Current Vascular Pharmacology - Volume 5, Issue 3, 2007

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Cannabinoid drugs exert their effects primarily through activation of cannabinoid CB1 and CB2 receptors. Both CB1 and CB2 receptors have been implicated in a number of cardiovascular processes, including vasodilation, cardiac protection, modulation of the baroreceptor reflex in the control of systolic blood pressure, and inhibition of endothelial inflammation and the progress of atherosclerosis in a murine model. These effects are mainly mediated through central and peripheral nervous system CB1 receptors, vascular CB1 receptors and immune cell CB2 receptors. Relevant cellular effects include: the inhibition of neurotransmitter release in the nucleus tractus solitarius and in peripheral adrenergic neurons; regulation of NOS activity in vascular beds; inhibition of vascular smooth muscle cell excitability; regulation of endothelial cell migration and proliferation; and effects on immune cell proliferation, activation, and inflammatory functions. We review the pre-clinical evidence for beneficial effects of cannabinoid drugs in a range of vascular and cardiovascular pathologies. We also discuss the clinically relevant potential of cannabinoids.

Atrial fibrillation (AF) is a highly prevalent arrhythmia and responsible for significant morbidity, mortality and health care cost. Considerable work has been performed to improve medical options but treatment success still remains suboptimal. The use of conventional anti-arrhythmic agents has been limited by potentially fatal ventricular proarrhythmia. Thus, novel drug targets have been characterised and are currently being tested in experimental and clinical studies. The atrially (but not ventricularly) expressed ion channel subunit Kv1.5 (conducting the ultra-rapid delayed rectifier, IKur) is a prominent candidate. A variety of drugs that inhibit this current is being evaluated. Human experience with these agents is limited. Atrial expression of connexin 40 and downregulation of this protein in AF turn its modulation into a potential therapeutic approach. The acetylcholine-activated current (IKACh) is another novel candidate target for 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 as for IKur-blockers none to date has shown pure selectivity for this current. This article summarizes relevant aspects of the cellular electrophysiology of AF and reviews the actions of pharmacological agents presently available or in development as novel anti-arrhythmic therapy.

Peripheral arterial disease (PAD) remains a major cause of morbidity. Despite advances in revascularisation procedures and medical treatment, limb salvage and relief of pain are still not satisfactory in patients with severe disease. This has prompted the exploration of alternative modes of treatment including enhancement of new vessel formation (angiogenesis). Angiogenic Growth Factors (AGF), mainly Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF) and Hepatocyte Growth Factor (HGF) have emerged as exciting therapeutic modalities. Both experimental and clinical studies have demonstrated that topical (mainly intramuscular) AGF gene therapy results in improved peripheral vasculature and alleviation of symptoms. However, most clinical work is limited to small patient series and the long-term safety and efficacy are still unclear. Clinical benefit must be balanced against potential untoward effects, such as tumour growth and atherosclerotic plaque angiogenesis leading to plaque instability. VEGF is important in the pathogenesis of diabetic microvascular disease. Further studies are required before implementation of AGF therapy in clinical practice.

Atrial fibrillation (AF) is associated with a 6 fold increased risk for ischemic stroke. Observational studies suggest that one in four to five strokes is due to AF. Depending on the risk profile of an individual patient, the yearly risk for ischemic stroke is between 2% and 14%. AF is accompanied by an increased propensity for atrial clot formation due to a combination of decreased atrial blood flow, increased activity of the platelet/plasmatic coagulation system and prothrombotic changes at the atrial endocardium. This review summarizes the current guidelines for thromboembolic prevention in patients with AF. In many cases, continuous oral anticoagulation therapy (OAT) with vitamin K antagonists (VitKAs) is indicated if AF is accompanied by more than one additional risk factor for thromboembolic complications. However, therapeutic range of VitKAs (Phenprocoumon, Warfarin, and others), the most commonly used oral anticoagulants, is narrow and their use requires regular anticoagulation monitoring. Possibly due to these limitations, about one third of eligible patients are not treated with VitKAs. Furthermore, in many treated patients OAT is not well controlled. Thus, in clinical practice anticoagulation therapy in AF is suboptimal. Therefore, new and more convenient pharmacologic approaches to prevent thromboembolism with i.e. direct thrombin inhibitors (DTI), synthetic polysaccharides (factor Xa Inhibitors), and others are discussed, and their possible future role in the treatment of AF is evaluated.

It has been claimed that early use of statins in acute coronary syndromes (ACS) protects patients against recurrent ischemic events. This protective effect takes place as early as 4 months after treatment initiation in non-ST elevation ACS, as reported in the MIRACL trial. Mechanisms such as improvement in endothelial function and inflammation are possible explanations for this early effect. These findings have been used to propose statins as part of the acute phase therapy. However, the use of statins during hospitalization is an unresolved issue, because there is a lack of evidence regarding the benefit of initiating therapy in the acute phase. Most randomized trials included patients after several days of the index event and did not report in-hospital outcome. This review critically discusses the use of statins in ACS and the level of evidence regarding their beneficial effect in acute phase treatment.

Endothelial dysfunction and increased arterial stiffness are considered independent predictors of cardiovascular risk. Endothelial dysfunction primarily reflects decreased availability of nitric oxide, a critical endothelium-derived vasoactive factor with vasodilatory and anti-atherosclerotic properties. Techniques for assessing endothelial dysfunction include ultrasonographic measurement of flow-mediated vasodilatation of the brachial artery and plethysmographic measurement of forearm blood flow responses to vasoactive agents. Arterial stiffness can be assessed using pulse wave analysis to generate measures of pulse wave velocity, arterial compliance and wave reflection. It has been demonstrated that the preventive effect of statins on coronary events is not only attributed to cholesterol-lowering, but also to various effects on the vascular wall, which include improved endothelial function as well as antioxidant and anti-inflammatory activity. Previous studies have reported improvement of arterial stiffness by the antioxidant and anti-inflammatory effects of statin therapy in patients with or without hypercholesterolemia. The present review considers the pathophysiology underlying endothelial dysfunction and increased arterial stiffness associated with atherosclerotic disease and the beneficial effects of statins on these markers of atherosclerosis.

The endothelin axis (ET axis), comprising the three peptides endothelin (ET)-1, -2, -3 and their receptors ETAR and ETBR, is expressed in various cells and tissues. The biologically active ET-1 is formed by endothelin-converting enzyme (ECE) from inactive big-ET-1. ET-1 has emerged as an important peptide in a host of biological functions, including development, cellular proliferation, apoptosis and angiogenesis, thereby playing an important physiological and pathophysiological role. As these effects are mediated by ETAR, activation of ETBR prevents apoptosis, inhibits ECE expression and mediates the clearance of ET-1. Emerging data indicate that the ET axis is involved in tumourigenesis and tumour progression of various cancers. Expression of the ET axis has been demonstrated in a wide range of human tumours. Since most data have been reported for female malignancies, this review will focus on the role of the ET axis in cancers of the ovary, the cervix and the breast. In ovarian cancer, activation of ETAR by ET-1 is a key mechanism in the cellular signalling network promoting cancer growth and progression. Similar effects have been shown for cervical and endometrial cancer. In breast cancer, ET-1 via ETAR promotes proliferation and invasion, mediates bone metastases and predicts unfavourable response to chemotherapy. The outstanding role of ET-1 and ETAR in carcinogenesis and tumour progression has led to an extensive search for interfering agents, resulting in the development of selective ETAR antagonists on the one hand and inhibitors of the endothelinconverting enzyme (ECE) on the other. Targeting the ET axis via ETAR or ECE blockade seems to be a promising approach in the treatment of female malignancies.