Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 6, Issue 4, 2008

Sodium ion transporters in sarcolemma are involved in numerous vital cell functions, such as excitability, excitationcontraction coupling, energy metabolism, pH and volume regulation, development and growth. In a number of cardiac pathologies, the intracellular sodium concentration ([Na+]i) is elevated. Since [Na+]i and intracellular Ca2+ concentration ([Ca2+]i) are coupled through the Na+/Ca2+-exchanger, these cardiac pathologies display disturbed calcium handling. For instance, [Na+]i is increased in heart failure (HF) leading to Na+/Ca2+-exchanger mediated increase in [Ca2+]i, reduced contractility and increased propensity to arrhythmias. Several studies support the contention that an increase in [Na+]i and [Ca2+]i transduces a signal the nucleus, that triggers development of cardiac remodelling and hypertrophy. Pharmacological intervention, which favourably interferes with [Na+]i and [Ca2+]i homeostasis, might prevent hypertrophy, cardiac remodelling, arrhythmias and HF. The most important sodium transport mechanisms that may underlie increased [Na+]i are: Na+/H+-exchanger (NHE-1), Na+-HCO3 - co-transporter (NBC), Na+-K+-Cl- co-transporter (NKCC), Na+- channel, Na+/K+-ATPase and Na+/Ca2+-exchanger (NCX) Preclinical studies showed that pharmacological interventions, targeted against sarcolemmal sodium ion transporters, proved effective in ameliorating heart failure. In this respect: 1) NHE-1 inhibition reduces cardiac remodelling, hypertrophy and HF, although, in the patients following coronary artery bypass graft surgery, it was associated with an increase of stroke. 2) The activity of NBC is up-regulated, during the development of hypertrophy and may be a therapeutic strategy to prevent the development of hypertrophy and HF. 3) NKCC is increased in post-infarction HF, and the inhibition of NKCC attenuated post-infarction remodelling. 4) Inactivation of sodium channels is impaired in HF, which may result, in increased Na+ influx and prolongation of the action potential. 5) Blockade of NCX may be useful as a part of a combined therapeutic approach. Inhibition of reversed mode, or activation of forward mode NCX reduce Ca2+ overload. 6) Inhibition of Na+/K+-ATPase (digoxin), is used to increase contractility, however, it enhances progression of HF. Oppositely, new drugs which increase activity of Na+/K+-ATPase may prevent the development of cardiac remodelling hypertrophy and HF. In this review we give an overview and discuss the therapeutic relevance of the different sodium ion transport mechanisms in the setting of heart failure.

The metabolic syndrome (MS) has become a worldwide health problem. It is difficult for patients to follow a diet/exercise regime that would improve their symptoms, therefore the investigation of agents that may deal with its more serious aspects is an important medical field for research. The cardiovascular consequences associated with the syndrome and some of the therapeutic approaches are discussed. The different agents can be divided into several groups: Inorganic/ organic: Zinc complexes with garlic components as insulino-mimetics; Selenium as antioxidant; Copper, Zinc and Manganese as microcomponents of antioxidant enzymes. Organic: Natural or Synthetic: Glycine is effective in lowering blood pressure, TBARS, intra-abdominal fat tissue and triglycerides in sucrose-fed rats. Pharmaceutical products: Fibrates, Lipid-lowering drugs. Antidiabetics. Anti-gout agents On the other hand there are natural products such as those of animal origin: Sex hormones (also synthetic) used in the problems of menopause and hypoandrogenism frequently found in the MS, antioxidant Omega-3-oils (fish oils) or Vegetal: for example Digitalis pupurea, century-old cardiovascular medication as well as Magnolia officinalis; Spirulina maxima with beneficial effects as antioxidant and lipid-lowering agent, among others. Prickly Pear Cacti. (Opuntia Ficus- Indica Cochlospermum vitifolium (Willd.) Spreng) whose many properties against diabetes and hypercholesterolemia have been empirically known for many years. Perezone (from Perezia plants, a.k.a. Peonia) described as an antiplatelet aggregating agent. The mixed elements in the Mediterranean diet: Fish, salads (peppers, tomatoes), olive oil, garlic, red wine which combines fish oils, garlic and avocado as well as antioxidants from the rest of its components.

Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity.

The Insulin-like growth factor-1 (IGF-1) system is dynamic and complex, involving many binding proteins, binding-proteinrelated proteases, and receptors. It has emerged in time as a powerful defence to life processes of many cytotypes, tissues and systems. Mainly in body metabolism, diabetes and cardiovascular system, but also in brain and kidney, IGF-1 plays a key role in maintaining homeostasis, increasing progenitor cell potential, and improving physiologic performance both in rest and stress conditions. Its vasculoprotective and insulin sensitizing ability exerts a protective role on flow-metabolism coupling and organs function. Therapeutical human use of recombinant human IGF-1 (rhIGF-1) has been widely applied only in Laron syndrome, while being verified in many randomized controlled trials to improve glycemic control in type 1 and type 2 diabetes, and proposed in neurological disease such as amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer disease. Sparse evidence exists moreover about rhIGF-1 use in insulin resistance, burns, catabolic and post-surgery states, acute and chronic renal failure, amyotrophic lateral and multiple sclerosis, brain injury, and immunoincompetence. Along with these data, results are available on cardiovascular benefit of administration of other growth factors, such as erythropoietin and vascular endothelial growth factor, or on cardiovascular side effects of growth factor antagonists such as trastuzumab in cancer therapy. We intended therefore to summarize in this review available human and animals evidence about rhIGF-1 effects on different systems with insights on rhIGF-1 cardiovascular effects. In view of its ability to improve flow-metabolism coupling, IGF-1 could indeed represent a new cardiovascular disease treatment option for many cardiac disorders such as ischemic heart disease and heart failure.

Investigation of the mechanisms of atherosclerosis has determined that inflammation plays a central role in the development, progression, and outcome of acute coronary syndrome (ACS). C-reactive protein (CRP) plasma levels increase in patients with ACS. CPR is an important prognostic marker in ACS, following angioplasty, and in the long-term management of post-infarction patients. Although CRP will remain over time a useful marker, the role and implications of increased plasma concentrations of other acute phase proteins (APPs), such as alpha-1-antitrypsin (A1AT), alpha-1 glycoprotein (A1GP), haptoglobin (HG), ceruloplasmin (CP), and C3c and C4 complement fraction, in patients with ACS are still not completely defined. This short review summarizes the experimental and clinical evidence regarding the role, and the biological and clinical significance of these other APPs in ACS.

The anthracyclines constitute a group of drugs widely used for the treatment of a variety of human tumors. However, the development of irreversible cardiotoxicity has limited their use. Anthracycline-induced cardiotoxicity can persist for years with no clinical symptoms. However, its prognosis becomes poor after the development of overt heart failure, possibly even worse than ischemic or idiopathic dilated cardiomyopathies. Due to the successful action of anthracyclines as chemotherapic agents, several strategies have been tried to prevent/attenuate their side effects. Although anthracycline-induced injury appears to be multifactorial, a common denominator among most of the proposed mechanisms is cellular damage mediated by reactive oxygen species. However, it remains controversial as to whether antioxidants can prevent such side effects given that different mechanisms may be involved in acute versus chronic toxicity. The present review applies a multisided approach to the critical evaluation of various hypotheses proposed over the last decade on the role of oxidative stress in cardiotoxicity induced by doxorubicin, the most used anthracycline agent. The clinical diagnosis and treatment is also discussed.

Weight adapted low molecular weight heparin (LMWH) treatment is recommended as initial anticoagulant therapy of deep vein thrombosis, pulmonary embolism, in patients with myocardial ischemia or when oral anticoagulation (OAC) must be interrupted peri- operatively. Traditionally unfractioned heparin (UFH) was used as standard short acting anticoagulant, with the therapy monitored by frequent laboratory testing. Currently LMWH have broadly replaced UFH as first- choice anticoagulant due to more preferable pharmacokinetics and a better safety profile. Therapeutic anticoagulation with LMWH can be achieved by subcutaneous weight adapted application and measurement of anti-factor Xa- activity (anti-Xa) has been established as gold standard for LMWH- monitoring. However, since almost all LMWH dosing regimens have been developed empirically without laboratory monitoring, there is still a debate ongoing about the usefulness and impact of anti-Xa-testing. Data are lacking that prove a clear correlation between obtained levels of anti-Xa and the patients´ clinical outcome. Newer methods have been developed aiming to determine a broader spectrum of LMWH depending anticoagulant activity. Even though there are some promising preliminary results, these alternative methods are not ready for routine clinical use yet. Nevertheless, current guidelines advise determination of anti-Xa in special patient populations with markedly altered LMWH metabolism or to exclude residual LMWH- activity before surgery at very high risk of bleeding. The aim of this article is to review critically the usefulness of anti- Xa guidance of LMWH- therapy and to give new perspectives on upcoming methods of LMWH- monitoring.

Soluble guanylyl cyclase (sGC) is one of the key enzymes of the nitric-oxide (NO)/cyclic 3',5'-guanosine monophosphate (cGMP) pathway. Located in virtually all mammalian cells, it controls the vessel tone, smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In vivo sGC activity is mainly regulated by NO which in turn is released from L-arginine by nitric oxide synthases. One of the main diseases of the cardiovascular system, endothelial dysfunction, leads to a diminished NO synthesis and thus increases vessel tone as well as the risk of thrombosis. The predominant therapeutic approach to this condition is a NO replacement therapy, as exemplified by organic nitrates, molsidomin, and other NO releasing substances. Recent advances in drug discovery provided a variety of other approaches to activate sGC, which may help to circumvent both the tolerance problem and some non-specific actions associated with NO donor drugs. Substances like BAY 41-2272 stimulate sGC in a heme-dependent fashion and synergize with NO, allowing to enhance the effects both of endogenous NO and of exogenous NO donors. On the other hand, heme-independent activators like BAY 58-2667 allow to activate sGC even if it is rendered unresponsive to NO due to oxidative stress or heme loss. Furthermore, a few substances have been described as specific inhibitors of sGC that allow to alleviate the effects of excess NO production as seen in shock. This review discusses the cardiovascular effects of heme-dependent and heme-independent activators as well as of inhibitors of sGC.

Dimethylated L-arginine analogs have been attracting the attention of both basic researchers and clinicians for 15 years since 1992 when Vallance et al. were first to observe several fold elevations of asymmetric and symmetric dimethyl-L-arginine levels (ADMA and SDMA, respectively) in plasma of hemodialyzed patients. ADMA - in contrast to SDMA - competes with L-arginine at the level of NO synthase with consequent inhibition of NO generation. Later studies have revealed excessive ADMA accumulation in the presence of atherosclerotic risk factors and endothelial dysfunction even in patients free of clinical evidence of atherosclerosis. Moreover, ADMA concentrations were elevated also in proportion to the severity of carotid, coronary and peripheral atherosclerosis. Additionally, in vitro studies have shown the ability of proinflammatory cytokines and oxidized low-density lipoproteins to increase liberation of ADMA by cultured endothelial cells. This evidence has provoked a hypothesis that ADMA may accelerate atherogenesis by inhibition of endothelial NO synthase. Indeed, ADMA concentration proved to be an independent adverse outcome predictor in end-stage renal disease and in coronary artery disease. On the other hand, it remains an intriguing issue how ADMA is able to exert any biological effects in the presence of saturating L-arginine concentrations which are well above the Michaelis-Menten constant of endothelial NO synthase for Larginine. Recent years have brought novel fascinating findings in the field of research on dimethylated L-arginine analogs. First, ADMA has been shown to accelerate replicative senescence of endothelial cells via inhibition of the activity of telomerase, an enzyme counteracting telomere attrition, a molecular “clock”. Second, ADMA impairs the mobilization and activity of bone marrow-derived endothelial progenitor cells that participate in continuous endothelial renewal and neovascularization of ischemic tissues. Third, SDMA - previously considered an inactive stereoisomer of ADMA - has been demonstrated to inhibit NO synthesis via competition with L-arginine uptake by endothelial cells. As SDMA rises in earlier stages of renal dysfunction than ADMA, it may contribute to excessive cardiovascular morbidity in chronic kidney disease.

Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease. It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions. Clopidogrel effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y12 receptor on the platelet membrane. Aspirin works by irreversibly acetylating the cyclooxygenase (COX-1) enzyme, thus suppressing the production of thromboxane A2 (TxA2) and inhibiting platelet activation and aggregation. Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel. The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed. Clopidogrel and aspirin responsiveness as they are measured in the laboratory by various techniques (platelet aggregometry and point-of-care assays such as platelet function analyzer [PFA-100] and rapid platelet function assay [RPFA]) are evaluated. The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical, cellular and genetic factors are defined. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction, stroke or death. The therapeutic interventions to deal with nonresponsiveness are reported, although specific recommendations are not clearly established. In the future, routine measurement of platelet function in patients with cardiovascular disease may become the standard of care. Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient.

Physiologic clotting is a defensive action. The new cell-based model of hemostasis proposes three steps - initiation, amplification and propagation - occurring on specific cell surfaces to generate a thrombus in a tightly regulated manner. The initiation phase relies on key players including tissue factor (TF), factor VIIa (fVIIa), platelets, Ca2+, phospholipids, and factor X/Xa (fX/fXa). Exposure of TF on sub-endothelial and other blood cells triggers a coagulation response, which may have to be inhibited to prevent a deleterious thrombotic effect. Inhibiting TF-initiated coagulation, akin to ‘nipping coagulation in the bud’, is predicted to have major advantages, including a more efficient separation of the antithrombotic and hemorrhagic responses. The availability of crystal structures of TF, fVIIa and TF- fVIIa complex makes structure-based drug design feasible. Although no initiation phase small molecule inhibitor has reached the clinic as yet, several molecules have displayed promise. We discuss recent results on the discovery of inhibitors of the initiation phase with special emphasis on peptides, peptidomimetics and organic small molecules.

The sense of touch is one of the most vital; still, it is incompletely understood. We review the afferent function that allows for the relay of sensory information from the periphery (the skin) to the central nervous system. Within this afferent function, we examine the different integrating levels including several candidates for cutaneous transducers, the conduction of the information via the afferent nervous fibres and the transmission of the sensory stimuli to higher brain structures, resulting in the perception of the different senses. We then examine the efferent system that stimulates the skin by secreting neurotransmitters. Finally, we discuss the tools available to study the cutaneous neurovascular interaction and conclude on a novel test that assesses this interaction triggered by the application of a local non noxious pressure (tactile stimulation).

Angiogenesis is a complex process that is regulated by pro- and antiangiogenic factors. These factors can emanate from diverse sources including cancer cells, stromal cells, blood and extracellular matrix. Their relative contribution is likely to change with tumor type and tumor site. Vascular endothelial growth factor (VEGF) is now well confirmed as the primary and the most potent inducer of angiogenesis. To activate cellular signaling pathways, VEGF binds to receptor kinases VEGF-R1, R2 and R3. It then promotes several events required for the formation of new blood vessels, such as endothelial cell survival, proliferation, migration and vascular permeability. Activation of endothelial cells, leads to the secretion of enzymes which degrade the extracellular matrix (ECM) and hence promote metastasis. Similarly it promotes survival by inducing Bcl-2 expression on VEGF receptor positive leukemia. Besides being a potent mitogen for macrovascular cells derived from arteries, veins and lymphatics, it is also highly involved in a number of angiogenic related disorders including inflammatory diseases, rheumatoid arthritis, psoriasis, retinopathies and age related macular degeneration. Neovascularization and increased vessel permeability are being recognized as major causes of VEGF related pathogenesis. Therefore, inhibition of VEGF pathway is a strategy being widely pursued to provide new therapeutics for the treatment of VEGF related disorders. Over twenty compounds with anti-angiogenic properties ranging from VEGF neutralizing antibody, soluble receptors, receptor antagonists or tyrosine kinase inhibitors (TKIs) are either approved or are currently under clinical (phase I - III) study. This review aims to provide an updated account of how VEGF inhibitors are shaping up to become an important class of drugs used in the treatment of cancer.

Most cardiac Na+ channels open transiently within milliseconds upon membrane depolarization and are responsible for the excitation propagation. However, some channels remain active during hundreds of milliseconds, carrying the so-called persistent or late Na+ current (INaL) throughout the action potential plateau. INaL is produced by special gating modes of the cardiac-specific Na+ channel isoform. Experimental data accumulated over the past decade show the emerging importance of this late current component for the function of both normal and especially failing myocardium, where INaL is reportedly increased. Na+ channels represent a multi-protein complex and its activity is determined not only by the pore-forming α subunit but also by its auxiliary β subunits, cytoskeleton, and by Ca2+ signaling and trafficking proteins. Remodeling of this protein complex and intracellular signaling pathways may lead to alterations of INaL in pathological conditions. Increased INaL and the corresponding Na+ influx in failing myocardium contribute to abnormal repolarization and an increased cell Ca2+ load. Interventions designed to correct INaL rescue normal repolarization and improve Ca2+ handling and contractility of the failing cardiomyocytes. New therapeutic strategies to target both arrhythmias and deficient contractility in HF may not be limited to the selective inhibition of INaL but also include multiple indirect, modulatory (e.g. Ca2+- or cytoskeleton- dependent) mechanisms of INaL function.