Current Vascular Pharmacology - Volume 1, Issue 3, 2003

Tertiary amine local anesthetics (LAs) are clinically valuable agents for controlling pain and for treating some cardiac arrhythmias. These drugs inhibit conduction of electrical activity by blocking voltage-gated sodium channels. Interestingly, LAs can influence the conduction of electrical activity in heart muscle without markedly altering normal skeletal muscle activity. This review discusses the interactions between sodium channels and LAs, the methods used to investigate these interactions, and the mechanisms proposed to explain the greater LA sensitivity of cardiac sodium channels as compared with skeletal muscle sodium channels.

Endothelin-1 (ET-1) is a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3 genes). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor compared to the other two isoforms. Besides being a very potent vasoconstrictor, ET-1 also acts as a mitogen on the vascular smooth muscle and thus it may play a role in the development of vascular diseases. There is evidence that impaired auto-regulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. It is known that the ability of the diabetic's circulation to distribute blood is affected, especially during increased blood flow. In most tissues this causes no serious burden, but three tissues are usually susceptible to disturbance. They are the retina, renal cortex, and peripheral nerves. Retinal vascular auto-regulation is defined as the ability of the blood vessels to keep blood flow constant under varying perfusion pressure in order to match it to tissue oxygen and metabolic requirements. The failure of auto-regulation is an important and often early feature of diabetic retinopathy. Since human retina vessels lack extrinsic innervation, retinal vessel calibre and local blood flow are normally regulated by non-nervous mechanisms intrinsic to the retina. There is now a considerable body of evidence suggesting that retinal pericytes are the main regulators of vascular tone in the retinal capillaries because they contain components of contractile proteins similar to vascular smooth muscle cells and because they also possess ET-1 receptors. Furthermore, ET-1 has been shown to cause vasoconstriction of retinal vessels as well as to have mitogenic effects on retinal pericytes. Hence, alterations in the pericyte-ET interaction may have a role causing early hemodynamic and histopathological abnormalities found in diabetic retinopathy. On the contrary, Chakrabarti et al. demonstrate that retinas from the chronic diabetic BB / W rats (6 months) show an increase in ET-1, ET-3, ETA receptor and ETB receptor mRNA expressions when compared to those from control rats. Similar results are noted by them using immunohistochemical methods. Finally, an increased ocular, and retina tissue levels of ET-1 in diabetic rats have also been reported by Chakravarthy et al., as well as by Takagi et al., All of these findings suggest that endothelins may also be involved in the pathogenesis of more advanced diabetic retinopathy, such as capillary occlusion and subsequent neovascularization. This review summarizes the reported literature on the role of ET-1 in the development of diabetic retinopathy.

Different types of ATP-sensitive K+ (KATP) channels have been identified in cardiomyocytes, vascular smooth muscle cells, pancreatic β-cells, neurons and mitochondria. Years before the discovery of the KATP channel in cardiomyocytes, pharmacological openers of this channel had been developed for the treatment of angina pectoris and hypertension. The KATP channel plays an important role not only in coronary blood flow regulation but also in protection of cardiovascular cells from ischemia / reperfusion injury. In animal models of myocardial ischemia / reperfusion, activation of the mitochondrial KATP channels by their pharmacological openers has been shown to attenuate endothelial dysfunction and to reduce myocardial necrosis. Conversely, blockade of the KATP channel aggravates microvascular necrosis and the no-reflow phenomenon after ischemia / reperfusion, resulting in augmentation of post-infarct ventricular dysfunction. Recent clinical studies have shown that a combination of coronary reperfusion therapy and infusion of nicorandil, a hybrid of KATP channel opener and nitrate, improved left ventricular function in patients with acute myocardial infarction. Furthermore, chronic treatment with nicorandil has been shown to significantly improve prognosis of patients with highrisk stable angina pectoris. Both of these clinical benefits cannot be attributed to the nitrate property of nicorandil. However, a recent basic investigation has suggested that the protective function of KATP channel openers is compromised by concurrent hypercholesterolemia and administration of sulfonylureas for diabetes mellitus. These interferences in the beneficial action of KATP channel openers by concurrent illness and pharmacological agents need to be further investigated to allow a more effective use of KATP channel openers in patients with coronary artery diseases.

Platelet aggregation, and activation of coagulation cascade are the key events in the development of acute coronary syndromes (ACS). Patients with this syndrome are at high risk of adverse events, such as death and myocardial infarction (MI). Optimized medical treatment for the non-ST segment elevation ACSs should consist of a combined antithrombotic / anti-anginal regimen. Standard anti-thrombotic treatment is currently unfractionated heparin (UH) and aspirin, and in high-risk patients glycoprotein IIb / IIIa inhibitors. UH has been shown to reduce the risk of death or myocardial infarction in aspirin-treated patients with ACSs, but it has a number of limitations, such as need for regular monitoring and the risk of hemorrhage and thrombocytopenia. Compared to UH, the low molecular weight heparins (LMWH) possess several important theoretical advantages for the treatment of patients with ACSs, including less non-specific binding, resistance to inactivation by platelet factor-4, more reliable anticoagulation effects, and greater factor anti-Xa activity. Recently published trials strongly support the use of LMWHs in the treatment of ACSs. These agents provide an alternative to UH that is at least as effective. The available evidence favours the use of these agents in acute cardiac care. This article explores the recent clinical data on the use of LMWHs in acute cardiac care, and looks critically at the differences between traditional therapies. Recommendations regarding the use of anti-thrombotic agents in patients with ACSs are also discussed.

HMG-CoA reductase inhibitors (statins) are effective lipid-lowering drugs widely used in patients with dyslipidemia at risk of cardiovascular diseases. Primary and secondary prevention studies have revealed a significant reduction of risk for cardiovascular diseases. However, recent studies have demonstrated that statins have direct vascular effects (pleiotropic effects) independent of lipid-lowering action. Vascular remodeling, defined as changes in size and / or structure of adult vasculature, not only allows physiological adaptation and healing but also underlines the pathogenesis of major cardiovascular diseases. Vascular remodeling can be inward, occlusive, and outward. Various cardiovascular diseases probably represent a terminal phenotype of such vascular remodeling. In this review, we will focus on the basic actions and clinical implications of statin therapy to each type of vascular remodeling in response to various stimuli.

Initially described as the most potent vasoconstrictor peptide, endothelin (ET) has also been shown to possess extraordinary immunomodulatory and proinflammatory properties. Because of this broad spectrum of biological activities, a possible role of the ET-system in solid organ transplantation has soon become a focus of research. Several studies demonstrated a pathogenetic involvement of ET in ischemia / reperfusion injury of heart, liver, kidney, and lung grafts. ET accumulates during cold storage of organs and can be detected in the effluent preservation solution. In addition ET is very likely to play a pivotal role in the development of chronic rejection, which represents the major cause of late allograft loss. Increased expression of components of the ET-system has been described in areas of neointimal proliferation, a hallmark of chronic graft rejection. Both selective ET-A as well as non-selective ET-A / B receptor antagonists improved histomorphological and functional sequelae of chronic rejection. However these data have largely been derived from experimental animal transplantation, and ET receptor blockers have only recently been introduced in clinical medicine. A significant number of investigational drugs are now being tested in humans, with a main focus on cardiovascular diseases, such as congestive heart failure and pulmonary hypertension. First results have markedly dampened the initial enthusiastic vision of ET receptor blockers being organoprotective super-weapons. Thus the clinical potential of ET antagonists in general, and especially in solid-organ transplantation, is still to be defined.

Although cannabinoids have been recreationally employed for thousands of years, it was not until the discovery of their specific receptors, in the early nineties, that the molecular basis of cannabinoid activity have began to be understood. Growing research in this field has demonstrated not only that the action of cannabinoids in mammals is mainly receptor-mediated, but also that endogenous cannabinoids, such as anandamide, are produced, metabolized, and taken up across the cell membrane through a facilitated uptake process. The exogenous administration of cannabinoids, as well as the manipulation of their endogenous levels have been related to a variety of effects, such as analgesia, impairment of cognition and learning, appetite enhancement and peripheral vasodilation. Hence, the endocannabinoid system, including the CB1 and CB2 receptors, the metabolizing enzyme fatty acid amide hydrolase and the anandamide transporter, is a potential target for the development of novel therapeutic drugs in the treatment of various conditions, such as pain, feeding disorders and vascular disease among others. Although most of the research in the field of cannabinoids has been focused on their effects in the central nervous system, a growing line of evidence indicates that cannabinoids can also play a major role in the control of physiopathological functions in the cardiovascular system. In this context, endocannabinoids have been proposed as novel possible hypotensive agents, and have been involved in the hypotension observed in septic shock, acute myocardial infarction and cirrhosis. In addition, a protective role for endocannabinoids has been described in ischemia.

Hypertension is a well-known risk factor for atherosclerosis, but the molecular mechanisms that link elevated blood pressure to atherosclerosis progression remain uncertain. The interactions of mechanical forces and cells of the vasculature are relevant to many cardiovascular diseases. Once a monocyte infiltrates a tissue, it establishes extracellular matrix contacts and is subjected to deformation through those contacts. Macrophages participate in atherogenesis and commonly localize at sites of coronary plaque rupture. Although macrophages may be subjected to excess mechanical stress in these conditions, how biomechanical forces affect macrophage function remains incompletely defined. Recent work demonstrates that human monocytes / macrophages respond to mechanical deformation with selective augmentation of matrix metalloproteinases and induction of immediateearly genes. In human monocytes / macrophages and THP-1 cells, biomechanical strain can induce expression of the class A scavenger receptor, an important lipoprotein receptor in atherogenesis. In addition, DNA microarray analysis reveals that cyclic mechanical strain induces only a few genes (>2.5-fold), including interleukin-8 and IEX- 1 in THP-1 cells. Thus, biomechanical deformation of monocytes / macrophages contributes to degradation of extracellular matrix, monocyte differentiation, and promotion of atherosclerosis. These findings suggest that mechanical stress in vivo, such as hypertension, may play an important role in atherogenesis and instability of coronary-artery plaques through biomechanical effects on vascular macrophages.

Routinely used iodinated contrast media have complex vasomotor effects on several arterial districts. All classes of iodinated radiographic contrast media are vasoactive, with iso-osmolar dimers inducing the smallest changes in vascular tone. The mechanisms responsible for contrast-induced vasomotor changes are not fully elucidated and are likely to be multifactorial. Although contrast-induced vasomotility is usually considered as an unwanted “side effect”, recent findings suggest that it might indeed be useful in exploring the functional integrity of the vessel wall. We found that atherosclerosis has an impact on the type of the contrast-induced coronary vasomotor reaction. In fact, angiographically normal coronary segments show divergent vasomotor reactions to iodixanol or iopromide according to the presence / absence of, and distance from, a coronary atherosclerotic lesion located in their proximity. The mechanism responsible for this vasomotor effect does not apparently involve flow-mediated vasodilatation or endothelial nitric oxide synthesis. On the other hand, a cyclooxygenase product may be, at least in part, responsible for the vasodilating effect of non-ionic agents on epicardial coronary arteries, since contrast-induced vasodilatation is strongly inhibited in the presence of indomethacin. These findings have potential clinical implications, since the analysis of contrast-induced coronary vasomotion might result in a new test capable of evaluating vascular functional integrity. Such a test might be alternative or complementary to the tests based on muscarinic agonists (acetylcholine) or serotonin, which are known to evaluate the nitric oxide pathway.

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is associated with a severalfold increased risk of cardiovascular morbidity and mortality. Statins and anti-platelet therapy have been unequivocally shown to be beneficial in patients with coronary artery disease, but minimal data exist on the effectiveness of these agents in patients with PAD and those undergoing peripheral vascular interventions. One recent study has demonstrated that statins are very effective as secondary preventive measures in patients with PAD but continue to be underutilized in this cohort. In our institutional peripheral interventional database, after adjustment for demographics and comorbidities, statin therapy (OR=0.21, 95% CI 0.05 - 0.86, p=0.03) and clopidogrel therapy (OR=0.17, 95% CI 0.04 - 0.78, p=0.02) were both associated with a significant reduction of the composite event rate of death, myocardial infarction and stroke at 6 months. In this article, we critically review the existing literature on the role of anti-platelet and statin therapy in reducing cardiovascular events in patients with PAD. Appropriate use of these agents may significantly decrease the cardiovascular morbidity and mortality of patients with PAD.

Fifteen years after its discovery, NO has fully reached an established position in physiology, medicine and therapeutics. It is difficult to find a biological function or a pathological condition where NO does not play a relevant role. Discoveries in the NO field have historically evolved from cardiovascular research, although its influences have already covered nearly all the medical specialties. This review analyzes, step by step, the pathway through which NO is synthesized in the cells of the cardiovascular system and the main physiological and pathological routes it undergoes once it is released. We focus on various diseases affecting the cardiovascular system (atherosclerosis, hypertension, diabetes mellitus and septic shock). We describe in detail those steps of the NO pathway in which anomalies have been detected and may account for the pathophysiology of these diseases. In atherosclerosis, hypertension and diabetes mellitus, the endothelial form of NOS is upregulated, but is very sensitive to environmental conditions, such as substrate or cofactor deficiencies or increases in LDL or glucose. In this situation NOS synthesizes superoxide anion instead of NO leading to oxidative and nitrosative stress. In diabetes mellitus and, very importantly, in septic shock, the inducible form of NOS is highly upregulated. Overproduction of NO appears to underlie the hypotension and tissue damage of septicemia and the destruction of ß-cells in diabetes mellitus. New knowledge of the role of NO in these diseases has started to influence therapeutic design. We also review the current status of research on NO-based therapies.

Large Arteriovenous Fistulae (AVF) can increase cardiac output. This may result in the development of congestive heart failure, a clinical situation associated with increased activity of Vasoconstrictor neurohormonal systems: the Renin-angiotensin system (RAS), Sympathetic nervous system (SNS), the Endothelin system and Arginine vasopressin (AVP). At the same time there is compensatory activation of systemic and vasodilating systems: Atrial natriuretic peptide (ANP) and Nitric oxide (NO). Previous data from our laboratory and other groups suggest that urinary sodium excretion in this situation is largely determined by the balance between two antagonistic hormonal systems: the vasoconstrictor / sodium-retaining factors such as RAS, endothelin, and SNS, and vasodilatory / natriuretic substances such as ANP and NO. In decompensated patients, enhanced activities of the sodium-retaining systems overwhelm the effects of vasodilatory / natriuretic systems, which lead to a net reduction in sodium and water excretion. For compensation to occur, the effects of natriuretic mechanisms must prevail over those of the opposing systems, resulting in renal sodium / water excretion. This notion is supported by clinical and experimental studies where pharmacological intervention corrected the imbalance present in AVF. Thus, a shift in the balance in favor of natriuresis may be achieved either by increasing the activity of natriuretic factors or reducing the influence of the antinatriuretic systems. Based on that, the use of angiotensin converting enzyme (ACE) inhibitors and / or angiotensin II (ATII) blockers may be beneficial in the management of patients with large AVF.