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M Volpe

Publications and source records attributed to M Volpe.

At least 37 records · Page 2Linked to original sources

Therapeutic applications of angiotensin II receptor antagonists.

The renin-angiotensin system (RAS) represents today one of the most strategic targets of the therapy of cardiovascular diseases. During the last 30 years a number of more or less successful approaches to inhibit the activity of the RAS have been attempted. In particular, the use of ACE-inhibitiors has led to significant improvments in the outcom/treatment of hypertension, congestive heart failure, ischemic heart disease and nephropathies. On the other hand, Ace-inhibitors are not specifically targeted to RAS since they interfere with an enzyme with multiple different substrates. Furthermore, the inhibition of ACE does not prevent the formation of angiotensin II through alternative pathways, and thus the inhibition of RAS is often incomplete, especially under pathologic conditions stimulating RAS. For these reasons, the recent discovery of angiotensin II receptors antagonists, which selectively inhibit the action of angiotensin II at the level of the AT1 subtype receptor, is particularly attracting. This article reviews the background, the rationale and some of the clinical findings and potential applications with this new class of compounds.

Angiotensin Receptor Antagonists↗

Adenoviral RB2/p130 gene transfer inhibits smooth muscle cell proliferation and prevents restenosis after angioplasty.

Smooth muscle cell (SMC) proliferation that results in neointima formation is implicated in the pathogenesis of atherosclerotic plaques and accounts for the high rates of restenosis that occur after percutaneous transluminal coronary angioplasty, a widespread treatment for coronary artery disease. Endothelial lesions trigger intense proliferative signals to the SMCs of the subintima, stimulating their reentry into the cell cycle from a resting G(0) state, resulting in neointima formation and vascular occlusion. Cellular proliferation is negatively controlled by growth-regulatory or tumor-suppressor genes, or both, such as the retinoblastoma gene family members (RB/p105, p107, RB2/p130). In the present study, we show that RB2/p130 inhibited SMC proliferation in vitro and in vivo. We used the rat carotid artery model of restenosis to demonstrate that adenovirus-mediated localized arterial transduction of RB2/p130 at the time of angioplasty significantly reduced neointimal hyperplasia and prevented restenosis. Furthermore, the ability of pRb2/p130 to block proliferation correlated with its ability to bind and sequester the E2F family of transcription factors, which are important mediators of cell cycle progression. These results imply that RB2/p130 could be an important target for vascular gene therapy.

Adenoviridae↗

Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat.

Through the genotype/phenotype cosegregation analysis of an F(2) intercross, from the crossbreeding of stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHR), we previously identified a quantitative trait locus for stroke on rat chromosome 5 (STR2) that colocalized with the genes encoding atrial and brain natriuretic peptides (ANP and BNP) and conferred a stroke-delaying effect. To further characterize ANP and BNP as candidates for stroke, we performed additional studies. Comparative sequence analysis revealed point mutations in both the coding and regulatory regions of ANP, whereas no interstrain differences were found for BNP. In in vitro studies in COS-7 and AtT-20 cells that were performed to test the relevance of a G-->A substitution at position 1125, a Gly-->Ser transposition in the SHRSP pro-ANP peptide resulted in different posttranslational processing of the SHRSP ANP gene product that was also associated with higher cGMP production (P<0.05). Furthermore, an analysis of a 5' end mutation affecting a PEA2 regulatory binding site in the 5' untranslated regulatory sequence of SHRSP ANP demonstrated a significantly lower ANP promoter activation in endothelial cells (P<0.05 versus the SHR ANP). In addition, the expression of ANP was significantly reduced in the brain, but not in the atria, of SHRSP compared with SHR (P<0.0001). No differences were detected with regard to BNP expression. The present results reveal substantial differences in ANP, but not BNP, structure and product among SHR and SHRSP, which supports a role of ANP in the pathogenesis of stroke in the SHRSP animal model.

Animals↗

The gene encoding atrial natriuretic peptide and the risk of human stroke.

BACKGROUND: Recent evidence from an animal model of stroke, the stroke-prone spontaneously hypertensive rat, implicated the gene encoding atrial natriuretic peptide (ANP) as a possible candidate contributing to the likelihood of experiencing a stroke. The purpose of the present study was to investigate the role of ANP in the pathogenesis of cerebrovascular accidents in humans. METHODS AND RESULTS: We investigated 2 previously known markers at ANP, G1837A and T2238C, for their possible association with the occurrence of stroke. This was the largest matched case-controlled sample studied thus far; the sample was drawn from a large prospective study (the Physician's Health Study). When assuming a dominant mode of inheritance, a statistically significant positive association was observed for the 1837A allele, indicating an odds ratio of 1.64 (95% confidence interval, 1.01 to 2.65) for stroke. This observation led to the discovery of a new molecular variant in exon 1, G664A, which was responsible for a valine-to-methionine substitution in the proANP peptide. This mutation, which was in linkage disequilibrium with the G1837A marker, was associated with the occurrence of stroke (odds ratio, 2.0; 95% confidence interval, 1.17 to 3.19; P=0.01). CONCLUSIONS: Our findings suggest that molecular variants of the ANP gene may represent an independent risk factor for cerebrovascular accidents in humans. The strong parallelism to the experimental data obtained in the stroke-prone animal model provides assurance for the relevance of our observation.

Adult↗

Acute anti-ischemic effect of testosterone in men with coronary artery disease.

BACKGROUND: The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men. METHODS AND RESULTS: After withdrawal of antianginal therapy, 14 men (mean age, 58+/-4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579+/-204 versus 471+/-210 seconds; P<0. 01) and total exercise time (631+/-180 versus 541+/-204 seconds; P<0. 01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm; P<0.05) and at peak exercise (26 746+/-3109 versus 22 527+/-5443 mm Hgxbpm; P<0.05). CONCLUSIONS: Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.

Aged↗

Independent and incremental prognostic value of heart rate variability in patients with chronic heart failure.

BACKGROUND: Decreased heart rate variability (HRV), indicating derangement in cardiac autonomic control, has been reported in patients with chronic heart failure. However, the independent and incremental prognostic value of HRV over clinical data and measures of left ventricular dysfunction has been less thoroughly investigated. This study was designed to evaluate the predictive value of HRV and Poincaré plots as assessed by 24-hour Holter recording in patients with chronic heart failure. METHODS: Ninety-seven patients, mean age 55 +/- 13 years, with radionuclide left ventricular ejection fraction </=40% underwent echocardiographic examination and 24-hour Holter recording. Heart failure was caused by coronary artery disease in 57 patients (59%) and idiopathic dilated cardiomyopathy in 40 (41%). RESULTS: During follow-up (39 +/- 18 months), 32 cardiac deaths occurred. By Cox multivariate analysis, significant predictors of death were left ventricular end-systolic volume (hazard ratio 1.04), low- to high-frequency ratio (hazard ratio 0.09), percentage of differences between successive normal R-R intervals >50 ms (hazard ratio 0.93), and age (hazard ratio 1.06). Furthermore, HRV analysis improved (P <. 001) the prognostic power of a model including clinical and echocardiographic data, left ventricular ejection fraction, and ventricular arrhythmias at Holter recording, whereas the inclusion of Poincaré plots did not add further predictive value. CONCLUSIONS: Our investigation demonstrated that HRV has independent and incremental prognostic value in patients with chronic heart failure and seems useful to stratify patients at high risk of cardiac death.

Adolescent↗

Differential brain atrial natriuretic peptide expression co-segregates with occurrence of early stroke in the stroke-prone phenotype of the spontaneously hypertensive rat.

OBJECTIVE: To determine how the downregulation of atrial natriuretic peptide (ANP) gene expression, previously demonstrated to occur only in the brain of the stroke-prone spontaneously hypertensive rat (SHRsp), in contrast to the stroke-resistant SHR (SHRsr), co-segregates with stroke occurrence in SHRsp/SHRsr F2 descendants in order to study the 'protective' role towards stroke previously demonstrated in SHRsp for the quantitative trait locus STR2 that also carries the ANP gene. DESIGN AND METHODS: Eight male SHRsp, eight male SHRsr and 16 male SHRsp/SHRsr F2-intercross animals (progeny of brother/sister mated F1 hybrids from an original cross between F0 SHRsp and SHRsr) were selected for this study. All rats were exposed to a stroke-permissive Japanese-style diet starting at the age of 6 weeks. Half of the F2 animals had early strokes; the remainder had late strokes. Blood pressure was measured before sacrifice. Analysis of brain ANP expression using an RNase protection assay was performed in all animals. RESULTS: Downregulation of brain ANP in the stroke-prone phenotype was found to co-segregate with the occurrence of early strokes in the F2 rats independently of blood pressure levels. CONCLUSIONS: The observed lower expression of ANP in the brains of stroke-prone rats appears to be the result of an inhibitory effect by another gene or genes. It seems unlikely that this specific trait represents a primary protective mechanism.

Animals↗

Modulation of the AT2 subtype receptor gene activation and expression by the AT1 receptor in endothelial cells.

OBJECTIVE: To investigate whether angiotensin II type 2 (AT2) receptor (AT2-r) promoter activity and expression are modulated by angiotensin II (Ang II), and whether the AT1 receptor (AT1-r) is involved in this effect. DESIGN AND METHODS: Primary endothelial cells obtained from NEONATAL rat aorta, expressing both receptors, were transfected with the rat AT2-r promoter region cloned into a pCAT-reporter vector. The reporter-expression study was performed in a transient transfection assay system. Transfected cells were studied following angiotensin-converting enzyme inhibition to prevent endogenous formation of Ang II. Cells were subsequently stimulated for 6 h with Ang II, either alone or in combination with the AT1-r antagonist DuP753. AT2-r mRNA was assessed by RNase protection assay during the same pharmacological stimuli. RESULTS: Stimulation with Ang II caused an increase in promoter activity (+50%, P < 0.05 versus baseline), whereas mRNA expression was reduced by 50% (P < 0.05 versus baseline). Concomitant treatment with DuP753 and Ang II was associated with a 98% increase in promoter activity (P < 0.05 versus baseline). DuP753 also prevented the reduction in mRNA; it actually produced a 100% increase in AT2-r mRNA accumulation (P < 0.01 versus baseline). Studies with the AT2-r antagonist PD123319 indicate that the AT2-r is also involved in the regulation of AT2-r gene promoter activity. CONCLUSIONS: These data indicate that Ang II increases AT2-r promoter activity and decreases AT2-r mRNA accumulation in endothelial cells. The AT1 subtype receptor is involved in the modulation of both effects of Ang II. These findings suggest that changes in the expression of AT2 receptors may occur during treatment with AT1-r antagonists, and they indicate the existence of a cross-talk between AT1 and AT2 receptors.

Angiotensin II↗

Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy.

This study evaluated the effects of acute isotonic volume expansion on heart rate variability (HRV) in 10 patients with dilated cardiomyopathy (DCM) and in 10 age- and sex-matched normal volunteers. Echocardiographic left ventricular volumes and HRV measurements by continuous Holter recording were assessed at baseline, at 60 and 120 min during intravenous saline load (0.9% NaCl, 0.25 ml. kg(-1). min(-1)), and 60 min after infusion was terminated. Data analysis was performed by repeated-measures ANOVA. After volume expansion, left ventricular ejection fraction increased (F = 9.8; P < 0.001) in normal subjects and decreased (F = 8.7; P < 0.001) in DCM patients. During volume expansion a significant difference was also detectable between the two groups in root-mean-square successive difference (F = 25.2; P < 0.001), percentage of differences between successive normal R-R intervals >50 ms (F = 97.6; P < 0.001), high-frequency power (F = 50.1; P < 0.001), and low-frequency power (F = 41.6; P < 0.001), all of which reflect parasympathetic modulation of heart rate; in fact, these measurements increased in normal subjects and decreased in DCM patients. In normal subjects, the increase in HRV measurements during volume expansion suggests a parasympathetic activation, mediated by stimulation of cardiopulmonary and arterial mechanoreceptors. On the contrary, in DCM patients the parasympathetic withdrawal, already detectable at baseline, increases during volume expansion.

Adult↗

Genetic basis of cerebrovascular accidents associated with hypertension.

Among hypertension-associated cardiovascular diseases, stroke represents one of the most common disorders. In fact, it significantly affects mortality and morbidity rates of all industrialized countries. Only recently, stroke has been considered as a complex trait and not as a mere consequence of hypertension. Indeed, it appears to be the result of an interaction among several genetic and environmental factors. The identification of the genetic determinants of stroke is a difficult task in humans, due to the genetic heterogeneity of human populations and the confounding presence of other risk factors. Thus, an experimental approach, through the use of a highly inbred animal model for stroke, offers a valuable alternative and additional support for a genetic dissection of cerebrovascular disease. In fact, the genetic analysis of stroke in the animal model of the stroke-prone spontaneously hypertensive rat provided clear evidence that stroke is a genetically determined complex trait, and that factors such as blood pressure and diet only play a permissive role. Finally, by using the experimental approach, we established that the gene encoding atrial natriuretic peptide, significantly linked to cerebrovascular disease in rats, is a genetic determinant of stroke in humans. The identification of the genetic basis of stroke represents an important step towards the institution of targeted preventive and therapeutic approaches to reduce the risks of cerebrovascular accidents. This article reviews the background, the experimental approach and the outcome of a strategy based on the use of the stroke-prone spontaneously hypertensive rat model, which aims at identifying the genetic basis of stroke.

Animals↗

[DRG charge and real cost of a radical prostatectomy: preliminary considerations before a study of cost reduction].

Aim of the work was to evaluate the real cost of a radical prostactemy in comparison with the DRG's tariff rates. This work has been conduct before a next study whose objective is the reduction of the costs. The unitary estimated cost of the radical prostatectomies performed from 1997 to April 1998 in the Urological Division of the Università Cattolica S. Cuore has been extrapolated from the entire clinical activity of the same period. The real cost of an uncomplicated radical prostatectomy was also detected. The estimated cost was Lit. 8,225,872 in comparison to the DRG's tariff rate of Lit. 8,842,000; instead the real cost was Lit. 9,085,407. Forty-seven percent of this sum was for routine care in the Division, while 30% for operating room, 5% for pharmacy, 4% for laboratory and 14% for other items. In our institution an operation of high specialization like radical prostatectomy already performed without any complication is little remunerative. Routine care was the major cost: we think its improvement is the first step in order to contain the expense. In this way we can expect secondarily also a reduction in the days of stay.

Costs and Cost Analysis↗

Impaired vasorelaxant responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats.

BACKGROUND: We have previously shown that a locus on rat chromosome 5, termed STR 2, co-localizes with the genes encoding atrial natriuretic and brain natriuretic peptides, and is closely linked to the development of strokes in rats of a F2 hybrid cohort obtained by crossing stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats. We also demonstrated that there are significant differences in vascular functioning that are co-segregated with stroke latency of stroke-prone spontaneously hypertensive rats. OBJECTIVE: To investigate the vascular responses to natriuretic peptides in the stroke-prone phenotype of spontaneously hypertensive rats. DESIGN AND METHODS: In view of the important vasoactive properties of natriuretic peptides, we tested the vascular responses to 10(-11)-10(-9) mol/l atrial natriuretic peptide and to 10(-11)-10(-7) mol/l brain natriuretic peptide in isolated rings of aortas and internal carotid arteries obtained from stroke-prone and stroke-resistant spontaneously hypertensive rats. The 6-week-old rats were exposed for 4 weeks either to their regular diet (n = 15 of both strains) or to the stroke-permissive Japanese-style diet (n = 14 of both strains). A group of 14 normotensive, age-matched and sex-matched Wistar-Kyoto rats was also studied. RESULTS: Systolic blood pressures in stroke-prone and stroke-resistant spontaneously hypertensive rats were similar, and were significantly higher than those in Wistar-Kyoto rats. Vascular responses to nitroglycerin, atrial natriuretic peptide, and brain natriuretic peptide in rats of the two hypertensive strains and in Wistar-Kyoto rats fed their regular diet were comparable. In contrast, the vasorelaxant responses to atrial natriuretic peptide in stroke-prone spontaneously hypertensive rats fed Japanese diet were lower both in aortas and in internal carotid arteries than were those in spontaneously hypertensive rats (both P < 0.05 by analysis of variance) and in Wistar-Kyoto rats (both P < 0.05). Similarly, vasorelaxant responses to brain natriuretic peptide were lower both in aortas and in internal carotid arteries of stroke-prone spontaneously hypertensive rats than they were in spontaneously hypertensive rats (both P < 0.05) and in Wistar-Kyoto rats (P < 0.05). The responses to nitroglycerin in the stroke-prone spontaneously hypertensive rats and spontaneously hypertensive rats fed Japanese-style diet were also similar. CONCLUSION: The vasorelaxant effects of natriuretic peptides are impaired in stroke-prone spontaneously hypertensive rats. This abnormality could play a role in the pathogenesis of stroke incidence in this hypertensive model.

Animals↗

Role of the angiotensin II AT2-subtype receptors in the blood pressure-lowering effect of losartan in salt-restricted rats.

OBJECTIVE: The aim of this study was to evaluate the potential role of the angiotensin II (Ang II) AT2 receptors (AT2) in the control of blood pressure (BP) in the rat and the effects of AT2 receptors on BP during AT1 receptor (AT1) antagonism. METHODS: The study was performed in 52 Sprague-Dawley rats, which were preliminarily salt-restricted (SR) to enhance circulating and tissue renin-angiotensin system activity. To explore whether AT2 plays a role in BP regulation, the BP effects of the selective AT2 and AT1 receptor antagonists PD123319 (PD) (50 microg/kg/min) and losartan (Los) (10 mg/kg/day), were studied. Seven rats were used as a control group. To define whether AT2 plays a role in the BP response observed during AT1 antagonism, 17 Los treated rats were divided into two groups: seven were treated with both antagonists (Los + PD) and 10 rats received Los + vehicle. The effects of both drugs were also studied in bilaterally nephrectomized rats (NX). All treatments were maintained for 1 week RESULTS: Los reduced BP significantly in both intact (P < 0.001) and NX (P < 0.05) rats, while PD increased BP in intact and NX rats (both P < 0.001). In the Los + PD group BP levels were significantly higher (P < 0.001 vs Los and Los + vehicle, P = ns vs pretreatment), while vehicle infusion did not modify the BP response to Los. CONCLUSION: The results show that in salt-restricted rats AT2 blockade offsets the BP-lowering effect of losartan and suggest that AT2 receptors contribute to the hypotensive effects of losartan. Thus, AT1 receptor antagonists such as losartan, which are becoming widely used in the clinical treatment of hypertension, may reduce BP not only by blockade of AT1 receptors, but also through the stimulation of AT2 receptors by the excess of angiotensin II.

Angiotensin II↗

An analysis of microvessel density, androgen receptor, p53 and HER-2/neu expression and Gleason score in prostate cancer . preliminary results and therapeutic implications.

OBJECTIVES: To investigate relationships between microvessel density (MVD), androgen receptors (AR), mutant p53 and HER-2/neu expression and Gleason score (GS) to further understand the tumor biology of prostate cancer (CAP). METHODS: Slides of CAP from patients who underwent radical prostatectomy or channel transurethral resection of the prostate (TURP) were tested for androgen receptors by immunocytochemical assay and MVD was analyzed by staining with antibodies to the endothelial cell membrane molecule PECAM-1/CD-31. The p53 monoclonal antibody D07 and HER-2 9G6 mouse monoclonal antibody were used to assess p53 and HER-2/neu expression, respectively. The results were correlated with GS and clinical stage by multivariate analysis. RESULTS: We found a fourfold greater expression of MVD in prostate cancer specimens compared to neighboring normal prostate tissue. We observed a greater concentration of MVD in the higher Gleason scores (r = 0.40, p = 0. 06), and a correlation of Gleason score with mutant p53 expression (r = 0.57, p <0.05). We did not observe any associations between AR or HER-2/neu to Gleason score. More than half of the patients with specimens with 50% or greater expression of mutant p53 were in stage D2 (T4NxM1b) at the time of biopsy. CONCLUSIONS: We observed a correlation between mutant p53 and GS, and a greater concentration of MVD in the higher GS. Since the neovascularity of prostate tumors can be attenuated by radiation and hormones, while mutant p53 may confer resistance to such treatment, it appears that p53 expression may also play an important role in addition to angiogenesis in the virulence of prostate cancer. These data may aid in allocating patients to different treatment modalities.

Adenocarcinoma↗