Current Vascular Pharmacology - Volume 2, Issue 1, 2004

Corticosteroid hormones play an important role in the control of vascular smooth muscle tone by their permissive effects in potentiating vasoactive responses to catecholamines through glucocorticoid receptors. Increased cortisol response has been associated with an increase in arterial contractile sensitivity to norepinephrine and vascular resistance. Glucocorticoids regulate vascular reactivity by acting on both endothelial and vascular smooth muscle cells. Both glucocorticoid receptor protein and mRNA have been identified in endothelial and vascular smooth muscle cells. In endothelial cells, glucocorticoids suppress the production of vasodilators, such as prostacyclin and nitric oxide. In vascular smooth muscle cells, glucocorticoids enhance agonist-mediated pharmacomechanical coupling at multiple levels. The effect of glucocorticoids on vascular reactivity is regulated by 11 β-hydr oxysteroid de hydrogenase (11β-HSD ). The presence of 11β-HSD in many tissue s suggests that it modulates the access of corticosteroids to the irreceptors at both renal and extra-renal sites. The two 11β-HSD isozyme scatalyze the inte rconversion of cortisol and cortisone . Type 1 11β-HSD has bidirec tiona l activity, while the type 2 mainly conver ts cortisol into cor tisone, the biologically inactive form. Both type 1 and type 2 11β-HSD have been found in vascular e ndothelial and smooth muscle c ells, suggesting that a bnormal 11β- HSD expression may play a pathoge nicrole in the common forms of hypertension. In this a rticle, we review possible mechanisms involved in the glucocorticoid-mediated potentiation of vascular reactivity, its regulation by 11β-HSD , and their physiological and pathophysiologica l significance.

Subarachnoid hemorrhage (SAH)-induced cerebral vasospasm causes serious neurological morbidity and mortality mainly because of the absence of effective treatment. Therefore, we reviewed the molecular mechanisms involved in the development of the cerebral vasospasm based on the experimental data in the two-hemorrhage canine model. The characteristic feature of vasospasm is a continuous elevation of intracellular Ca2+ levels in the cerebral artery, as indicated by the continuous activation of μ-calpain and Ca2+ / calmodulin-dependent myosin light chain kinase (MLCK) phosphorylation of the myosin light chain. In contrast, KCl- or serotonin-induced vasocontraction displays a transient increase in Ca 2+ concentration. The elevation of intracellular Ca2+ levels in vasospasm is induced through enhanced Ca2+ release from the sarcoplasmic reticulum and influx from the extracellular space by the activation of tyrosine kinase pathway and also probably by the proteolysis of Ca2+ channel by μ--calpain. Topical application of L-type Ca2+ channel blockers, ethylene-glycol-bis(β-aminoethylether)N,N'-tetraacetic acid, genistein, calpeptin (a selective inhibitor of calpain), or ML-9 (a selective inhibitor of MLCK) induces the reversal of vasospasm probably as a result of a decrease in intracellular Ca 2+ levels mainly due to a reduction of Ca2+ influx by these three inhibitors. Rho-kinase is also activated during vasospasm. It inhibits myosin phosphatase through phosphorylation at the myosin phosphatase target subunit 1 and also probably through phosphorylation of the 17-kDa smooth muscle-specific myosin phosphatase inhibitor (CPI-17) to bring about Ca2+-independent vasospasm. This interpretation is supported by the reversal of vasospasm with Y-27632, a specific inhibitor of Rho-kinase. Arachidonic acid produced during vasospasm might inhibit myosin phosphatase probably directly and via activation of Rho-kinase or atypical protein kinase C (PKC). PKC activated during vasospasm may inhibit myosin phosphates directly and by phosphorylating CPI-17. The protein levels of thin filament-associated proteins, calponin and caldesmon, are decreased in vasospasm, whereas their phosphorylation levels are increased. Both changes probably contribute to the enhancement of vascular smooth muscle contractility. Furthermore, contractile and cytoskeletal proteins appear to be degraded in vasospasm probably by proteolysis with μ--calpain, suggesting that degradation of the structural and functional mechanisms related to smooth muscle contraction occurs. Thus, the mechanisms responsible for the development of cerebral vasospasm are complicated, but the prevention of intracellular Ca2+ elevation induced by SAH may not activate MLCK, calpain and PKC to largely suppressing the development of vasospasm.

Platelet aggregation induced by stirring of a platelet suspension after activation by the exogenous addition of stimulants, such as ADP, epinephrine and thrombin, has long been used as a platelet function test, and for the screening of antiplatelet agents. Since platelet aggregation has been demonstrated to be mediated exclusively by the binding of plasma fibrinogen to the activated GP IIb / IIIa, anti-GP IIb / IIIa agents, which can completely inhibit platelet aggregation, were expected to become among the most potent of antithrombotic agents. The strong preventive effects of anti-GP IIb / IIIa agents against thrombotic complications after coronary intervention, and the weaker preventive effects of the same agents against the onset of coronary thrombosis in unstable angina pectoris patients point to both the efficacy and the limitations of anti-GP IIb / IIIa antithrombotic agents. Recently, many investigators have reported that platelets play a major role in thrombus formation at sites exposed to blood flow. Several platelet-function assay systems have been developed to elucidate the mechanism of thrombus formation under blood flow conditions. Numerous studies have demonstrated that von Willebrand factor (VWF) and its interaction with its receptors on platelets, including GP Ibα and GP IIb / IIIa, play essential roles not only in platelet activation, but also in platelet adhesion and possibly platelet cohesion. These findings prompted us to explore whether the VWF-mediated process of thrombus formation could be exploited as a target for potential antiplatelet agents. Moreover, recent studies have demonstrated that multiple synergistic signals, including those mediated by catecholamine receptors, purine nucleotide receptors, as well as some types of collagen receptors are involved in the process of VWF-mediated platelet thrombus formation. We now have new antiplatelet agents on the horizon, targeted against thrombus formation under blood flow conditions.

Fibroblast growth factor 2 (FGF2) is expressed ubiquitously in mesodermal and neuroectodermal cells. Human FGF2 occurs in isoforms translated from a common mRNA by alternative use of AUG (low-molecular weight isoforms) and CUG (high-molecular weight isoforms) start codons. Whereas the high-molecular weight isoforms function in an intracrine manner, the low-molecular weight isoform functions as autocrine, paracrine, and intracrine ligands. FGF2's signals are mediated by a family of high- and low-affinity receptors. The nuclear localization of FGF2 appears to be essential for its mitogenic effects with different isoforms localizing in different nuclear substructures. By regulating the transcription or activity of multiple other genes, FGF2 plays an important role in proliferation, differentiation, and survival of cells of almost all organ systems. Its potent angiogenic effects observed in tissue culture models and healthy animals have prompted clinical trials testing effects of FGF2 protein or genetic material on ischemic tissues. Unfortunately, FGF2-mediated therapeutic angiogenesis has yielded inconclusive results. One possible reason is that single-gene therapy is not sufficient to support the numerous effectors required to generate mature vessels assembled by multiple cells, including pericytes, smooth muscle cells, and endothelial cell subtypes. Another possible reason is that potentially negative effects of dyslipidemia, a common finding in patients with macro- and microvascular disease, on gene therapy have not been taken into account. We have demonstrated that electronegative low-density lipoprotein (LDL) from hypercholesterolemic human plasma downregulates FGF2 by both transcriptional and posttranscriptional mechanisms. In our models, FGF2 downregulation results in angiostasis and endothelial cell apoptosis. Deprivation of endogenous FGF2 may lead to dysregulation of the activities of other survival and angiogenesis-related genes. Delineation of the molecular mechanisms modulating the expression and actions of FGF2 may provide the basis for novel therapeutic interventions.

There is increasing evidence that dietary supplementation, such as L-arginine, anti-oxidant vitamins, soy phytoestrogens, flavonoids and omega-3 fatty acids exert vascular protective benefits particularly in terms of restoring endothelial function in cardiovascular disease states. The endothelium has been a major focus over the past 20 years as being a primary site at which dysfunction occurs in association with, and contributing to, vascular pathologies. Such states include mild compromise of the cardiovascular system as observed in smokers, hypercholesterolemics and hypertensives, through to end-point heart failure. This review will focus on the experimental and clinical evidence examining the effect of nutriceuticals on vascular function, in particular endothelium-derived factors, and argues that there is a role for nutriceuticals in the clinical management of the cardiovascular compromised individual.

The predominant isoform of the endothelin peptide family, endothelin-1 (ET-1) exerts various biological effects. These include effects on arterial smooth muscle cells causing intense vasoconstriction and stimulation of cardiac cells. ET-1 promotes changes in cardiomyocytes that are consistent with electrical remodelling such as changes in ionic current density and inhomogeneous prolongation of action potential duration resulting in increased dispersion. As for the underlying mechanisms, ET-1 was shown to suppress several cAMP-dependent ionic currents, such as ICa, IK and ICl in various mammalian cardiac preparations including human myocytes; however, the degree of suppression of these currents is different and highly dependent on experimental conditions. The proposed arrhythmogenic effects of ET-1 may also involve enhancement of Ca2+ release from intracellular stores, generation of IP3, and acidosis due to stimulation of the Na+ / H+ exchange. Furthermore, ET-1 acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilator, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Effects of ET-1 are mediated through interaction with two major types of cell surface receptors. ETA receptors have been associated with electrical remodelling, vasoconstriction and cell growth, while ETB receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of NO and prostacyclins, and inhibition of the expression of ET-1 converting enzyme. The derangement of endothelial function in various cardiovascular diseases, such as cardiomyopathies, hypertension or arteriosclerosis, is a crucial element of the pathomechanism, thus ET receptors are considered as important therapeutic targets. Indeed, ET receptor antagonists may be able to preserve or restore endothelial integrity and may have antiarrhythmic properties; therefore, they are promising tools in cardiovascular medicine.

Elevated peripheral vascular tone has been proposed as one of the detrimental factors causing increased cardiac after load and reduced exercise capacity in patients with congestive heart failure (CHF). A number of studies have shown impaired endothelium-dependent vasodilation in limb resistance and conduit vessels in CHF, suggesting that this is one of the important etiologies of vascular dysfunction. Several clinical trials have shown that pharmacological inhibition of the renin-angiotensin-aldosterone system by angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, or aldosterone receptor antagonists, significantly improves prognosis in this disorder. However, the relationship between the clinical utility of this type of drug and its pharmacological effects on the peripheral vasculature has not been extensively assessed in patients with CHF. The present review summarizes recent reports including our own observations on the pharmacological effects and mechanisms of this type of drug on vascular endothelial function in the peripheral vasculature in human CHF.

Spinal cord injury (SCI) leads to profound haemodynamic changes. Constant outflows from the central autonomic pattern generators modulate the activity of the spinal sympathetic neurons. Sudden loss of communication between these centers and the sympathetic neurons in the intermediolateral thoracic and lumbar spinal cord leads to spinal shock. After high SCI, experimental data demonstrated a brief hypertensive peak followed by bradycardia with escape arrhythmias and marked hypotension. Total peripheral resistance and cardiac output decrease, while central venous pressure remains unchanged. The initial hypertensive peak is thought to result from direct sympathetic stimulation during SCI and its presence is anaesthetic agent dependent. Hypotension improves within days in most animal species because of reasons not totally understood, which may include synaptic reorganization or hyper responsiveness of α receptors. No convincing data has demonstrated that the deafferented spinal cord can generate significant basal sympathetic activity. However, with the spinal shock resolution, the deafferented spinal cord (in lesions above T6) will generate lifethreatening hypertensive bouts with compensatory bradycardia, known as autonomic hyperreflexia (AH) after stimuli such as pain or bladder / colonic distension. AH results from the lack of supraspinal control of the sympathetic neurons and altered neurotransmission (e.g. glutamatergic) within the spinal cord. Despite significant progress in recent years, further research is necessary to fully understand the spectrum of haemodynamic changes after SCI.

When a spontaneous autoxidation of arachidonic acid to prostaglandin-like products was first described almost 40 years ago, it was thought to be an artifact that interfered with the detection of enzymatically generated prostaglandins. It has now been generally accepted that the autoxidation of arachidonic acid occurs in vivo and leads to formation of isoprostanes and other products. Sensitive methods can detect the isoprostanes as useful biological markers, which help to estimate, non-invasively, the burden of free radicals formed in pathologies resulting from oxidative stress. After the discovery of NO, it has been hypothesized that NO and its active congeners (reactive nitrogen species, RNS), such as nitrogen dioxide radical (NO 2), nitrous acid, peroxynitrite, can also participate in lipid peroxidation, either as initiators or modulators of processes initiated by the hydroxyl radical. In biological systems these RNS not only originate from the biosynthesis of NO but also from exogenous sources such as polluted air and dietary nitrite. While the ability of NO2 to induce lipid peroxidation has been long known, more recent studies have discovered novel processes that have been termed lipid nitration. Polyunsaturated fatty acids appear to be readily targeted by RNS. Among the products of arachidonic acid nitration by NO2, interesting lipids have been detected, such as nitroeicosatetraenoic acids, α,β- nitrohydroxyeicosatrienoic acids, and trans-arachidonic acids. The products of fatty acid nitration have the potential to function as biomarkers and / or lipid mediators of mechanisms distinct from fatty acid peroxidation but offering insight into the contribution of specific RNS such as NO2 to the damage of biological membrane resulting from nitrooxidative stress.