Current Vascular Pharmacology - Volume 5, Issue 4, 2007

The obesity pandemic will likely have a significant impact on the global incidence of cardiovascular disease. Although the mechanisms linking obesity and cardiovascular disease are unclear, recent studies have implicated the adipocyte as a potentially important mediator of vascular complications. The adipocyte is no longer considered a passive storage depot for triglycerides and fatty acids, but rather an active metabolic organ capable of producing several factors, commonly referred to as adipokines, that may have effects on many physiological and pathophysiological processes. With increasing fat mass, several adipose-related factors are upregulated that may affect local and distant inflammatory processes, including atherothrombosis. Other factors, such as adiponectin, are downregulated with increasing fat mass. Although most adipokines are thought to promote vascular disease, several studies over the past few years indicate adiponectin is actually protective against both diabetes and vascular disease. There are now available pharmacologic agents capable of altering the adipocyte transcription profile. This review will focus on the potential impact of adipocyte-derived factors towards vascular disease and emerging therapeutic strategies that may alter these effects.

Ischemic stroke is the third cause of death and the most common cause of neurological disability. A main target of treatment is the still salvageable tissue surrounding the core of infarction and called “ischemic penumbra”. Up to now the only drug approved for the treatment of acute ischemic stroke is recombinant tissue plasminogen activator to achieve early arterial recanalization and hypoxic tissue reperfusion and improve neural function. However, thrombolytic therapy has to be administered soon after the event since its efficacy is time dependent. This intervention also carries an increased risk of hemorrhagic transformation. In the rescue of poorly perfused cerebral regions an important role is played by collateral blood supply through the circle of Willis and through small pial vessels surrounding the lesion. The extent of collateralization is variable and at least in part regulated by the modulation of arteriolar nitric oxide (NO)-dependent endothelial function. Drugs that can improve endothelial function and cerebrovascular reactivity could have a role in collateral formation and infarct volume limitation. Statins affect endothelial NO production demonstrating their potential to influence endothelial NO synthase (eNOS) and in treating stroke. Phosphodiesterase (PDE) inhibitors improve functional recovery after stroke in rats enhancing neuro and synapto genesis and increasing guanosine 3,5-cyclic monophosphate (cGMP). The aim of this review is to highlight the potential of these two classes of drugs in the treatment of acute ischemic stroke by analysing their pharmacological effects and involvement in the NO and cGMP pathways.

Alterations in microcirculatory permeability are a characteristic of early tissue injury. Moreover, tissue edema is an early indicator of tissue dysfunction, prior to organ failure, because tissue edema is associated with impaired gas exchange, arterial hypoxemia, and may also impair tissue oxygen distribution. As a result of increased microvascular permeability, plasma fluid is lost into the interstitial space, leading to hypovolemia. Currently, no effective pharmacological therapy is available to reduce increased permeability. High mortality rate in sepsis is still mainly associated with endothelial damage. In this regard platelets, besides leukocytes, play a major role for the development of microvascular hyperpermeability. This review considers endothelial cell dysfunction during endotoxemia including current insights into sepsis pathophysiology. New aspects of this complex pathogenesis are illustrated and their relevance for clinical sepsis therapy is emphasized.

Smoking is a significant independent risk factor for cardiovascular disease and is a leading cause of structural and functional alterations of the cardiovascular system. Most clinical and experimental investigations of the pathophysiology of cigarette smoking have studied the effects of smoke as a whole, while a few studies focused on specific components of cigarette smoke, e.g. nicotine and carbon monoxide, which are only 2 of the more than 4,000 different chemicals present in cigarette smoke. The findings point to some discrepancies when the effects of whole smoke are compared to nicotine alone, while there is almost uniform agreement that both active and passive smoking have detrimental effects on the cardiovascular system, although a milder effect was suggested for the latter. This review focuses on findings from clinical and experimental studies on the vascular effects of active and passive cigarette smoking and nicotine exposure. The findings are discussed in terms of tissue (conduit vs. resistance arteries and veins), species, age, gender and dosage. Although the exact pathophysiology of cigarette smoking has not been unveiled, cigarette smoking causes injury to the vascular endothelium, produces superoxide anions, reduces production and bioavailability of nitric oxide (NO), increases production and release of endothelin, causes endothelial dysfunction, thrombosis, atherosclerosis, infarction, coronary artery disease (CAD), stroke and death.

Antiplatelet therapy is used to reduce the risk of ischemic events in patients with cardiovascular disease. The balance of benefits and risks of antiplatelet drugs in coronary artery disease has been evaluated in large-scale randomised trials, however the absolute benefit for an individual patient and a specific platelet-active drug need further evaluation. Several well-conducted studies have demonstrated a substantial inter-individual variability in the platelet responsiveness to drugs. The historical “gold standard” test of platelet function (optical aggregation) has well established limitations for measuring the effect of antiplatelet drugs. Other new tests developed (i.e. PFA-100®, VerifyNow®) may overcome some of these limitations but they do not correlate well with each other. Despite these unresolved methodological questions, several recent clinical studies, but not all, suggest a significant correlation between antiplatelet resistance status and serious vascular events. In these conditions, laboratory monitoring for antiplatelet therapies raises several questions: (i) the necessity for a consensus on the definition of resistance and on the best test for evaluation of the condition, (ii) the demonstration that biological resistance has clinical significance, and (iii) the clinical impact of adapting the antiplatelet therapy. Therefore, it is not currently appropriate to test patients or to change therapy on the basis of such tests, other than in prospective and adequately powered clinical trials.

Cardiovascular risk increases exponentially by multiple risk factors. Similarly, by simultaneously treating these risk factors the therapeutic benefit can be multiplied. It is also relevant that some drugs exert extra benefit by acting beyond their main effect. A wide range of pleiotropic effects have been reported among lipid lowering statins and thirdgeneration calcium channel blockers. These include an increase of endothelial nitric oxide (NO) production, inhibition of free radical formation and reduction of migration and proliferation of smooth muscle cells independently from the main therapeutic effect of these drugs. Favorable “therapeutic cross effects” due to pleiotropic mechanisms can be defined as pleiosynergy.

Near infrared spectroscopy (NIRS) was first used as a tool for the in vivo monitoring of tissue oxygenation in the late seventies. Today, NIRS instruments are more and more used in clinical environments since they are now easy to use, sensitive, robust, provide rapid analysis and could be complementary to other non invasive methodologies such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). The feasibility of non-invasive analysis of brain activities is studied in the attempt to overcome the major limitation of invasive in vivo methodologies. In the present work, optic fibre probes were used as optical head of a novel, highly sensitive near infrared continuous wave spectroscopy (CW-NIR) instrument adapted for in vivo NIRS measurements in the brain of rodents. This prototype was designed for non-invasive analysis of the 2 main forms of haemoglobin: oxy-haemoglobin (HbO2) and deoxy-haemoglobin (Hb), chromophores present in biological tissues as these are markers of the degree of tissue oxygenation, thus providing an index of blood level and therefore of tissue metabolism. It was first tested in peripheral tissue (human gastrocnemius muscle) and then reset to perform measurement on rat brain. In animal studies, the optical head was firmly placed using stereotaxic apparatus upon the sagittal line of anaesthetised adult rat’s head, without any surgery. ‘Physiologic’ (i.e. with exogenous oxygen (O2) or carbon dioxide (CO2) supplied orally) or pharmacologic (i.e. with drugs of abuse such as cocaine) experiments have been performed to support the effectiveness of the methodology in preclinical studies. In addition, the possibility that changes in brain metabolism as measured by NIRS might be a useful index of brain penetration of new chemical entities has been investigated using different compounds from different chemical classes that were selected on the basis of their known brain penetration and overall pharmacokinetic profile. Finally, the feasibility of coupling NIRS with another although invasive in vivo method such as electrophysiology for concomitant analysis of cerebral cell firing in discrete brain areas was tested in the attempt to study in real time the putative correlation between blood levels, brain metabolism and neuronal activities in rat CNS, i.e. apply NIRS to pharmacodynamic investigations. The data gathered in rat treated with exogenous O2, indicate an original relationship between NIRS analysis of brain metabolism and electrical changes in this major nucleus of CNS involved in neurophysiologic and pathologic activities.

Percutaneous closure of a patent foramen ovale (PFO) was performed in 98 consecutive patients (mean age 52.5 ± 13 years, 61 women). Indications included recurrent transient ischaemic attack (47%), cryptogenic stroke (34%), peripheral embolism (11%), disabling migraine with aura (4%), professional scuba diving (1 pt) and severe platypneaorthodeoxia syndrome (1 pt). Each PFO was characterized by transesophageal echocardiography (TEE) according to anatomy, degree of shunt (1-mild, 2-moderate, 3-severe), right atrial anatomical features relevant for PFO closure (such as presence of an Eustachian valve, Chiari network, lipomatosis or absence of septum secundum) with a new classification scheme. According to this classification successful device delivery was obtained in 100% of pts. Major complications included heparin-induced thrombocytopenia in 1 pt and device dislodgment in 1 pt; minor complications were mostly related to the catheter introduction site (2 pts) and mild immediate shunt (2 pts). In conclusion, percutaneous PFO closure based on strict anatomic criteria is a safe procedure with minimal periprocedural complications.