Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 7, Issue 1, 2009

The intermediate-conductance Ca²⁺-activated K⁺ channel (KCa3.1) was first described by Gardos in erythrocytes and later confirmed to play a significant role in T-cell activation and the immune response. More recently, KCa3.1 has been characterized in numerous cell types which contribute to the development of vascular disease, such as T-cells, Bcells, endothelial cells, fibroblasts, macrophages, and dedifferentiated smooth muscle cells (SMCs). Physiologically, KCa3.1 has been demonstrated to play a role in acetycholine and endothelium-derived hyperpolarizing factor (EDHF) induced hyperpolarization, and thus control of blood pressure. Pathophysiologically, KCa3.1 contributes to proliferation of T-cells, B-cells, fibroblasts, and vascular SMCs, as well as the migration of SMCs and macrophages and platelet coagulation. Recent studies have indicated that blockade of KCa3.1, by specific blockers such as TRAM-34, could prove to be an effective treatment for vascular disease by inhibiting T-cell activation as well as preventing proliferation and migration of macrophages, endothelial cells, and SMCs. This vasculoprotective potential of KCa3.1 inhibition has been confirmed in both rodent and swine models of restenosis. In this review, we will discuss the physiological and pathophysiological role of KCa3.1 in cells closely associated with vascular biology, and the effect of KCa3.1 blockers on the initiation and progression of vascular disease.

Deep venous thrombosis (DVT) is a highly prevalent clinical problem associated with significant mortality and morbidity. In the United States alone, it is estimated that DVT affects approximately 50 per 100,000 people per year. This results in >600,000 inpatient and outpatient treatments per year and accounts for approximately 100,000 deaths from thromboembolic complications. Post-thrombotic syndrome (PTS) is associated with serious long-term physical, social and economic sequelae for patients. In this article, we attempt to perform a contemporary review of the literature pertaining to the use of thrombolytic therapy and endovascular thrombectomy in the treatment of acute DVT.

Aptamer molecules represent an attractive approach in pharmacological therapy. Thrombin is a plasma serine protease that plays a key role in coagulation and haemostasis, also playing a relevant role in endothelial and smooth muscle cell functions. Thus, the development and use of direct thrombin inhibitors represents a potent tool in cardiovascular therapeutics. This review describes the status of direct thrombin inhibitors, focusing on aptamer-based drug candidates, that are at present in pre-clinical and in clinical trials. In addition, more recent research strategies in the design of novel aptamer thrombin inhibitors are presented and discussed. In particular, their structural, conformational, pharmacokinetic and pharmacodynamic properties are discussed in relation with the specificity of their binding to relevant thrombin exosites, which regulate the enzyme interaction with natural substrates and cellular receptors. Despite the addition of new effective anticoagulants to the therapeutic armoury, there remains a need for safer and effective anticoagulants. The aptamer- based thrombin inhibitors may represent an attractive approach for future developments of more potent and safer anticoagulants.

The natriuretic peptides (NP) are a group of structurally similar but genetically distinct peptides with many favorable physiological properties that have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular diseases. The NP family includes atrial natriuretic peptide (ANP, 28AA), urodilatin (INN: Ularitide, 32 AA), B-type natriuretic peptide (BNP, 32AA), C-type natriuretic peptide (CNP, 22AA), and D-type natriuretic peptide (DNP, 38AA). They share common features and exhibit tissue distribution of gene expression as well as functional and pharmacological characteristics. The primary sites of synthesis of the NP are the heart and brain; additional extra cardiac and extra cranial sites include intestine and kidney. Membrane-bound guanyl cyclase-coupled NP receptors (NPR) (A- and B- types) are generally implicated in mediating NP effects via the production of cyclic GMP as the intracellular messenger. NPR-C lacking the guanyl cyclase domain may influence the target cell function through inhibitory guanine nucleotide (Gi) protein, and they likely also act as clearance receptors for circulating peptides. NPs are identified as regulatory diuretic-natriuretic substances responsible for salt and water homeostasis and as hormones lowering blood pressure. This review discusses the essential biochemistry, physiological properties of NP and their manifold functional implications in cardiovascular medicine.

The natriuretic peptides (NP) appear to be functional by midgestation, respond to volume stimuli, and regulate blood pressure and salt and water balance in the developing embryo. In addition, the NP may help regulate the blood supply to the fetus, acting as vasodilators in the placental vasculature. Peaks of ANP and BNP expression during gestation coincide with significant events in cardiac organogenesis, suggesting a role for NP in the formation of the heart. Levels of atrial natriuretic peptide (ANP) are higher in the fetal circulation than in adults, and fetal ventricles express higher levels of ANP and B-type natriuretic peptide (BNP) than adult ventricles. In this comprehensive review we have discussed the role NP during development of the fetal heart and circulation and in various cardiovascular diseases of neonatal and pediatric age group.

In response to an increased hemodynamic load, such as pressure or volume overload, cardiac hypertrophy ensues as an adaptive mechanism. Although hypertrophy initially maintains ventricular function, a yet undefined derailment in this process eventually leads to compromised function (decompensation) and eventually culminates in congestive heart failure (CHF). Therefore, determining the molecular signatures induced during compensatory growth is important to delineate specific mechanisms responsible for the transition into CHF. Compensatory growth involves multiple processes. At the cardiomyocyte level, one major event is increased protein turnover where enhanced protein synthesis is accompanied by increased removal of deleterious proteins. Many pathways that mediate protein turnover depend on a key molecule, mammalian target of rapamycin (mTOR). In pressure-overloaded myocardium, adrenergic receptors, growth factor receptors, and integrins are known to activate mTOR in a PI3K-dependent and/or independent manner with the involvement of specific PKC isoforms. mTOR, described as a sensor of a cell's nutrition and energy status, is uniquely positioned to activate pathways that regulate translation, cell size, and the ubiquitin-proteasome system (UPS) through rapamycinsensitive and -insensitive signaling modules. The rapamycin-sensitive complex, known as mTOR complex 1 (mTORC1), consists of mTOR, rapamycin-sensitive adaptor protein of mTOR (Raptor) and mLST8 and promotes protein translation and cell size via molecules such as S6K1. The rapamycin-insensitive complex (mTORC2) consists of mTOR, mLST8, rapamycin- insensitive companion of mTOR (Rictor), mSin1 and Protor. mTORC2 regulates the actin cytoskeleton in addition to activating Akt (Protein kinase B) for the subsequent removal of proapoptotic factors via the UPS for cell survival. In this review, we discuss pathways and key targets of mTOR complexes that mediate growth and survival of hypertrophying cardiomyocytes and the therapeutic potential of mTOR inhibitor, rapamycin.

Atrial fibrillation (AF) is a highly prevalent arrhythmia and responsible for significant morbidity, mortality and health care cost. The prevalence of AF is expected to increase markedly with the aging population. The use of conventional antiarrhythmic agents has been limited by potentially fatal ventricular proarrhythmia. Rhythm control could become the preferred treatment strategy for AF if antiarrhythmic agents that are similarly or more effective, but safer, than currently approved AF agents become available. A subanalysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data showed that normal sinus rhythm confers a survival benefit in AF, suggesting that rhythm control, if achieved without the adverse effects related to current antiarrhythmic medications, may offer a significant survival advantage over rate control. Considerable work has been performed to explore novel, potentially safer antiarrhythmic drug targets for AF therapy, and some of these drug targets are currently being tested in experimental and clinical proof of concept studies. This article summarizes relevant aspects of the cellular electrophysiology of AF and reviews the actions of pharmacological agents being considered for the prevention and treatment of AF, focusing on atrial selective antiarrhythmic agents. A variety of drugs that inhibit the atrium-specific ultra rapid delayed rectifier potassium current (IKur) are being evaluated pre-clinically, but human experience with these agents is limited. The acetylcholineactivated current (IKACh) is another novel candidate target for atrial-specific drug therapy. The constitutively active form of this current is increased in human AF and pharmacological inhibition might be of therapeutic value. Certain drugs have IKACh blocking properties, but similar to IKur-blockers, none have been shown to have pure selectivity for this current. Newer agents being studied also include gap junction modulators and angiotensin-converting enzyme inhibitors. There is great hope that at least some of these agents will ultimately be available for effective and safer clinical treatment and prevention of AF.

Obstructive sleep apnoea syndrome (OSAS) represents a highly prevalent disease and is recognized as a major public health burden. Large-scale epidemiological studies have demonstrated an independent relationship between OSAS and various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood, but given the complexity of the disorder, a multifactorial etiology is likely. Inflammatory processes have emerged as critical in the pathogenesis of atherosclerosis in general and they mediate many of the stages of atheroma formation. Circulating levels of several markers of inflammation have been associated with future cardiovascular risk. These markers include cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM- 1) and selectins, cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), chemokines such as IL- 8, and C-reactive protein (CRP). There is increasing evidence that inflammatory processes also play a central role in the cardiovascular pathophysiology of OSAS. This is supported by cell culture and animal studies identifying a preferential activation of inflammatory pathways by intermittent hypoxia (IH), the hallmark of OSAS. A number of studies have selectively examined the expression of inflammatory factors in OSAS patients with different conclusions. These different findings may have been contributed to by a number of methodological factors such as small subject numbers, inadequately matched study populations, particularly in terms of body mass index (BMI), and inclusion of patients with pre-existing cardiovascular or metabolic diseases. This review will focus on the potential role of various inflammatory markers in OSAS with a critical analysis of the current literature.

microRNAs have recently opened new pathways to explain gene expression and disease biology in many scenarios, including cardiac diseases. microRNAs are endogenous small non-coding RNAs that mediate post-transcriptional repression or messenger RNA degradation. By annealing to inexactly complementary sequences in the 3' untranslated region of the target messenger RNA, protein level is down-regulated. Several microRNAs appear to act cooperatively through multiple target sites in one gene and, conversely, most microRNAs can target several genes. miR-133 and miR-1 are specifically expressed in cardiac and skeletal muscle and control myogenesis, cardiac development, cardiac performance and cardiomyocyte hypertrophy (mainly by tuning transcription factors and other growth-related targets). They also modulate the expression of certain cardiac ion channels and related proteins with proarrhythmic effect. Besides them, other microRNAs have been shown to exert influence on the myocardial growth, the electrical balance and the angiogenesis processes that take place in the heart. Bioinformatics is a useful tool to identify potential targets of a given microRNA, although there is still substantial concern about their reliability. Experimental manipulation of microRNAs has provided a tantalizing basis to speculate that future research on microRNAs may yield important progress in the prevention of sudden cardiac death and in the treatment of cardiac heart failure. However, the final effect of the blockage of microRNAs in vivo remains unclear, since each of them can target hundreds of genes with different intensity. The era of the microRNAs in cardiovascular diseases has just started.