Current Medicinal Chemistry – Cardiovascular & Hematological Agents, Vol. 2, No. 2, 2004
Contents
Vascular Effects of
Antiarrhythmic Drugs and the Roles of K+ Channels Pp. 99-106
H. Kinoshita and Y. Hatano
Drug Targeting of
Estrogen Receptor Signaling in the Cardiovascular System: Preclinical and
Clinical Studies Pp. 107-122
Silvia
M. Sanz-Gonzalez, Antonio Cano, M. A. Valverde, Carlos Hermenegildo and Vicente Andres
L-Arginine Transport
in Disease Pp. 123-131
Antonio
Claudio Mendes Ribeiro and Tatiana M. C. Brunini
Cardiovascular
Alterations After Spinal Cord Injury: An Overview Pp. 133-148
Guadalupe
Bravo, Gabrie Guizar-Sahagun, Antonio Ibarra, David Centurion and Carlos M. Villalon
Understanding the
Mechanism and Prevention of Arterial Occlusive Thrombus Formation by
Anti-Platelet Agents Pp. 149-156
S.
Goto
Progress in the Field
of GPIIb/IIIa Antagonists Pp. 157-167
Julien
Hanson, Xavier de Leval, Jean-Louis David, Claudiu Supuran, Bernard
Pirotte and Jean- Michel Dogne
The Endothelium and
Platelets in Cardiovascular Disease: Potential Targets for Therapeutic
Intervention Pp. 169-178
K.T.
Tan, S.P. Watson and G.Y.H. Lip
Cardiovascular Effects
of the Phytoestrogen Genistein Pp. 179-186
Domenica
Altavilla, Alessandra Crisafulli, Herbert Marini, Maria Esposito, Rosario
D’Anna, Francesco Corrado, Alessandra Bitto and Francesco Squadrito
Abstracts
[Back
to top] Vascular Effects of Antiarrhythmic Drugs and
the Roles of K+ Channels
H. Kinoshita and Y.
Hatano
Since many of antiarrhythmic drugs can act on variable ion channels of cardiac myocytes, these compounds may also play a role in the activity of similar ion channels expressed on the vascular smooth muscle cells. In contrast, some of these ion channels expressed on vasculature have different subtypes of the channels, indicating that antiarrhythmic drugs may differentially affect ion channels on cardiac myocytes and vascular smooth muscle cells. Therefore, it is crucial to note the effects of antiarrhythmic drugs on the regulation of vascular function. Previous studies using isolated blood vessels as well as cultured vascular smooth muscle cells indicate that antiarrhythmic drugs have some modulator effects on K+ channels expressed on the vascular smooth muscle cells. In addition, this modulation may be modified and dependent on the sort of stimuli, including those of pharmacological and pathophysiological. The K+ channel is one of the most important ion channels modulating vascular function to preserve the organ blood flow including that of the brain as well as the heart, and that several available K+ channel openers are expected to treat cardiovascular disorders, including hypertension, ischemic heart disease. Therefore, these results may provide us a hint to understand the advantage and/or disadvantage of these compounds on the vascular function.
[Back
to top] Drug Targeting of Estrogen Receptor Signaling
in the Cardiovascular System: Preclinical and Clinical Studies
Silvia M.
Sanz-Gonzalez, Antonio Cano, M. A. Valverde, Carlos Hermenegildo and Vicente Andres
Atherosclerosis and associated coronary heart disease events have lower prevalence in women than in men, especially during young adult years. Although multiple lines of evidence suggest that estrogens contribute to this difference, the efficacy of hormone replacement therapy for the prevention of cardiovascular disease in postmenopausal women is controversial. The protective action of estrogen in the cardiovascular system appears to be mediated indirectly by an effect on serum lipoprotein and triglyceride profiles and on the expression of coagulant and fibrinolytic proteins, and by a direct effect on the vessel wall itself. Estrogen has both rapid effects involving alteration of membrane ionic permeability and activation of membrane-bound enzymes and increases in endothelial cell nitric oxide synthase activity, as well as longer-term effects on gene expression that are mediated, at least in part, by the ligand-activated transcription factors, estrogen receptor a and b. Compounds with pure antiestrogenic activity and selective estrogen receptor modulators that regulate estrogen receptor function in a tissue-specific manner have been developed in an attempt to achieve the cardioprotective effects of estrogens while minimizing the undesirable risks associated with hormone replacement therapy (e.g., endometrial and breast cancer). In this review, we will discuss recent developments on the mechanisms of estrogen action in the cardiovascular system. The results of clinical trials testing the long-term efficacy of hormone replacement therapy for the treatment of cardiovascular disease will also be discussed.
[Back
to top] L-Arginine Transport in Disease
Antonio Claudio Mendes
Ribeiro and Tatiana M. C. Brunini
The importance of membrane transport in normal physiological cell function is unquestionable. However, to what extent alterations in the transport of amino acids are the cause and/or consequence of pathological changes observed in disease states is a question not yet completely clarified. Kinetic experiments with blood cells provide a simple and useful model for researching alterations in amino acid transport. The cationic amino acid L-arginine is the precursor of nitric oxide (NO), a key second messenger involved in functions such as endothelium-dependent vascular relaxation, immune defence and platelet activation. The transport of L-arginine, being rate-limiting for nitric oxide production, is extremely relevant to pathological conditions where NO synthesis and/or actions are affected. The current review provides an overview of L-arginine transport in disease, specifically in uraemia, heart failure, hypertension, diabetes mellitus, septic shock and sickle cell disease.
[Back
to top] Cardiovascular Alterations After Spinal Cord
Injury: An Overview
Guadalupe Bravo,
Gabrie Guizar-Sahagun, Antonio Ibarra, David Centurion and Carlos M.Villalon
The recent developments in the management of spinal cord injury (SCI) have led to a reduction in mortality and in the consequences, resulting from incomplete spinal cord damage in those who survive. In this respect, it is noteworthy that SCI not only results in paraplegia or tetraplegia, but also in systemic, cardiovascular and metabolic alterations secondary to autonomic dysfunction. After SCI there is a decrease in sympathetic discharge and an increase in parasympathetic drive, resulting in profound changes in arterial blood pressure and heart rate. When SCI is induced in experimental animals, an immediate hypotension occurs (acute phase) which has been attributed to an autonomic imbalance involving a predominance of parasympathetic activity. Subsequently, an episodic hypertension may develop (chronic phase) as a part of a condition denominated autonomic dysreflexia. This hypertension is caused by afferent stimulation below the level of injury and can be so severe that sometimes may lead to cerebral haemorrhage, seizures, and death. In the light of the above lines of evidence, experimental SCI may provide an ideal model to study the nature of cardiovascular mechanisms following traumatic injury. Thus, the present review will deal with an update of the possible cardiovascular complications associated to SCI (including spinal shock, autonomic dysreflexia, deep venous thrombosis, and risk for coronary heart disease). This will be discussed within the context of the development of drugs with potential therapeutic usefulness in the acute and chronic stages of SCI.
[Back
to top] Understanding the Mechanism and Prevention of Arterial Occlusive
Thrombus Formation by Anti-Platelet Agents
S. Goto
For many years, platelet aggregation, which is mediated exclusively by the binding of fibrinogen to activated glycoprotein (GP) IIb/IIIa, has been used for the screening of antiplatelet agents. However, clinical experience with anti-GP IIb/IIIa agents, which can completely inhibit platelet aggregation, has shown that these drugs are not the most ideal agents for the prevention of atherothrombosis. Recently, many investigators have reported that platelets play a major role in thrombus formation at sites exposed to blood flow, and also that there is a crucial difference between the mechanism of platelet thrombus formation under blood flow conditions in vivo and that of platelet aggregation occurring in conventional aggregometry. Indeed, multiple receptor-ligand interactions, including von Willebrand factor (VWF) binding with platelet GP Iba and GP IIb/IIIa, collagen binding with collagen receptors, as well as stimulation of platelet receptors, such as adenosine 5’-diphosphate (ADP) receptors, appear to be involved in the process of in vivo arterial thrombus formation. Moreover, not only platelets, but also the coagulation cascade activated by the procoagulant activity expressed on the surface of activated platelets, are believed to play a crucial role in the formation of occlusive thrombi. These findings suggest that drugs which block events upstream of the final common pathway for platelet aggregation might be better antiplatelet agents than those that merely inhibit platelet aggregation. We may then expect new antiplatelet agents on the horizon that exert their actions against both thrombus formation under blood flow conditions and against the procoagulant activity appearing on the surface of activated platelets.
[Back
to top] Progress in the Field of GPIIb/IIIa Antagonists
Julien Hanson, Xavier de Leval, Jean-Louis David, Claudiu Supuran, Bernard Pirotte and Jean- Michel Dogne
Platelet aggregation plays an important role in pathological situations such as myocardial infarction, unstable angina, peripheral artery disease, and stroke. Thus, pharmacological agents that specifically inhibit platelet aggregation are of great interest in the treatment and prevention of these cardiovascular diseases. Since binding of activated glycoprotein IIb/IIIa complex, a platelet surface integrin, to fibrinogen is the final step leading to platelet aggregation regardless of the initial stimulus, many researches have focused on the development of drugs that could antagonize this integrin. Three intravenous glycoprotein IIb/IIIa antagonists are currently marketed for the prevention of myocardial infarction in patients undergoing percutaneous intervention: Abciximab, Eptifibatide and Tirofiban. To further test the clinical efficacy of these agents, oral glycoprotein IIb/IIIa antagonists have been developed but only led to disappointing clinical results. Nevertheless, due to recognized usefulness of oral agents for the prevention and treatment of cardiovascular diseases, a great number of new orally active compounds are under clinical or preclinical evaluation. The aim of this review is to describe the chemical, pharmacological and clinical properties of existing and forthcoming glycoprotein IIb/IIIa antagonists.
[Back
to top] The Endothelium and Platelets in Cardiovascular Disease: Potential
Targets for Therapeutic Intervention
K.T.
Tan, S.P. Watson and G.Y.H. Lip
The interaction between platelets and endothelium has been implicated in many disease processes. It is now known that platelets may be involved in the initiation of atheroma, modulate various inflammatory responses, and contribute to endothelial dysfunction, in addition to their classical role in thombosis. Indeed, various drugs targeting platelets and endothelium have been shown to be of benefit in disease states.
The last few years has seen an exponential increase in our knowledge of platelet and endothelial biology. As a result of this, many new drugs, for example the ADP-antagonists and the GpIIbIIIa antagonists, have been developed for use in the clinical setting. There is also renewed interest in the use of older drugs (for example, the statins) in modulating platelet-endothelial interactions. This review focuses on the recent advances in our understanding of the interaction(s) between platelets and endothelium and how this knowledge could be manipulated for therapeutic gain.
[Back
to top] Cardiovascular Effects of the Phytoestrogen Genistein
Domenica Altavilla, Alessandra Crisafulli, Herbert Marini, Maria Esposito, Rosario D’Anna, Francesco Corrado, Alessandra Bitto and Francesco Squadrito
Phytoestrogenic molecules have received a great deal of attention over the last few years because of their potentially preventive roles against a few of today’s most prevalent chronic diseases, namely cardiovascular diseases, osteoporosis and hormone related cancers. Of the several phytoestrogens, genistein in particular has been shown to be the most efficacious in animal models and experimental studies. Genistein in vitro relaxes rat arteries by a nitric oxide dependent mechanism and enhances the dilator response to acetylcholine of atherosclerotic arteries. Genistein supplementation improves endothelial dysfunction induced by oophorectomy in rats and reduces infarct size in an experimental model of myocardial ischaemia-reperfusion injury. Furthermore, genistein in postmenopausal women increases plasma nitric oxide breakdown products, reduces endothelin-1 levels and improves endothelial dependent vasodilation in post-menopausal women. All these findings, taken together, would suggest that this molecule might represent an attractive alternative for cardiovascular protection.