Effects of lisinopril on experimental ischemia in rats. Influence of infarct size

OBJECTIVE - Angiotensin-converting enzyme inhibitors (ACEIs) have gained importance in preventing or attenuating the process of ventricular remodeling after myocardial infarction. The significance of infarct size in regard to the response to ACEIs, however, is controversial. This study aimed to analyze the effects of lisinopril on mortality rate, cardiac function, degree of cardiac hypertrophy and fibrosis in rats with different infarct sizes. METHODS - Lisinopril (20 mg/kg/day) dissolved in drinking water was administered to rats immediately after coronary artery occlusion. After being sacrificed, the infarcted animals were divided into two groups: one group of animals with small infarcts (< 40% of the left ventricle) and another group of animals with large infarcts (> 40% of the left ventricle). RESULTS - The mortality rate was 31.7% in treated rats and 47% in the untreated rats. There was no statistical difference between the groups with small and large infarcts in regard to myocardial concentration of hydroxyproline. In small infarcts, the treatment attenuated the heart dysfunction characterized by lower levels of blood pressure and lower values of the first derivative of pressure and of the negative derivative of pressure. The degree of hypertrophy was also attenuated in small infarcts. In regard to large infarcts, no differences between the groups were observed. CONCLUSION - Treatment with the ACEIs had no effect on mortality rate and on the amount of fibrosis. The protective effect of lisinopril on heart function and on the degree of hypertrophy could only be detected in small infarcts

Arterial-hypertension in the elderly

The authors review the epidemiology, the etiological factors, the effect of the treatment in the evolution of the cardiovascular disease in arterial hypertension in elderly, and the use of angiotensin-converting-enzyme inhibitors such as a treatment option.

ESTUDO COMPARATIVO DUPLO-CEGO DA EFICACIA E SEGURANCA DO CILAZAPRIL COMPARADAS A NIFEDIPINE 'RETARD' NO TRATAMENTO DA HIPERTENSAO ARTERIAL LEVE E MODERADA

Purpose: To evaluate the antihypertensive efficacy and safety of cilazapril compared to nifedipine retard in mild to moderate hypertension. Methods: Forty randomized out-patients with mild moderate hypertension, diastolic pressure (DP) between 95 and 115 mmg/Hg, with placebo for 15 days were randomized and allocated for treatment, double-blind, once daily with cilazapril 2.5 mg (n = 20) or nifedipine retard 20 mg (20 = n) for four weeks. The non-responders (DP > 90 mmHg) had the dosage increased twice, b.i.d., while responders were maintained up to 10 weeks. Clinical visits were performed before, at baseline and every two weeks and the laboratory test was performed after placebo run-in, 4th and 10th weeks of treatment. Results: The blood pressure (BP) were similar between groups at the end of the placebo (cilazapril 151 ± 14/103 ± 5 - nifedipine 157 ± 17/108 ± 7 mmHg, p > 0.05). DP decreased already at second weeks (cilazapril 95 ± 9 - nifedipine 96 ± 11 mmHg, p < 0.05, compared to week 0) in both groups at the end of study with no differences inter groups. BP normalization was obtained in 58% of the patients with cilazapril and in 61% in the nifedipine group. Adverse biochemical effects were not observed in any group. Six (16%) patients of the cilazapril and 15 (39%) of nifedipine related collateral events, although no difference were observed between groups. Conclusion: Cilazapril 2.5 to 5 mg normalized BP in 58% of mild and moderate hypertension patients, and this efficacy was similar to sustained-release nifedipine 20 to 40 mg. Cilazapril had no adverse effects on the biochemical parameters with low incidence of collateral effects.

Efeito do lisinopril sobre parametros cardiacos e mortalidade no infarto experimental em ratos

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Involvement of central cholinergic mechanisms on sodium intake induced by gabaergic activation of the lateral parabrachial nucleus

Bilateral injections of the GABAA agonist muscimol into the lateral parabrachial nucleus (LPBN) disrupt satiety and induce strong ingestion of water and 0.3M NaCl in fluid-replete rats by mechanisms not completely clear. In the present study, we investigated the effects of the blockade of central muscarinic cholinergic receptors with atropine injected intracerebroventricularly (i.c.v.) on 0.3M NaCl and water intake induced by muscimol injections into the LPBN in fluid-replete rats. Male Holtzman rats with stainless steel cannulas implanted bilaterally into the LPBN and unilaterally into the lateral ventricle (LV) were used. Bilateral injections of muscimol (0.5nmol/0.2μL) into the LPBN induced 0.3M NaCl (32.2±9.9mL/4h, vs. saline: 0.4±0.2mL/4h) and water intake (11.4±4.4mL/4h, vs. saline: 0.8±0.4mL/4h) in fluid-replete rats previously treated with i.c.v. injection of saline. The previous i.c.v. injection of atropine (20nmol/1μL) reduced the effects of LPBN-muscimol on 0.3M NaCl (13.5±5.0mL/4h) and water intake (2.9±1.6mL/4h). The i.c.v. injection of atropine did not affect 0.3M NaCl (26.8±6.2mL/2h, vs. saline i.c.v.: 36.5±9.8mL/2h) or water intake (14.4±2.5mL/2h, vs. saline i.c.v.: 15.6±4.8mL/2h) in rats treated with furosemide+captopril subcutaneously combined with bilateral injections of moxonidine (α2-adrenoceptor/imidazoline agonist, 0.5nmol/0.2μL) into the LPBN, suggesting that the effect of atropine was not due to non-specific inhibition of ingestive behaviors. The results show that active central cholinergic mechanisms are necessary for the hypertonic NaCl and water intake induced by the blockade of the inhibitory mechanisms with injections of muscimol into the LPBN in fluid-replete rats. The suggestion is that in fluid-replete rats the action of LPBN mechanisms inhibits facilitatory signals produced by the activity of central cholinergic mechanisms to maintain satiety. © 2012 Elsevier B.V.

Infarct Size as Predictor of Systolic Functional Recovery after Myocardial Infarction

Background: The effects of modern therapy on functional recovery after acute myocardial infarction (AMI) are unknown.Objectives: To evaluate the predictors of systolic functional recovery after anterior AMI in patients undergoing modern therapy (reperfusion, aggressive platelet antiaggregant therapy, angiotensin-converting enzyme inhibitors and beta-blockers).Methods: A total of 94 consecutive patients with AMI with ST-segment elevation were enrolled. Echocardiograms were performed during the in-hospital phase and after 6 months. Systolic dysfunction was defined as ejection fraction value < 50%.Results: In the initial echocardiogram, 64% of patients had systolic dysfunction. Patients with ventricular dysfunction had greater infarct size, assessed by the measurement of total and isoenzyme MB creatine kinase enzymes, than patients without dysfunction. Additionally, 24.5% of patients that initially had systolic dysfunction showed recovery within 6 months after AMI. Patients who recovered ventricular function had smaller infarct sizes, but larger values of ejection fraction and E-wave deceleration time than patients without recovery. At the multivariate analysis, it can be observed that infarct size was the only independent predictor of functional recovery after 6 months of AMI when adjusted for age, gender, ejection fraction and E-wave deceleration time.Conclusion: In spite of aggressive treatment, systolic ventricular dysfunction remains a frequent event after the anterior myocardial infarction. Additionally, 25% of patients show functional recovery. Finally, infarct size was the only significant predictor of functional recovery after six months of acute myocardial infarction.

Oral acetylsalicylic acid and prevalence of actinic keratosis

Objective: To investigate the influence of a regular oral use of acetylsalicylic acid in the prevalence of actinic keratosis.Methods: A case-control study with dermatologic outpatients above 50 years of age assessed between 2009 and 2011. Cases were defined as those who had been under regular use of oral acetylsalicylic acid for more than six consecutive months. The assessment focused on: age, sex, skin-type, tobacco smoking, use of medication, occurrence of individual or family skin cancer, and sunscreen and sun exposure habits. Actinic keratoses were counted in the medial region of the face and upper limbs. Counts were adjusted by co-variables based on a generalized linear model.Results: A total of 74 cases and 216 controls were assessed. The median time of acetylsalicylic acid use was 36 months. Cases differed from controls as to the highest age, highest prevalence of use of angiotensin-converting enzyme inhibitors and fewer keratosis on the face and on the upper limbs (p < 0.05). The multivariate model showed that the use of acetylsalicylic acid was associated to lower counts of face actinic keratosis and upper-limb erythematous actinic keratosis (p < 0.05), regardless of other risk factors.Conclusion: The regular use of oral acetylsalicylic acid for more than six months was associated to a lower prevalence of actinic keratosis, especially facial and erythematous ones.

Liquid nitrogen for the treatment of actinic keratosis: A longitudinal assessment

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

An update on the pharmacogenetics of treating hypertension

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Comprehensive Evaluation of the Effects of Enalapril on Matrix Metalloproteinases Levels in Hypertension

Angiotensin-converting enzyme inhibitors (ACEi) may downregulate matrix metalloproteinases (MMPs). We examined whether enalapril affects MMP-2, MMP-8, and MMP-9 levels and activity, and their endogenous inhibitors (tissue inhibitors of MMPs, TIMP-1 and TIMP-2) levels in hypertensive patients. Moreover, we assessed the effects of enalaprilat on MMP-9 and TIMP-1 secretion by human endothelial cells (HUVECs). Thirty-eight hypertensive patients received enalapril for 8 weeks and were compared with thirty-eight normotensive controls. Blood samples were collected at baseline and after treatment. Plasma ACE activity was determined by a fluorimetric assay. Plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA and gelatin zymography. A fluorogenic peptide cleavage assay was used to measure MMP activity. HUVECs cells were stimulated by phorbol-12-myristate-13-acetate (PMA) and the effects of enalaprilat (10(-10) to 10(-6) M) on MMP-9 and TIMP-1 levels were determined. Enalapril decreased blood pressure and ACE activity in hypertensive patients (P < 0.05), but had no effects on plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 levels, or MMP activity. Enalaprilat had no effects on PMA-induced increases in MMP-9 and TIMP-1 secretion by HUVECs or on MMP activity. We show consistent evidence, both in vivo and in vitro, that enalapril does not affect MMPs and TIMPs levels in hypertensive patients.

Diastolic function parameters are improved by the addition of simvastatin to enalapril-based treatment in hypertensive individuals

Objective: Diastolic dysfunction (DD) is a frequent condition in hypertensive patients whose presence increases mortality and whose treatment remains unclear. The aim of this study was to investigate in a prospective, double-blinded, placebo-controlled randomized design the additive effect of simvastatin on DD in enalapril-treated hypertensive patients with average cholesterol levels. Methods: Hypertensive patients with DD and LDL-cholesterol <160 mg/dL underwent a run-in phase to achieve a systolic blood pressure (SBP) <135 mmHg and diastolic blood pressure (DBP) <85 mmHg with enalapril. Hydrochlorothiazide was added when need to achieve blood pressure control. Four weeks after reaching the optimum anti-hypertensive regimen patients were randomized to receive 80 mg simvastatin (n = 27) or placebo (n = 28) for a period of 20 weeks. Echocardiograms were performed before and after treatment with measurement of maximum left atrial volume (LAV), conventional and tissue Doppler velocities in early diastole (E, e') and late diastole (A, a'). Results: After 20 weeks, the simvastatin group presented reduction in SBP (-4 +/- 2 mmHg, p = 0.02), increase in E/A ratio (1.0 +/- 0.05 to 1.2 +/- 0.06, p = 0.03) and decrease of LAV indexed to body surface area (24.5 +/- 0.9 to 21.1 +/- 0.8 ml/m(2), p = 0.048), as compared with placebo arm. No change in systolic function and no correlation between the E/A ratio, LAV and changes in blood pressure or lipid profile were observed. Conclusions: The addition of simvastatin to enalapril in hypertensive patients with average cholesterol levels improves parameters of diastolic function independently of changes in blood pressure or cholesterol. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Evidence-based polytherapies and long-term mortality after acute myocardial infarction in very old subjects compared with elderly and adults: a nested case-control study

Background: Clinical trials have demonstrated that selected secondary prevention medications for patients after acute myocardial infarction (AMI) reduce mortality. Yet, these medications are generally underprescribed in daily practice, and older people are often absent from drug trials. Objectives: To examine the relationship between adherence to evidence-based (EB) drugs and post-AMI mortality, focusing on the effects of single therapy and polytherapy in very old patients (≥80 years) compared with elderly and adults (<80 years). Methods: Patients hospitalised for AMI between 01/01/2008 and 30/06/2011 and resident in the Local Health Authority of Bologna were followed up until 31/12/2011. Medication adherence was calculated as the proportion of days covered for filled prescriptions of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), β-blockers, antiplatelet drugs, and statins. We adopted a risk set sampling method, and the adjusted relationship between medication adherence (PDC≥75%) and mortality was investigated using conditional multiple logistic regression. Results: The study population comprised 4861 patients. During a median follow-up of 2.8 years, 1116 deaths (23.0%) were observed. Adherence to the 4 EB drugs was 7.1%, while nonadherence to any of the drugs was 19.7%. For both patients aged ≥80 years and those aged <80 years, rate ratios of death linearly decreased as the number of EB drugs taken increased. There was a significant inverse relationship between adherence to each of 4 medications and mortality, although its magnitude was higher for ACEIs/ARBs (adj. rate ratio=0.60, 95%CI=0.52–0.69) and statins (0.60, 0.50–0.72), and lower for β-blockers (0.75, 0.61–0.92) and antiplatelet drugs (0.73, 0.63–0.84). Conclusions: The beneficial effect of EB polytherapy on long-term mortality following AMI is evident also in nontrial older populations. Given that adherence to combination therapies is largely suboptimal, the implementation of strategies and initiatives to increase the use of post-AMI secondary preventive medications in old patients is crucial.

La terapia combinata di cellule mesenchimali stromali e aceinibitori riduce la fibrosi renale in un modello animale di ostruzione ureterale unilaterale

Le cellule mesenchimali stromali (MSC) sono cellule multipotenti e numerosi studi hanno mostrato i loro effetti benefici nel danno renale acuto ma non sono ancora stati dimostrati potenziali effetti nella malattia renale cronica. L'ostruzione ureterale unilaterale (UUO) è un modello di fibrosi interstiziale nel quale l'attivazione di molecole vasoattive, citochine profibrotiche e infiammatorie gioca un ruolo patogenetico nello sviluppo dell'apoptosi e atrofia tubulare. Il sistema renina-angiotensina (RAS) gioca un ruolo chiave nello sviluppo della fibrosi renale e i farmaci che hanno come target l'angiotensina II, principale mediatore del RAS, sono attualmente la terapia più efficace nel ridurre la progressione della malattia renale cronica. E' noto che gli ACE-inibitori (ACEi) inducono un aumento compensatorio della renina plasmatica per la mancaza del feedback negativo sulla sua produzione. Tuttavia, la renina (R) promuove il danno renale non solo stimolando la produzione di ANGII, ma anche up-regolando geni profibrotici attraverso l'attivazione del recettore renina/prorenina. Lo scopo dello studio è stato indagare se l'infusione di MSC riduceva il danno renalein un modello animale di UUO e comparare gli eventuali effetti protettivi di ACEi e MSC in UUO. Abbiamo studiato 5 gruppi di ratti. A: sham operati. B: ratti sottoposti a UUO che ricevevano soluzione salina. C: ratti sottoposti a UUO che ricevavano MSC 3X106 nella vena della coda al giorno 0. D:ratti sottoposti a UUO che ricevevano lisinopril dal g 1 al g 21. E: ratti sottoposti a UUO che ricevevano MSC 3X106 nella vena della coda al giorno 0 e lisinopril dal g 1 al g 21. I ratti sono stati sacrificati al giorno 7 e 21. I risultati dello studio mostrano che MSC in UUO prevengono l'aumento della renina, riducono la generazione di ANGII e che in terapia combinata con ACEi riducono ulteriormente l'ANGII, determinando una sinergia nel miglioramento della fibrosi renale.

[Microalbuminuria--a new cardiovascular risk factor?]

Microalbuminuria is an established risk factor for renal disease, especially in the diabetic population. Recent studies have shown that microalbuminuria has also a highly relevant predictive value for cardiovascular morbidity and mortality. From normal to overt proteinuria levels, albuminuria shows a continuous marked increase in cardiovascular risk. This association is independent of other "classical" cardiovascular risk factors such as hypertension, hyperlipidemia or smoking. Furthermore it has a predictive value not only for patients with diabetic or renal disease, but also for hypertensive individuals or the general population. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been shown to display not only reno--but also cardioprotective effects. Their unique ability to lower albuminuria by 40% is related to a significant risk reduction in cardiovascular mortality. New clinical trials are needed to define "normal" albuminuria levels and how low we should go.