Current Medicinal Chemistry - Cardiovascular & Hematological Agents - Volume 2, Issue 1, 2004

Phytosterols and omega-3 fatty acids (n-3) are natural food ingredients with potential cardiovascular benefits. Phytosterols inhibit cholesterol absorption, thereby reducing total cholesterol (TC) and LDL-cholesterol levels. Numerous clinical studies have shown that a daily intake of 1.5-2.0 g of phytosterols can result in a 10-15 % reduction in LDL levels, while consumption of n-3 is associated with a significant reduction in plasma triglyceride (TG) concentrations. Furthermore, n-3 may also beneficially modify a number of other risk factors of coronary heart disease (CHD). Thus, it is reasonable to suggest that combination of phytosterols and n-3 may further reduce cardiovascular risk factors. Esterification of phytosterols with non-n-3 fatty acids has substantially improved their incorporation into a variety of foods without affecting the efficacy of phytosterols. Therefore, it is assumed that esterification of phytosterols with n-3 may have advantages for both food industry and health. Evidence suggests that this combination is effective in reducing the levels of several cardiovascular risk factors including TC and TG concentrations, pro-aggregatory factors, arrhythmic eicosanoid and thromboxane A2 levels. In this mini-review, we have critically reviewed and summarized data from clinical and animal studies in which phytosterols and n-3, alone or in combination, were used. We have also provided information on structure-function relationship for these two natural compounds. Biological properties of several phytosterol derivatives including phytosterol-glucoside have been also discussed. Although the animal studies are supportive of this combination therapy, human studies are needed to address its long term effects.

A large number of anticoagulant polysaccharides from marine algae have been isolated and characterized. Algal anticoagulant polysaccharides exert their anticoagulant activity through potentiating antithrombin III (AT III) and / or heparin cofactor II (HC II) that are important endogenous inhibitors, called SERPIN. The anticoagulant mechanism is the one by which heparin, heparin sulfate and dermatan sulfate exert their activity. On the other hand, some algal anticoagulant polysaccharides exert anticoagulant activity through directly inhibiting fibrin polymerization and / or thrombin activity without potentiating AT III and HC II. Furthermore, new functions of algal anticoagulant polysaccharides have been discovered recently, as it has been shown that heparin and its derivatives have important roles in many biological processes. Algal anticoagulant polysaccharides activate fibrinolysis system and modulate endothelial cell functions. Our recent studies conducted on marine algal biologically active compounds have shown anti-platelet and anticoagulant proteins and fibrinolytic enzymes. Therefore, algal polysaccharides and proteins have attracted the attention of biomedical scientists. This article provides a short review of algal anticoagulants and recent developments in this area. It focuses on their biological activities, structures, and potent uses as medical agents.

Gram-negative sepsis is associated with disseminated intravascular coagulation (DIC) due to endothelial damage, which is induced by inflammatory mediators released from phagocytes activated by lipopolysaccharide (LPS). DIC is a systemic hemorrhagic syndrome, which results from the consumption of coagulation factors for the formation of multiple thrombi in the systemic microvessels; it is associated with multiple organ failure. Therefore, not only the systemic activation of coagulation but also the inflammatory response has been perceived as the therapeutic target for DIC in sepsis. We gave attention that protein C inhibitor (PCI) acts as an inhibitor of both plasma kallikrein and thrombin, which are known to act not only as procoagulant proteases but also as chemotactic factors toward phagocytes. Then, we hypothesized that PCI possibly acts as an anti-DIC agent rather than an inhibitor of the protein C anticoagulant pathway under the pathophysiology of DIC, accompanied by the decrease in the thrombomodulin expression on endothelial cells. Our studies have suggested that PCI purified from human urine (uPCI) improves the pathophysiology of DIC through the inhibition of activities of plasma kallikrein and thrombin, and the activities of PCI are regulated by N-glycans. This review introduces the anti-DIC action of PCI and about the modification of N-glycosylation site(s) of PCI to heighten the value of PCI as an anti-DIC agent.

The incidence of supraventricular arrhythmias is high following open-heart surgery, occurring in 25% to about 50% of patients. The most common of these arrhythmias is atrial fibrillation (AF). Postoperative AF has been associated with increased incidence of other complications and increased hospital length of stay. Atrial arrhythmias are most frequent in the first two to three days after cardiothoracic surgery, but they can occur at any point in the recovery period. Age and concomitant valular heart disease are consistently the independent factors most strongly associated with postoperative atrial fibrillation. Prevention of AF seems to be a reasonable clinical goal, and, consequently, many randomized trials have evaluated the effectiveness of pharmacological and nonpharmacological interventions for prevention of AF. The main indication for AF prophylaxis remains the shortening of length of hospital stay and possibly reduction in stroke. The optimal treatment strategies for reducing postoperative AF are not well established. Commonly used therapeutic approaches include the use of rate-controlling drugs such as β-blockers, calcium antagonists, and digoxin. Some pharmacological strategies including β-blockers, sotalol, and amiodarone have shown to reduce risk of postoperative AF and may reduce length of hospital stay. There is no convincing evidence that reducing postoperative AF reduces stroke. This review summarizes current evidence from randomized controlled trials to estimate the effect of pharmacological and non pharmacologic interventions on the occurrence of AF after open-heart surgery and its effects on postoperative outcome.

In vitro experiments and in vivo studies indicate that estrogens exert various beneficial effects on the vascular wall. In the present review the recent literature and the results of our own studies on this topic are summarized. By modulating the synthesis of nitric oxide, prostacyclin and endothelin and blocking calcium channels estrogens positively affect the vasotonus. Atherogenesis, which is considered an inflammatory, fibroproliferative process, may be delayed by estrogens via downregulation of inflammatory markers, such as cell adhesion molecules and chemokines. The delay is further supported by the inhibition of smooth muscle cell proliferation and downregulation of angiotensin receptor gene expression as well as by its antioxidative property. In addition, estrogens may stabilize the atherosclerotic plaque by reducing the expression of matrix metalloproteinases. The thrombogenic potency of the ruptured plaque may be reduced also by estrogens via downregulating the synthesis of plasminogen activator inhibitor-1. In addition, own clinical studies suggest that other non-endothelial derived vasoactive surrogate markers, such as serotonin and urodilatin, may be positively influenced by estrogens. Differential effects of progestin addition were observed concerning the direct estrogenic effects on the vasculature. Antagonistic progestin effects have been observed for some markers and may depend on the type of progestin and on its administration mode. Thus, the role of progestin addition remains to be elucidated in further studies.

Co-localization of urocortin (Ucn) and its putative receptor (CRF-R2b) in peripheral tissues, including the heart and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, Ucn gene expression and / or immunoreactivity are increased in the ventricles of patients with failing hearts. Hemodynamic effects of Ucn include vasodilation and increases in cardiac contractility, coronary blood flow and conductance, cardiac output and heart rate. Due to the likely benefit of such actions in states of cardiac compromise, our laboratory has recently reported the first study examining the effects of Ucn in ovine experimental heart failure. We observed profound and sustained cardiovascular (reduced cardiac preload and afterload and increased cardiac output), hormonal (inhibition of vasopressin, endothelin and renin-angiotensin-aldosterone axis) and renal effects (natriuresis, diuresis and augmented creatinine clearance). Such effects incorporate many of the therapeutic goals of heart failure management. Recently, two further members of the CRF peptide family have been identified. In contrast to Ucn, Ucn II and III are reported to be highly selective for the CRF-R2β, displaying negligible affinity for CRF-R1. As such, one could speculate that these new peptides might produce the salutary effects in heart failure as seen with Ucn, without concomitant activation of the stressrelated hormone ACTH (mediated via CRF-R1). Clearly, further study is essential to confirm whether manipulation of this new family of peptides (especially Ucn II and Ucn III) offers benefit to the syndrome of heart failure with potential clinical applications in humans.

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide spread enzymes, present in mammals in at least 14 different isoforms: some of these isozymes are cytosolic (CA I, CA II, CA III, CA VII), while others are membrane-bound (CA IV, CA IX, CA XII and CA XIV); CA V is mitochondrial, and CA VI is secreted in the saliva. Three acatalytic forms are also known (CARP VIII, CARP X and CARP XI). Several important physiological and physio-pathological functions are played by many CA isozymes, which are strongly inhibited by aromatic and heterocyclic sulfonamides. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped in the design of potent inhibitors, some of which possess important clinical applications. The use of such CA inhibitors (CAIs) as antiglaucoma drugs will be discussed in detail, together with the recent developments that led to isozyme-specific and organ-selective inhibitors. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CAIs were shown to inhibit the growth of several tumor cell lines in vitro and in vivo, constituting thus interesting leads for developing novel antitumor therapies. Future prospects for drug design applications for inhibitors of these ubiquitous enzymes will be dealt with. Although activation of CAs has been a controversial issue for some time, recent kinetic, spectroscopic and X-ray crystallographic experiments offered an explanation for this phenomenon, based on the catalytic mechanism. It has been demonstrated recently, that molecules that act as carbonic anhydrase activators (CAAs) bind at the entrance of the enzyme active site participating in facilitated proton transfer processes between the active site and the reaction medium. In addition to CA II - activator adducts, X-ray crystallographic studies have also been reported for ternary complexes of this isozyme with activators and anion (azide) inhibitors. Structure-activity correlations for diverse classes of activators will be discussed for the isozymes for which the phenomenon has been studied, i.e., CA I, II, III and IV. The possible physiologic relevance of CA activation will also be addressed, together with the recent pharmacological applications of blood CA isozymes activators, as potential memory enhancing drugs.

Type 1 receptors (AT1) for the peptide hormone angiotensin II play a crucial role in the cardiovascular homeostasis. In this regard, several selective, orally active non-peptide antagonists have been developed for the treatment of hypertension and congestive heart failure. Pre-clinically, they have been routinely tested for their ability to inhibit angiotensin II induced contraction of rabbit aorta strips. This led to the distinction between surmountable antagonists, which only produce a parallel rightward shift of the angiotensin II concentration- induced response curve, and insurmountable antagonists that also decrease the maximal response. The molecular mechanism that is responsible for insurmountable antagonism has been extensively investigated in Chinese Hamster Ovary cells transfected expressing the human AT1 receptor. These experiments revealed that all biphenyltetrazole-countering AT1 receptor antagonists are competitive with angiotensin II and that the insurmountable behaviour of some of them is related to the formation of a long lasting / tight binding state of the antagonist-receptor complex. This may contribute to their long lasting clinical effect. This paper also focuses on the influence of a number of methodological approaches used to study AT1 receptor antagonists on their observed in vitro receptor binding properties.

Despite recent advances in non-pharmacologic approaches antiarrhythmic drugs still play a dominant role in the treatment of cardiac arrhythmias. Large randomized controlled clinical trials have pointed out the importance of a proper benefit to risk evaluation in various patient subsets. This led to a continuous decline in the use of sodium channel blockers due to their possible proarrhythmic effects particularly in patients with reduced left ventricular function and ischemic heart disease. On the contrary, beta-blockers and more complex class III compounds such as sotalol and amiodarone have been prescribed increasingly. However, side effects commonly observed boosted the development of agents with simpler ion channel-blockade and less adverse reactions. In this review newer so-called“pure” class III agents will be discussed. Their common mechanism of action is an antifibrillatory effect both on the atrial and ventricular level. Clinically, they are used in the chemical cardioversion and the prevention of atrial fibrillation or atrial flutter as well as for the maintenance of sinus rhythm after its successful restoration. This report contains a detailed analysis of the pharmacokinetics, results of clinical studies and implications regarding the use in daily practice for three distinct compounds: ibutilide, dofetilide and azimilide. As efficacy is still limited their current and future role in hybrid therapies combining drug therapy with alternative treatment modalities (catheter ablation, pacemakers and implantable cardioverter defibrillators) is discussed. In addition, an outlook for a future drug design implementing changes in electrically remodeled atrial tissue will be given.