6,963 publications from this institution
Background Mesenchymal precursor cells (MPC) are cells that exerted cardio-protective, anti-remodeling, and pro-angiogenic actions in pre-clinical models of acute myocardial infarction (AMI). They ...
Ahlquist in 1948 first recognised that there were two distinct types of adrenoceptor, which he was able to differentiate by comparing the rank order of potency of several adrenergic agonists in various tissues.1 Alpha-adrenoceptors which mediate smooth muscle contraction were characterised by the potency order adrenaiine> noradrenaline >isoprenaline and beta adrenoceptors, mediating relaxation, by the rank order isoprenaline > adrenaline > noradrenaline. Since then specific antagonists such as phentolamine, which blocks a-adrenorecep tors, and propranalol, which blocks ?-adrenoreceptors3 have been developed. Beta-adrenoceptors have been subclassified into ?x-receptors, which mediate positive inotropic cardiac re? sponses and lipolysis and for which adrenaline and noradrena? line are equipotent, and ?o-receptors, which mediate relaxation in vascular, bronchial, and uterine smooth muscle for which adrenaline is more potent than noradrenaline.2 Antagonists such as practolol, atenolol, and metroprolol are more potent at ?x than ?2-receptors (and are therefore termed cardioselective), whereas agonists such as salbutamol and terbutaline are more potent at ?2than ?rreceptors (and are therefore termed bronchodilators). Some tissues show a response intermediate between ?A and ?2-receptors, which may be explained by the co-existence of both types of ?-receptor. More recently, the existence of a-receptor subtypes has been recognised, based on the development of selective agents.3 Alphai-receptors are the classical post-synaptic a-receptors which mediate smooth muscle contraction, whereas a2-receptors, located presynaptically, reduce the amount of noradrenaline released from the nerve ending?that is, an autoinhibitory effect. There is some evidence that a2-receptors may also be located post-synaptically and on platelets. Prazosin is a selective antagonist of aj-receptors and the plant alkaloid yohimbine a selective antagonist of a2-receptors, whereas phento lamine is equipotent at ax and a2-receptors. Clonidine is a more potent agonist at a2 than ax-receptors.
Coronary angioplasty is an effective treatment for patients with angina at rest, either refractory or initially stabilized but returning despite pharmacologic treatment, and with early postinfarction angina. The procedure has a high initial success rate, but there is an increased risk of major complications resulting from a higher incidence of acute closure, which may be related to preexisting thrombus. Resolution of this problem may be achieved by the use of more potent antiplatelet treatment, pretreatment with thrombolytic agents, or treatment that can be applied locally (e.g., laser energy, atherectomy) at the site of the unstable plaque. Results in this study have been obtained from selected groups of patients: those with predominantly single-vessel disease and well-preserved left ventricular function. It remains to be determined whether the same benefits can be achieved in patients with multivessel disease or in those who have severely reduced left ventricular function.
Background —In addition to its known properties as a competitive, nonselective β and α-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis. Methods and Results —In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 hours before scheduled directional coronary atherectomy and continuing for 5 months after a successful procedure. The primary end point was the minimal luminal diameter as determined during follow-up angiography 26±2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 (88.9%), a ≤50% diameter stenosis was achieved without the use of a stent. Evaluable follow-up angiography was available in 292 eligible patients (90%). No differences in minimal luminal diameter (1.99±0.73 mm versus 2.00±0.74 mm), angiographic restenosis rate (23.4% versus 23.9%), target lesion revascularization (16.2 versus 14.5), or event-free survival (79.2% versus 79.7%) between the placebo and carvedilol groups were observed at 7 months. Conclusions —The maximum recommended daily dose of the antioxidant and β-blocker carvedilol failed to reduce restenosis after successful atherectomy. These findings are in contrast to those of the Multivitamins and Probucol Trial, which raises doubts regarding the validity of the interpretation that restenosis reduction by probucol was via antioxidant effects. The relationship between antioxidant agents and restenosis remains to be elucidated.
Nitric oxide (NO) is increased in the lung periphery of patients with chronic obstructive pulmonary disease (COPD). However, expression of the NO synthase(s) responsible for elevated NO has not been identified in the peripheral lung tissue of patients with COPD of varying severity.Protein and mRNA expression of nitric oxide synthase type I (neuronal NOS [nNOS]), type II (inducible NOS [iNOS]), and type III (endothelial NOS [eNOS]) were quantified by Western blotting and reverse transcription-polymerase chain reaction, respectively, in specimens of surgically resected lung tissue from nonsmoker control subjects, patients with COPD of varying severity, and smokers without COPD, and in a lung epithelial cell line (A549). The effects of nitrative/oxidative stress on NOS expression and activity were also evaluated in vitro in A549 cells. nNOS nitration was quantified by immunoprecipitation and dimerization of nNOS was detected by low-temperature SDS-PAGE/Western blot in the presence of the peroxynitrite generator, 3-morpholinosydnonimine-N-ethylcarbamide (SIN1), in vitro and in vivo.Lung tissue from patients with severe and very severe COPD had graded increases in nNOS (mRNA and protein) compared with nonsmokers and normal smokers. Hydrogen peroxide (H(2)O(2)) and SIN1 as well as the cytokine mixture (IFN-gamma, IL-1beta, and tumor necrosis factor-alpha) increased mRNA expression and activity of nNOS in A549 cells in a concentration-dependent manner compared with nontreated cells. Tyrosine nitration resulted in an increase in nNOS activity in vitro, but did not affect its dimerization.Patients with COPD have a significant increase in nNOS expression and activity that reflects the severity of the disease and may be secondary to oxidative stress.
Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as nuclear factor-κB. Gene expression is regulated by acetylation of core histones through the action of coactivators, such as CREB-binding protein, with intrinsic histone acetyltransferase (HAT) activity. Conversely, gene repression is mediated via histone deacetylases (HDACs) and other corepressors. In asthma, there is an increase in HAT activity and some reduction in HDAC activity, which is restored by corticosteroid therapy. Corticosteroids switch off inflammatory genes in asthma through the inhibition of HAT activity and by the recruitment of HDAC2 to the activated inflammatory gene complex. In chronic obstructive pulmonary disease, there is a reduction in HDAC2 activity and expression, which may account for the amplified inflammation and resistance to the actions of corticosteroids. The reduction in HDAC2 may be secondary to oxidative and nitrative stress as a result of cigarette smoking and severe inflammation, and may also occur in severe asthma, smoking asthmatic patients and cystic fibrosis. Similar mechanisms may also account for the steroid resistance seen with latent adenovirus infections. The reduction in histone deacetylase activity can be restored by theophylline, which may be able to reverse steroid resistance in chronic obstructive pulmonary disease and other inflammatory diseases.
