Bovine AAV transcytosis inhibition by tannic acid results in functional expression of CFTR in vitro and altered biodistribution in vivo.

Bovine adeno-associated virus (BAAV) can enter a cell either through a transcytosis or transduction pathway. We previously demonstrated that particles entering via the transcytosis pathway can be redirected to transduce the cell by blocking particle exocytosis with tannic acid (TA). To investigate whether this approach is useful in lung gene therapy applications, we tested the effect of TA on BAAV transduction in cystic fibrosis airway epithelia in vitro, and in mouse lung in vivo. Our findings suggest that BAAV transcytosis can occur in vivo and that treatment with TA reduces transcytosis and increases lung transduction. TA treatment did not impair the sorting and the activity of the BAAV expressed cystic fibrosis transmembrane regulator membrane protein.

Convenient and reproducible in vivo gene transfer to mouse parotid glands.

OBJECTIVES: Published studies of gene transfer to mouse salivary glands have not employed the parotid glands. Parotid glands are the likely target tissue for most clinical applications of salivary gene transfer. The purpose of the present study was to develop a convenient and reproducible method of retroductal gene transfer to mouse parotid glands. METHODS: The volume for vector delivery was assessed by infusion of Toluidine Blue into Stensen's ducts of Balb/c mice after direct intraoral cannulation. Recombinant, serotype 5 adenoviral vectors, encoding either firefly luciferase or human erythropoietin (hEpo), were constructed and then administered to parotid glands (10(7) vector particles/gland). Transgene expression in vivo was measured by enzyme activity (luciferase) or an enzyme-linked immunosorbent assay (hEpo). Vector biodistribution was measured by real-time quantitative (Q) PCR. RESULTS: The chosen volume for mouse parotid vector delivery was 20µL. Little vector was detected outside of the targeted glands, with both QPCR and luciferase assays. Transgene expression was readily detected in glands (luciferase, hEpo), and serum and saliva (hEpo). Most secreted hEpo was detected in saliva. CONCLUSION: These studies show that mouse parotid glands can be conveniently and reproducibly targeted for gene transfer, and should be useful for pre-clinical studies with many murine disease models.

Coronary stenting for ST-elevation myocardial infarction vs. other indications in patients on oral anticoagulation: any difference in in-hospital management and outcome?

AIM: The aim of this paper was to compare the in-hospital management and outcome of patients on oral anticoagulation (OAC) undergoing coronary artery stenting (PCI-S) for ST-elevation myocardial infarction (STEMI) vs. other indications. METHODS: One hundred and sixteen patients on OAC at the time of PCI-S who were prospectively enrolled in a multi-center, observational registry, were evaluated. Patients were segregated according to whether PCI-S was performed for STEMI (group 1) or other indications, such as non ST-elevation acute coronary syndromes, stable angina, silent ischemia, etc. (group 2), and the pharmacological and procedural management, as well as the in-hospital outcome, were compared. RESULTS: No significant differences were observed in vascular access site, sheath size and type of stent implanted, nor was significantly different the use of glycoprotein IIb/IIIa inhibitors, and the use and dose of intravenous unfractionated heparin. Although not statistically different, the in-hospital occurrence of death (3.7% vs. 1.1%; OR 3.3; 95% confidence intervals [CI] 0.2-56.0), stent thrombosis (3.7% vs. 1.1%; OR 3.3; 95% CI 0.2-56.0) and major bleeding (7.4% vs. 2.2%; OR 3.4; 95% CI 0.4-25.9) was consistently about 3-fold higher in group 1. CONCLUSION: The in-hospital pharmacological and procedural management of OAC patients undergoing PCI-S for STEMI vs. other indications appears not different. Although not significantly different however, the in-hospital occurrence of major bleeding, as well as of death and stent thrombosis, appears substantially higher in patients treated for STEMI, warranting therefore further larger, prospective studies.

Gene transfer using bovine adeno-associated virus in the guinea pig cochlea.

Gene transfer into the cells of the cochlea is useful for both research and therapy. Bovine adeno-associated virus (BAAV) is a new viral vector with potential for long-term gene expression with little or no side effects. In this study, we assessed transgene expression using BAAV with beta-actin-GFP as a reporter gene, in the cochleae of normal and deafened guinea pigs. We used two different routes to inoculate the cochlea: scala media (SM) or scala tympani (ST). Auditory brainstem response assessments were carried out before inoculation, 7 days after inoculation and immediately before killing, to assess the functional consequences of the treatment. We observed threshold shifts because of the surgical invasion, but no apparent pathology associated with the virus. Fourteen days after the injection, animals were killed and cochleae assessed histologically. Epi-fluorescence showed that BAAV transduced the supporting cells of both normal and deafened animals through SM and ST inoculations. Transgene expression in cells of the membranous labyrinth after ST inoculation is an important outcome because of the greater feasibility of this route for future clinical application. BAAV facilitates efficient transduction of the membranous labyrinth epithelium with minimum pathogenicity and may become clinically applicable for inner ear gene therapy.

Clinical Characteristics And Health Care Resources In Patients Treated With Oral Anticoagulants: Evidences From Italian Administrative Databases.

OBJECTIVES: 1) To evaluate anticoagulation treatment patterns and health care resource use in adult patients with a discharge diagnosis of non-valvular atrial fibrillation (NVAF) in an Italian real-world setting and 2) to describe the characteristics of NVAF patients in relation to treatment. DESIGN: A retrospective cohort study in a "real-world" setting. SETTING: Data were analysed by integrating administrative databases that included approximately 2,000,000 individuals assisted by the National Health System from two Italian Local Health Units. PARTICIPANTS: All adult patients with at least one hospital discharge or ≥2 outpatient visits with a diagnosis code for NVAF from 1/01/2011 to 31/12/2015 were included. MAIN OUTCOME MEASURES: Anticoagulation treatment patterns, health care resource use and major bleeding events that occurred during the follow-up period were evaluated. RESULTS: 32,863 NVAF patients were included, of whom 7,831 had at least one prescription of oral anticoagulants. Among them, 6,876 patients were vitamin K antagonists (VKA) users and 955 were non-vitamin K antagonist oral anticoagulant (NOAC) users at index date (ID). During the follow-up period, the use of antiplatelet drugs was higher among VKA-naïve users than the NOAC-naïve users. Among NOAC users, 76.1% showed an adherence level ≥80% during follow-up. The rate of bleeding events resulted higher for VKA patients compared to NOAC patients. The unadjusted incidence rate was 10.46 per 1000 person-year for VKA patients and 4.55 per 1,000 person-years for NOAC patients. The overall annual cost (in term of drugs, hospitalisations and outpatient specialist services) was € 5,156.13 for VKA and € 4,630.57 for NOAC. CONCLUSION: This unselected cohort study, on NVAF patients being prescribed oral anticoagulants, highlights that VKA was largely prescribed and the great majority of patients on NOACs were adherent to treatment. Most of the OAC patients still received antiplatelet agents in combination, and in NOAC patients, we registered a lower number of bleeding events compared with VKA.

TTF-2/FOXE1 gene polymorphisms in Sicilian patients with permanent primary congenital hypothyroidism.

Thyroid transcription factor-2 (TTF-2/FOXE1) is a polyalanine domain protein that regulates thyroid embryogenesis, but very few patients with permanent primary congenital hypothyroidism (pCH) harbor germline mutations of this or other transcription factors that are involved in thyroid development that might explain the etiology of pCH. Variations within the polyalanine tract are found in a variety of genes and are often reported in association with malformation syndromes; pCH is frequently associated with thyroid malformations and extra-thyroidal malformations. Therefore, in this study we investigated whether alanine (Ala) length polymorphisms and non-polymorphic mutations of the TTF-2 gene in pCH patients might be involved in the pathogenesis of pCH. The entire coding region of the TTF-2 gene was analyzed in 57 Sicilian patients and 142 healthy controls. We found that the homozygous Ala14 polymorphism (Ala14/14) was less frequent in the pCH group than in the controls. In contrast, significantly more pCH patients than controls harbored the Ala16 polymorphism (Ala16/16 and Ala14/16). However, neither the Ala14/14 nor the Ala16 polymorphism was related to extra-thyroidal malformations. Two of the 57 patients carried Ala11/14 and Ala12/14, and one Ala14/14 patient also had the silent polymorphism 387 C/T (Leu129Leu). Other than known polymorphic variants we found no mutation in the TTF-2 gene. Therefore, this study demonstrates that mutations in the TTF-2 gene are rare in pCH patients and suggests that variations in the length of the Ala-tract could at least partially explain the etiology of pCH but not that of extra-thyroidal malformations.

In Sicilian ethnic group non-classical congenital adrenal hyperplasia is frequently associated with a very mild genotype.

The spectrum of mutated alleles in non-classical congenital adrenal hyperplasia (NC-CAH) has been recently reported to be very large and haplotypes may significantly differ in the different ethnic groups. In order to confirm that population differences may exist in the genetic basis of this disease, we have analyzed the genetic presentation of NC-CAH in a Sicilian cohort of symptomatic patients and compared our findings with the ones reported in other studies of different ethnic groups. In 38 NC-CAH patients coming from two regions of Sicily and born of Sicilian parents, we found that 84.2% of the chromosomes examined bore only mild mutations and only the remaining 15.8% of the chromosomes bore at least 1 severe mutation. The overall predominant mutation was V281L, which was detected in 73.7% of alleles and in 89.5% of patients. About 58% of the patients were homozygotes for this mutation. V281L allele and homozygote frequencies were higher in the present series than in other European and Italian reports. In our NC-CAH population, which is one of the largest ever reported, the patients with two mild mutations exhibited a less severe impairment of both clinical and endocrine phenotype. On the basis of these results we can conclude that: a) in Sicilian ethnic groups NC-CAH is frequently associated with a very mild genotype; b) the most frequent genotype in our series is V281L homozygosis; c) clinical and biochemical expression of NC-CAH is more marked in the patients bearing a severe mutation; d) no correlations between genotype and phenotype were found in our patients affected by NC-CAH.

Contemporary antithrombotic treatment after coronary stenting in patients with indication for long-term anticoagulation.

AIM: Dual antiplatelet treatment with aspirin and a thienopyridine is the antithrombotic treatment recommended after percutaneous coronary intervention with stent implantation (PCI-S). Optimal treatment in patients with an indication for long-term oral anticoagulation (OAC) undergoing PCI-S is currently undefined. The aim of this study was to evaluate the contemporary management of these patients, and determine the safety and the efficacy of the various regimens. METHODS: A systematic review of the literature reporting on this issue was carried out. RESULTS: The adopted strategies showed substantial variability, and the regimens used included: substitution of OAC for dual antiplatelet therapy in 25-54% of cases, addition to OAC of a single antiplatelet agent in 12-25% and institution of triple therapy with OAC (or low-molecular-weight heparin), aspirin and a thienopyridine in about 60%. OAC was systematically aimed at a lower intensity in 33% of cases, whereas in another 29% this was pursued only when a high hemorrhagic risk was perceived. Both safety and efficacy of the various regimens appeared suboptimal, with a 30-day occurrence of major bleeding and thrombotic complications of 3-7% and 4%, respectively. CONCLUSIONS: Due to the suboptimal safety and/or efficacy of the various regimens adopted, the optimal antithrombotic treatment in patients with an indication for OAC undergoing PCI-S remains to be defined. Since the number of this patient subgroup is foreseen to progressively increase over the next years, large scale registries and clinical trials are warranted.

Functional studies of E7 proteins from different HPV types.

We have performed comparative studies on the E7 proteins from malignant and non-malignant Human Papillomavirus types HPV 1, 6, 11, 16, 18, 33). GST/E7 fusion proteins from all these HPV types associate with Rb1, p107 and the cyclin A/CDK2 complex. As has been shown for Rb1, the association with p107 and Cyclin A was weaker for the 'low risk' HPV6 and 11 E7 proteins as compared to 'high risk' HPV16, 18 and 33 E7 proteins. In contrast the E7 protein of the benign type HPV1 bound Rb1, p107 and cyclin A with the same affinity as the 'high risk' E7 proteins. The affinities of the E7/Rb1 interaction have been confirmed in vivo by the 'two hybrid' method in the yeast Saccharomyces cerevisiae. Although HPV1 E7 showed the same affinity in vitro and in vivo for Rb1 as the high risk HPV E7s, it did not have the ability to activate the E2F-1 transcription factor inhibited by Rb1, nor did it have any transforming activity when coexpressed with activated ras in primary rodent cells.

Organization of genes for ribosomal proteins S7 and S12, elongation factors EF-Tu and EF-G in the cyanobacterium Spirulina platensis.

The gene encoding ribosomal proteins S12 and probably S7 as well as protein synthesis elongation factors Tu (EF-Tu) and G (EF-G) of Spirulina platensis have been identified and cloned. Gene expression was determined for ribosomal protein S12 by genetic complementation of the appropriate Escherichia coli mutant, whereas for the EF-Tu gene it was determined by production of the protein in E. coli minicells. On the basis of these experiments we suggest the following gene order in the S. platensis chromosome: S12, S7, EF-G, EF-Tu.

Transient sympathovagal imbalance triggers "ischemic" sudden death in patients undergoing electrocardiographic Holter monitoring.

OBJECTIVES: The aim of this study was to investigate the relation between "ischemic" sudden death (arrhythmic death preceded by ST segment shift) and autonomic nervous system activity. Background. Mechanisms precipitating sudden death are poorly known despite the importance of detecting functional factors that may contribute to such a fatal event. METHODS: We analyzed the tapes of eight patients (seven men and one woman with a mean age of 66 +/- 8 years) who had ischemic sudden death during ambulatory electrocardiographic (Holter) monitoring. Four patients had unstable and four had stable angina; none was taking antiarrhythmic drugs. Twenty patients with angina and transient myocardial ischemia during Holter monitoring served as control subjects. Arrhythmias, ST segment changes and heart rate variability were analyzed by a computerized interactive Holter system. RESULTS: Five patients had ventricular tachyarrhythmias (ventricular fibrillation in three, ventricular tachycardia in two), and three had bradyarrhythmias (atrioventricular block in two, sinus arrest in one) as the terminal event; all eight patients showed ST segment shift (maximal change 0.46 +/- 0.16 mV; with ST elevation in two) that occurred 41 +/- 34 min (mean +/- SD) before sudden death. The standard deviation of normal RR intervals (SDNN) was 89 +/- 33 ms during the 10 +/- 6 h of Holter monitoring; 5 min before the onset of the fatal ST shift, SDNN measurements were significantly lower than during the initial 5-min period (48 +/- 10 vs. 29 +/- 9 ms; p=0.002). In control patients, the SDNN was 102 +/- 39 ms during Holter monitoring, whereas it measured 56 +/- 30 ms 5 min before the most significant episode of ST shift (p<0.01 vs. 29 +/- 9 ms [corrected] in the group with sudden death). CONCLUSIONS: Autonomic dysfunction, as detected by a marked decrease in heart rate variability, is present in the period (5 min) immediately preceding the onset of the ST shift precipitating ischemic sudden death. These data suggest that sympathovagal imbalance may trigger fatal arrhythmias during acute myocardial ischemia, thus resulting in sudden death.

Increased CD34+ cell peripheral traffic appears to be an unique feature of the allergic inflammation.

Evidence has been cumulated during the last years concerning the immaturity of the cells involved in the local and systemic aspects of allergic inflammation. Hematopoietic precursors (HPC) are mobilized from the bone matrix as multipotent cells or, more often, as progenitors that, after the initial white-lineage commitment reach through the peripheral blood (PB) their final destinations constituted by the target organs of allergy. Although several studies have investigated the CD34+ cells traffic and location at the level of the inflamed peripheral mucosae in allergic populations, limited information is available on their behaviour on the time-course of infectious diseases. The current study thus was designed to asses the peripheral traffic of CD34+ HPC during the infectious inflammation. To this end CD34+ HPCs have been enumerated, by flow-cytometric techniques, in PB of 24 adult healthy beings (Group A), 24 adult subjects with symptomatic extrinsic allergy (Group B) and in PB of 24 adult patients hospitalised for febrile infectious pathology (Group C). CD34+ cell values ranged 0.01-0.08% with a median of 0.03 in Group A. In Group B values ranged 0.17-0.75% with a median of 0.28 and in Group C values ranged 0.00-0.12% with a median of 0.07. Variance analysis test among the three groups was statistically significant (p<0.001) supporting the conclusion that CD34+ HPC mobilizing and increased peripheral traffic is an unique feature of the allergic inflammation.

New adenosine kinase inhibitors with oral antiinflammatory activity: synthesis and biological evaluation.

Several 5-iodotubercidin analogues in the pyrazolo[3,4-d]pyrimidine ring system were synthesized as potential inhibitors of adenosine kinase by a direct Lewis acid-catalyzed glycosylation procedure using both the preformed carbohydrate and the heterocyclic base as starting materials. The 5'-hydroxyl, -chloro, -azido, -deoxy, -amino, and -fluoro derivatives were prepared and evaluated in three systems for biological activity relative to adenosine, the true substrate, and 5-iodotubercidin, a known inhibitor. First, each compound was studied kinetically for inhibition of purified human placental adenosine kinase activity. The order of potency was: iodotubercidin > hydroxyl > amino > or = deoxy > fluoro > chloro >> azido. The Ki values for the 5'-hydroxyl and 5'-amino compounds, the two most potent inhibitors, were 80 and 150 nM, respectively. The inhibition appeared to be essentially competitive in nature, although a noncompetitive component of significance for the more potent inhibitors cannot be ruled out. Second, a bioassay was conducted in which the toxicity of 6-methylmercaptopurine riboside toward human CEM lymphoblasts was reversed by varying concentrations of the compounds. The order of effectiveness of the compounds in this system, representing a functional inhibition of adenosine kinase in cultured cells, was about the same as that with the purified enzyme, except that the 5'-chloro and 5'-fluoro compounds were ineffective. Third, the 5'-hydroxyl derivative was evaluated in vivo in a rat pleurisy inflammation model and displayed biological activity at a dose of 30 mg/kg given orally. Finally, the in vitro toxicity of each compound was assessed in CEM lymphoblasts. Results indicated that the two most potent inhibitors in the pyrazolo[3,4-d]pyrimidine ring system, the 5'-hydroxyl (7) and the 5'-amino (20), were 15-fold and 75-fold, respectively, less growth inhibitory than 5-iodotubercidin.

Holter detection of cardiac arrhythmias in intracranial subarachnoid hemorrhage.

To determine the frequency and severity of cardiac arrhythmias in intracranial subarachnoid hemorrhage, 120 nonselected patients were prospectively studied by 24-hour Holter monitoring. Arrhythmias were found in 96 of 107 patients (90%) with adequate Holter recording: ventricular premature complexes in 49, nonsustained ventricular tachycardia in 5, supraventricular premature complexes in 29, paroxysmal supraventricular tachycardia or atrial fibrillation in 9, sinoatrial block and arrest in 29, second-degree atrioventricular block in 1, atrioventricular dissociation in 4 and idioventricular rhythm in 2. Life-threatening ventricular arrhythmias (torsades de pointes-type ventricular tachycardia) occurred in 4 patients, degenerating into either ventricular flutter or fibrillation in 2. ST-segment changes suggestive of acute transitory myocardial ischemia were found in 8 patients (1.5 mm or more of ST depression in 7 patients and 1.5 mm or more of ST elevation in 1 patient). The frequency and severity of arrhythmias were significantly higher in patients studied within 48 hours of subarachnoid hemorrhage; serious ventricular arrhythmias were associated with QTc prolongation more than 550 ms and with hypokalemia less than 3.5 mEq/liter. No correlation was found between age, clinical condition, site and extent of subarachnoid hemorrhage and either the occurrence or severity of arrhythmias. The results of our study indicate an extremely high incidence of arrhythmias, sometimes serious, in subarachnoid hemorrhage, especially in the first 48 hours after hemorrhage. Continuous electrocardiographic monitoring is therefore mandatory.

Frequency and prognostic significance of silent coronary artery disease in patients with cerebral ischemia undergoing carotid endarterectomy.

To evaluate the prevalence and prognostic role of silent coronary artery disease (CAD) in patients with symptomatic high-grade carotid stenosis (70 to 99%) undergoing carotid endarterectomy, and with neither history nor symptoms of CAD, 106 patients (76 men, 30 women, mean age 58.7 years [range 42 to 71]) with recent cerebral ischemia were prospectively studied. Patients were stratified as to the presence (n = 27, 25%) or absence (n = 79, 75%) of silent CAD defined by concordant abnormal exercise electrocardiographic testing and thallium-201 myocardial scintigraphy. The male sex, the severity of the symptomatic carotid lesion (greater than 90%), and the coexistence of contralateral carotid disease identified patients with higher probability of coexisting CAD. The 106 patients underwent 121 operations (bilateral in 15). In the perioperative period, no deaths or cardiac events occurred, 1 patient suffered a recurrent stroke and 3 had a transient ischemic attack. During a mean follow-up period of 5.4 years, 9 patients died (1.7%/year): fatal myocardial infarction occurred in 5 (all in the silent CAD group), cancer in 3 and vertebrobasilar stroke in 1. Nonfatal events occurred in 9 patients: myocardial infarction in 1 (without silent CAD), unstable angina in 3 (with silent CAD), and cerebral ischemic attacks in 5. After 7 years, the Kaplan-Meier estimated survival free from coronary events was 51% in patients with silent CAD, and 98% in patients without CAD (p less than 0.01). In conclusion, among patients with symptomatic high-grade carotid stenosis undergoing carotid endarterectomy, even in absence of history or symptoms of CAD, a silent CAD is detectable in one fourth of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Type and extent of myocardial injury related to brain damage and its significance in heart transplantation: a morphometric study.

BACKGROUND: Focal myocardial necrosis reported in patients who died of brain lesions and in donor hearts soon after insertion has been attributed to catecholamine-related injury induced before operation, or in the perioperative period. Interpretation of the morphofunctional type of myocardial injury observed and its quantification may help understand both its pathophysiology and clinical relevance. METHODS: In 27 patients without heart disease who died of intracranial brain hemorrhage after berry aneurysm rupture, terminal clinical signs were correlated with the presence of absence of myocardial injury. All hearts were systematically examined, and the total histologic area was measured in square millimeters, with both the number of foci and myocardial cells showing necrosis, normalized to 100 mm2. Forty-five cases of fatal head trauma (26 "instantaneous" and 19 "rapid" deaths) in normal subjects and 38 cases of acquired immunodeficiency syndrome with (14 cases) or without (24 cases) severe brain damage were used as control subjects. RESULTS: Contraction band necrosis was the only form of myocardial necrosis found in 89% of patients with acute brain hemorrhage. Its extent was 26 +/- 34 foci and 67 +/- 104 necrotic myocardial cells x 100 mm2. In patients with acquired immunodeficiency syndrome, its frequency was 58% in those without and 78.5% with severe brain lesions, with foci and myocardial cell values of 1 +/- 1.5 and 10 +/- 22 and 7 +/- 16 and 17 +/- 32, respectively. In head trauma cases with instantaneous death, the frequency was 4% (one case only with foci 0.5 and myocardial cells 35), whereas with a rapid death it was 40% (foci 12 +/- 18 and myocardial cells 21 +/- 33). CONCLUSIONS: The observed myocardial injury was present in all groups examined, being maximal in patients with intracranial brain hemorrhage with longer survival and minimal in patients with head trauma who died instantaneously. In this setting, this lesion is typical of catecholamine myotoxicity and may express a sympathetic overstimulation either in the agonal period and independent of therapy or be caused by brain injury, especially intracranial brain hemorrhage. However, the extent of myocardial injury observed was minimal and should not jeopardize cardiac function if hearts from such subjects are transplanted.

Cardiovascular remodeling, apoptosis, and drugs.

Apoptosis, a form of programmed cell death, mediates the controlled deletion of so-called "unwanted" cells. This review deals with the key features of this cell death program, showing that apoptosis is regulated by factors extrinsic and intrinsic to the dying cell. The elucidation of the possible interactions between these factors may be of major interest in preventing the progression to cardiovascular remodeling in patients with hypertensive disease. New pathways of research are emerging for drugs, such as beta-blockers, ACE inhibitors, the calcium-antagonists, and the receptor antagonist of angiotensin II, all of which have beneficial effects on cardiovascular remodeling. This may be due to the direct effect of these drugs on the cell proliferation/apoptosis balance.

Reduced bcl-2 concentrations in hypertensive patients after lisinopril or nifedipine administration.

In 30 patients with essential hypertension and 30 healthy control subjects, we evaluated blood concentrations of B cell leukemia-2 (bcl-2), a protooncogene that can reduce apoptosis. Bcl-2 concentrations were higher in hypertensive than in normotensive subjects. The increase in pressure due to a cold pressor test caused a further increase in blood bcl-2 concentrations, in both hypertensive and normotensive subjects. Treatment of hypertensive patients with hypotensive drugs caused a reduction in bcl-2 concentrations, which was more marked after administration of lisinopril than of nifedipine. The results suggest that concentrations of bcl-2 are increased in patients with hypertension, which could be an important factor in cell proliferation underlying posthypertensive vascular remodeling. Moreover, lisinopril and nifedipine appear to be capable of reducing bcl-2 concentrations, with potentially beneficial effects on vascular modifications in patients with hypertension.