Biomedical subjects

Chiara Bolego

Publications and source records attributed to Chiara Bolego.

13 recordsLinked to original sources

PubMed2006

Raloxifene elicits combined rapid vasorelaxation and long-term anti-inflammatory actions in rat aorta.

Previous studies reported the ability of raloxifene to acutely relax arterial and venous vessels, but the underlying mechanisms are controversial. Anti-inflammatory effects of the drug have been reported in nonvascular tissues. Therefore, the aim of this study was to investigate the nature of short- and long-term effects of raloxifene on selected aspects of vascular function in rat aorta. Isometric tension changes in response to raloxifene were recorded in aortic rings from ovariectomized female rats that underwent estrogen replacement, whereas long-term experiments were performed in isolated aortic smooth muscle cells (SMCs). Raloxifene (0.1 pM-0.1 microM) induced acute vasorelaxation through endothelium- and nitric oxide (NO)-dependent, prostanoid-independent mechanisms. The relaxant response to raloxifene was significantly weaker than that to 17beta-estradiol and was sensitive to neither the nonselective estrogen receptor antagonist ICI 182,780 [7,17-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol] nor a selective estrogen receptor (ER) alpha antagonist. This rapid vasorelaxant effect was retained in aortic rings from rats treated with 0.1 mg/kg, but not 1 mg/kg, lipopolysaccharide, 4 h before sacrifice. In cultured aortic SMCs, raloxifene treatment (1 nM-1 microM) for 24 h reduced inducible NO synthase activation in response to cytokines. This effect was prevented by the selective ERalpha antagonist and was associated with up-regulation of ERalpha protein levels, which dropped markedly upon cytokine stimulation. These findings illustrate the relevance of classic ER-dependent pathways to the vascular anti-inflammatory effects rather than to the nongenomic vasorelaxation induced by raloxifene and may assist in the design of novel ER isoform-selective estrogen-receptor modulators targeted to the vascular system.

Animals↗

PubMed2006

Selective agonists of estrogen receptor isoforms: new perspectives for cardiovascular disease.

The cloning of estrogen receptors (ERs) and generation of ER-deficient mice have increased our understanding of the molecular mechanisms underlying the cardiovascular effects of estrogen. It is conceivable that clinical trials of estrogens so far failed to improve cardiovascular health because of the poor ER isoform selectivity and tissue specificity of endogenous hormones as well as incorrect treatment timing and regimens. Tissue-selective ER modulators (SERMs) may be safer agents than endogenous estrogens for cardiovascular disease. Yet, designing isoform-selective ER ligands (I-SERMs) with agonist or antagonist activity is required to pursue improved pharmacological control of ERs, especially taking into account emerging evidence for the beneficial role of vascular ER alpha activation. Ideally, the quest for unique ER ligands targeted to the vascular wall should lead to compounds that merge the pharmacological profiles of SERM and I-SERM agents. This review highlights the current bases for and approaches to selective ER modulation in the cardiovascular system.

Animals↗

PubMed2006

Hypolipidemic therapy for the metabolic syndrome.

The metabolic syndrome appears to affect a significant proportion of the population and is associated with increased risk for development of cardiovascular disease as well as of type-2 diabetes. No single treatment for the metabolic syndrome as a whole yet exists. While the primary management of patients with the metabolic syndrome involves healthy lifestyle promotion, the atherogenic dyslipidemia is a primary target for cardiovascular disease risk reduction in these patients. Statin therapy provides effective reduction of LDL-cholesterol, which represents the primary therapeutic goal of lipid-lowering therapy in patients at risk for cardiovascular disease. Fibrates in turn are effective in normalizing lipid levels (mainly triglycerides and HDL-cholesterol) in patients with the metabolic syndrome and may improve insulin resistance. Whereas statins remain the drug of choice for patients who need to achieve the LDL-cholesterol goal, fibrate therapy may represent an alternative for those with low HDL-cholesterol and high triglyceride levels. The simultaneous use of fibrates could be indicated in patients whose LDL-cholesterol is controlled by statin therapy but whose HDL-cholesterol and/or triglycerides are still inappropriate. Such a combination, however, needs careful monitoring due to the potential hazard of adverse drug interactions. Nicotinic acid and ezetimibe may be useful agents for therapy, particularly when combined with statins. A number of emerging therapies offer potential as future options for the pharmacological treatment of metabolic syndrome.

Cholesterol, LDL↗

PubMed2005

eNOS, COX-2, and prostacyclin production are impaired in endothelial cells from diabetics.

The vascular endothelium is a well-recognized target of damage for factors leading to increased cardiovascular risk. Among the agents playing an important role in cardiovascular homeostasis, nitric oxide and prostacyclin represent key markers of endothelial integrity. In the present work, we report for the first time the reduced expression of both endothelial nitric oxide synthase and cyclooxygenase-2 (COX-2) proteins, as well as decreased prostacyclin production, in unstimulated human endothelial cells from insulin-dependent diabetic mothers when compared to cells from non-diabetic, control subjects. According to a major role of COX-2 as a source of prostacyclin production even in unstimulated endothelial cells, prostacyclin production was concentration-dependently inhibited by the selective COX-2 inhibitor SC236. Overall, our results suggest a possible link between reduced endothelial COX-2 and NO-synthase expression and the increased risk of cardiovascular diseases affecting diabetic patients, and point to the use of endothelial cells from diabetic patients as a tool for investigating early dysfunction in pathological endothelium.

Cell Line↗

PubMed2005

Potential pro-inflammatory action of resveratrol in vascular smooth muscle cells from normal and diabetic rats.

BACKGROUND AND AIM: Based on the reported cardioprotective effects of resveratrol, a polyphenolic antioxidant abundant in grapes that binds to estrogen receptors, and the well-characterized anti-inflammatory properties of 17beta-estradiol, the effects of resveratrol on the functional expression of inflammatory enzymes were assessed in vascular smooth muscle cells (SMC) from normoglycaemic and streptozotocin-diabetic rats. METHODS AND RESULTS: SMC were isolated from the aorta four weeks after treating rats with streptozotocin or its vehicle. In SMC exposed to a cytokine mixture for 24h, unexpectedly, treatment with resveratrol (0.1-100microM) as well as the structurally related isoflavone genistein (1nM-1microM) enhanced expression of inducible NO synthase (iNOS). Genistein failed to mimic the elevated iNOS activity induced by resveratrol. Inhibition of estrogen receptors by the pure antiestrogen ICI 182,780 reversed the action of resveratrol on iNOS. In addition, resveratrol failed to alter cyclooxygenase-2 protein levels but reduced the accumulation of prostaglandin E(2) in the culture medium of SMC from normoglycaemic, but not diabetic rats. CONCLUSIONS: These results indicate that resveratrol, at concentrations approaching putative peak plasma levels in vivo, exhibited no anti-inflammatory properties in vascular SMC from normal and diabetic rats. By contrast, resveratrol displayed a potential pro-inflammatory activity in settings of vascular inflammation.

Animals↗

PubMed2005

Effect of the ATP-sensitive potassium channel opener ZM226600 on cystometric parameters in rats with ligature-intact, partial urethral obstruction.

The activity of a recent K(ATP) channel opener, the N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (ZM226600) was investigated on a female rat model of overactive bladder with outlet obstruction. Both ZM226600 and pinacidil instilled into the bladder (10(-7) M, 30 min) or following systemic administration (10, 100 nmol/kg e.v.) almost completely abolished bladder overactivity and improved residual volume and frequency of micturition. However, pinacidil affected arterial pressure. Oxybutynin instilled into the bladder (10(-7), 10(-6), 10(-5) M, 30 min) decreased detrusor overactivity by about 16%, 25% and 46% respectively, but also blocked micturition reflexes at highest doses tested. Oxybutynin reduced detrusor overactivity by about 50% and 80%, after systemic administration (10, 100 nmol/kg e.v.), but also blocked micturition reflexes at the highest dose tested. In conclusion, ZM226600 is more active than oxybutynin in reducing bladder overactivity, and it is devoid of vascular side effects observed with pinacidil. Its short duration of action (about 1 h) is probably the main problem to solve, in order to consider this compound a valid alternative to antimuscarinics in the therapy of bladder overactivity.

Adenosine Triphosphate↗

PubMed2005

The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-alpha agonists and is abolished by estrogen deprivation.

Estrogen is known to induce rapid vasodilatory response in isolated arteries. Because estrogen is a nonselective receptor agonist, the involvement of estrogen receptor (ER) subtypes in acute estrogenic responses has remained elusive. Acute administration of the selective ERalpha agonist 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl) tris-phenol (PPT) to precontracted aortic rings from intact female rats dose-dependently induced an ER-dependent vascular relaxation fully overlapping to that induced by 17beta-estradiol. By contrast, the selective ERbeta agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) had no acute effect on vasomotion. This short-term vasorelaxant action of PPT was abolished by the NO synthase inhibitor N(omega)-nitro-l-arginine methyl ester and by endothelium removal. In aortic tissues from ovariectomized (OVX) rats, however, neither 17beta-estradiol nor PPT induced acute vascular relaxation. The effect of PPT was restored in preparations from estrogen-replaced OVX rats, whereas DPN remained ineffective even after estrogen replacement. PPT acted through an ER-dependent mechanism, as shown by impaired response in the presence of the anti-estrogen ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Accordingly, isolated rat aortic endothelial cells expressed both ERalpha and ERbeta. These data show that selective ERalpha but not ERbeta agonists reproduced the acute vasodilation of estrogen via a receptor-mediated pathway in the aorta from intact as well as 17beta-estradiol-replaced OVX rats. This beneficial effect was undetectable in tissues from OVX rats. Selective pharmacological targeting of ER subtypes may thus represent a novel and promising approach in the treatment of vascular disease.

Animals↗

PubMed2005

Purine- and pyrimidine-induced responses and P2Y receptor characterization in the hamster proximal urethra.

1. Purine and pyrimidine compounds were investigated on hamster proximal urethral circular smooth muscle preparations. In situ hybridization studies were carried out to localize P2Y(1), P2Y(2), P2Y(4) and P2Y(6) mRNA. Protein expression was studied using Western blotting analysis with antibodies against P2Y(1) and P2Y(2) receptors. 2. The hamster urethra relaxed with an agonist potency order of: 2-MeSADP>beta,gamma-meATP=ATP=adenosine=ADP>2-MeSATP>alpha,beta-meATP>TTP>CTP=UTP>GTP=UDP. The high potency of 2-MeSADP is suggestive of an action via P2Y(1) receptors. Although the order is not characteristic for any known single P2Y receptor subtype, it may represent a combination of P2Y receptor subtypes. 4. The selective P2Y(1) receptor antagonist MRS2179 inhibited ATP-, 2-MeSADP-, 2-MeSATP-, beta,gamma-meATP-, and to a lesser degree alpha,beta-meATP-induced responses. 3. Adenosine, but not ATP, was inhibited by the adenosine receptor antagonist 8-phenyltheophylline, indicating that ATP was not acting via adenosine following enzymatic breakdown. 5. Western blotting analysis showed the expression of both P2Y(1) and P2Y(2) receptors, confirming the results obtained with in situ hybridization that showed the expression of both P2Y(1) and P2Y(2), but not P2Y(4) or P2Y(6) mRNA, in smooth muscle layers of the hamster proximal urethra. 6. It is proposed that the relaxant response of the urethra to ATP may be evoked through the activation of the combination of receptors for P2Y(1) and to a lesser extent P2Y(2) receptors, which may mediate a trophic effect in addition. A P2Y subtype responsive to alpha,beta-meATP and P1 receptors may contribute to urethral smooth muscle relaxation.

Animals↗

PubMed2003

Diabetes undermines estrogen control of inducible nitric oxide synthase function in rat aortic smooth muscle cells through overexpression of estrogen receptor-beta.

BACKGROUND: Previous reports from our group have shown that 17beta-estradiol reduces the synthesis and activity of inducible nitric oxide synthase (iNOS) in rat aortic smooth muscle cells (SMC) in response to inflammatory mediators. In this study, we investigated the effect of 17beta-estradiol on iNOS function in aortic SMC from streptozotocin-diabetic rats. METHODS AND RESULTS: Comparative analysis of NO release and of iNOS mRNA and protein content after 24-hour stimulation with a cytokine mixture revealed milder iNOS activation in diabetic than in control SMC. Furthermore, 17beta-estradiol dose-dependently blocked iNOS synthesis and activity in control but not in diabetic SMC. The defective estrogen response in diabetic SMC at 24 hours could not be attributed to reduced expression of estrogen receptors (ER). In fact, mRNA and protein levels of ERalpha and, to a greater extent, of ERbeta, were increased in diabetic compared with nondiabetic SMC. Cytokines decreased ERalpha and ERbeta expression in both groups. However, 17beta-estradiol dose-dependently restored the expression of ERalpha but further downregulated that of ERbeta, indicating a differential regulation of ER isoforms. CONCLUSIONS: Estrogenic control of iNOS was impaired in diabetic SMC. This was associated with a larger increase of ERbeta than of ERalpha protein, whereas 17beta-estradiol regulated the two isoforms in an opposite fashion. Thus, modifications in the estrogen modulation of iNOS and in the expression pattern of ER may be involved in diabetic vascular dysfunction.

Animals↗

PubMed2003

Impact of statins on novel risk markers.

Long-and-short term trials with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated significant reductions in cardiovascular and cerebrovascular events in patients with and without preexisting heart disease. Beyond improving the lipid profile, statins have additional effects that may contribute to their overall clinical benefit. Statin treatment appears to reduce global risk profile by affecting both novel and established lipid, inflammatory, and morphologic markers including low-density lipoprotein subclasses, lipoprotein (a), markers of endothelial function, inflammatory mediators, intima-media thickening, and coronary calcification. Although statins may be regarded as a rather homogeneous drug class in terms of biological activity, some agents feature unique properties that have beneficial effects on selected important risk matters.

Animals↗

PubMed2002

Smoking and gender.

Smoking is a major cause of coronary heart disease for both men and women and a positive correlation between tobacco use and cerebrovascular disease has been also described. In addition, cigarette smoking is the most powerful risk factor predisposing to atherosclerotic peripheral artery disease. More recently, passive smoking has been also shown to represent an important risk factor for coronary artery disease. Moreover, the incidence of coronary artery and cerebrovascular diseases in ex-smokers consistently decreases after cessation, further underlying the relevance of smoking as a risk factor for these pathological conditions. The effects of cigarette smoking on atherosclerosis initiation and progression as well on its complications are mostly responsible for the enhanced cardio- and cerebrovascular risk observed in smoking compared to non-smoking subjects. Since hormonal status may also play a role in the development and stability of the atherosclerotic plaque, smoking habits could influence the clinical complications of atheroclerosis in a gender dependent manner. Up to now, however, few studies have investigated the relative importance of smoking as a risk factor for fatal and non-fatal diseases in the two sexes within the same study population. On the basis of available clinical data, this review will discuss the risk of fatal and non-fatal diseases among smoking men and women with special emphasis on cardiovascular and cerebrovascular disease which also represents the most common cause of death among smokers. A description of the mechanisms involved in the tobacco-induced atherosclerotic damage will be also given in order to underline possible gender-related differences.

Adrenergic beta-Antagonists↗

PubMed2002

Novel statins: pharmacological and clinical results.

Rosuvastatin (ZD4522) and pitavastatin (NK-104) are novel HMG-CoA reductase inhibitors with a peculiar pharmacological profile. In particular, they show a high potency in decreasing LDL-C and their catabolism is not mediated by the cytochrome P-450 3A4, thus reducing the potential for drug-drug interaction and improving the management of blood cholesterol. As the magnitude of LDL-C reduction is directly associated with the decrease in the incidence of myocardial infarction and mortality for CAD, statins with increased LDL-C lowering potency may ensure the achievement of target LDL-C levels and offer a more aggressive cholesterol control, further improving CAD morbidity and mortality.

Animals↗

PubMed2002

Safety considerations for statins.

PURPOSE OF REVIEW: The hydroxymethyl glutaryl coenzyme A reductase inhibitors or statins offer important benefits for the large populations of individuals at high risk for coronary heart disease. These drugs have a good safety profile. Nevertheless, differences in physicochemical and pharmacokinetic properties between statins may translate into significant differences in long-term safety. This review focuses on long-term adverse effects related to statin use, namely hepatotoxicity and myopathy. Moreover, the most common drugs used in combination with statins in long-term therapies are analyzed in terms of possible drug/drug interactions affecting the safety of statins. RECENT FINDINGS: The withdrawal of cerivastatin from the global market in 2001, because of severe cases of rhabdomyolysis, highlighted concerns regarding the safety of the entire class. Afterwards, the role of statins and their interactions with other drugs in precipitating this condition have been carefully reviewed. In approximately 60% of the total number of cases, statin-related rhabdomyolysis was found to be related to drug/drug interactions. Recently, all cases of fatal rhabdomyolysis associated with statin use have been reported to the US Food and Drug Administration. This has shown that fatal rhabdomyolysis among statin users is a rare event, the reporting rates being much less than one death per million prescriptions in the case of all statins except cerivastatin. SUMMARY: The safety and tolerability of the available statins support their use as the first-line treatment of patients at high risk for coronary heart disease, since the clinical benefits greatly outweigh the small risk of myopathy. Nevertheless, clinicians should be aware of the adverse effects possibly related to statin therapy, particularly in patients at high risk for coronary heart disease and requiring long-term multiple-drug therapies.

Anticholesteremic Agents↗