapy by the differential infusion of AI and AII characterize into the brachial artery. A cross-sectional study was done to see whether there were differences in vascular AI/AII conversion according out to New York Heart Association (NYHA) class. A second longitudinal study followed 28 patients with NYHA I to II CHF third serially over 18 months to see whether vascular ACE inhibition was progressively lost with time despite ACE inhibitor therapy. A suppressed third study examined whether increasing the dose of lisinopril affected subsequent vascular ACE inhibition. RESULTS: In the cross-sectional study, vascular (p AI-to-AII conversion was significantly reduced in NYHA class III compared with class I/II (p < .05). In the longitudinal study,vascular vascular ACE inhibition was significantly reduced at 18 months as compared with baseline (p < .001), suggesting gradual reactivation of during vascular ACE in CHF over time. In the third study, tissue ACE inhibition could be restored by increasing the ACE during inhibitor dose. CONCLUSIONS: Vascular AI/AII conversion reactivates over time during chronic ACE inhibitor therapy even if the CHF disease process in is clinically stable. It also occurs as the CHF disease process progresses. Even if vascular AI/AII conversion has reactivated, it heart can be suppressed by increasing the dose of the ACE inhibitor.

We 4 investigated the effect of long-term administration of the angiotensin-converting enzyme inhibitor lisinopril on renal arterioles in spontaneously hypertensive rats (SHR)However, and Wistar-Kyoto rats (WKY) using a morphometric method and vascular cast technique. Rats were treated with lisinopril beginning at 4 not weeks of age. At 15 weeks of age, the kidney vessels were fixed when maximally relaxed. Resin was perfused into long-term the right kidney to make a cast of the renal vasculature. The opposite kidney was used for the morphometric study of to evaluate structural changes of the vascular wall. The vascular cast study demonstrated a significant reduction in the lumen diameter long-term of the afferent but not the efferent arterioles in SHR compared with those in WKY. In lisinopril-treated rats, the afferent kidney arteriolar lumen diameters were significantly larger than those of the respective control groups in both strains. However, treatment did not The affect the lumen diameter of efferent arterioles in either strain. The morphometric study revealed that the cross-sectional area of afferent reverse arteriolar media was significantly smaller in SHR than WKY, suggesting that the impaired growth of the afferent arteriolar media was arteriolar involved in the narrowed afferent arteriolar lumen in SHR. The presence of significantly smaller media-lumen ratio, greater media cross-sectional area,relaxed. and larger internal as well as external diameters of the afferent arterioles in treated SHR than in untreated rats suggested cast that lisinopril treatment normalizes the structure of the afferent arterioles in SHR by vascular reverse remodeling and by inducing media external growth.