Our view of the endothelium was transformed around 30 years ago, from one of an inert barrier to that of a key endocrine organ central to cardiovascular function. This dramatic change followed the ...discoveries that endothelial cells (ECs) elaborate the vasodilators prostacyclin and nitric oxide. The key to these discoveries was the use of the quintessentially pharmacological technique of bioassay. Bioassay also revealed endothelium‐derived hyperpolarizing factor (EDHF), particularly important in small arteries and influencing blood pressure and flow distribution. The basic idea of EDHF as a diffusible factor causing smooth muscle hyperpolarization (and thus vasodilatation) has evolved into one of a complex pathway activated by endothelial Ca2+ opening two Ca2+‐sensitive K+‐channels, KCa2.3 and KCa3.1. Combined application of apamin and charybdotoxin blocked EDHF responses, revealing the critical role of these channels as iberiotoxin was unable to substitute for charybdotoxin. We showed these channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, and close to interendothelial gap junctions. Activation of KCa channels hyperpolarizes ECs, and K+ efflux through them can act as a diffusible ‘EDHF’ stimulating Na+/K+‐ATPase and inwardly rectifying K‐channels. In parallel, hyperpolarizing current can spread from the endothelium to the smooth muscle through myoendothelial gap junctions upon endothelial projections. The resulting radial hyperpolarization mobilized by EDHF is complemented by spread of hyperpolarization along arteries and arterioles, effecting distant dilatation dependent on the endothelium. So the complexity of the endothelium still continues to amaze and, as knowledge evolves, provides considerable potential for novel approaches to modulate blood pressure.
LINKED ARTICLES This article is part of a themed issue on Vascular Endothelium in Health and Disease. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐3
Nitric oxide (NO{bullet}) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols ...(MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO{bullet} and S-nitrosated thiol proteins. MitoSNO1-induced NO{bullet} production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO{bullet} generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO{bullet} donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.
Increasing evidence suggests that some cannabinoids mediate their effects independently of the known cannabinoid CB
1 and CB
2 receptors. Two recently published patents indicate that several ...cannabinoid receptor ligands also bind to the orphan G-protein-coupled receptor GPR55. This receptor is reported to be expressed in several tissues and might function in lipid or vascular biology. Thus, GPR55 might represent a new cannabinoid receptor.
Endothelial dysfunction in small arteries is a ubiquitous, early feature of cardiovascular disease, including hypertension. Dysfunction reflects reduced bioavailability of endothelium-derived nitric ...oxide (NO) and depressed endothelium-dependent hyperpolarization that enhances vasoreactivity. We measured smooth muscle membrane potential and tension, smooth muscle calcium, and used real-time quantitative polymerase chain reaction in small arteries and isolated tubes of endothelium to investigate how dysfunction enhances vasoreactivity. Rat nonmyogenic mesenteric resistance arteries developed vasomotion to micromolar phenylephrine (α1-adrenoceptor agonist); symmetrical vasoconstrictor oscillations mediated by L-type voltage-gated Ca channels (VGCCs). Inhibiting NO synthesis abolished vasomotion so nanomolar phenylephrine now stimulated rapid, transient depolarizing spikes in the smooth muscle associated with chaotic vasomotion/vasospasm. Endothelium-dependent hyperpolarization block also enabled phenylephrine-vasospasm but without spikes or chaotic vasomotion. Depolarizing spikes were Ca-based and abolished by either T-type or L-type VGCCs blockers with depressed vasoconstriction. Removing NO also enabled transient spikes/vasoconstriction to Bay K-8644 (L-type VGCC activator). However, these were abolished by the L-type VGCC blocker nifedipine but not T-type VGCC block. Phenylephrine also initiated T-type VGCC-transient spikes and enhanced vasoconstriction after NO loss in nonmyogenic arteries from spontaneously hypertensive rats. In contrast to mesenteric arteries, myogenic coronary arteries displayed transient spikes and further vasoconstriction spontaneously on loss of NO. T-type VGCC block abolished these spikes and additional vasoconstriction but not myogenic tone. Therefore, in myogenic and nonmyogenic small arteries, reduced NO bioavailability engages T-type VGCCs, triggering transient depolarizing spikes in normally quiescent vascular smooth muscle to cause vasospasm. T-type block may offer a means to suppress vasospasm without inhibiting myogenic tone mediated by L-type VGCCs.
Researchers have identified kinematic differences between deceptive and non-deceptive rugby reorientation actions. However, the honest and deceptive signals corresponded to ‘deception detection’ ...(accuracy increasing) rather than signals that caused deception (accuracy decreasing). In this study, statistical parametric mapping and multilevel modelling were applied to examine the kinematic differences between sidestep and non-deceptive actions during the time window of deception. The analysis compared three-dimensional motion capture data from 144 deceptive actions and 144 genuine actions performed by six high-skilled rugby players. Results indicated that the kinematics of deceptive actions were characterized by a combination of exaggerated head roll, outside foot and centre-of-mass displacement, and attenuated thorax roll and yaw relative to genuine actions. These are candidate sources for the cause of deception, either individually or in combination with other sources. Furthermore, the results indicate that previously identified ‘honest’ signals may not be reliable sources of information earlier in the action sequence.
•Identified differences between genuine and deceptive actions in the time window in which players are susceptible to deception.•Analysis of discrete and continuous data.•Deceptive actions are characterised by a combination of exaggeration and attenuation.•Previously identified ‘honest’ signals may not be a reliable source of information for perceptual judgements.
Endocannabinoids and the Heart Hiley, C Robin
Journal of cardiovascular pharmacology,
2009-April, 2009-Apr, 2009-04-00, 20090401, Letnik:
53, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Endocannabinoids, such as anandamide and 2-arachidonoylglycerol, are synthesized from membrane phospholipids in the heart and other cardiovascular tissues. They activate cannabinoid CB1 and CB2 ...receptors, transient receptor potential V1 (TRPV1), peroxisome proliferator-activated receptors, and perhaps a novel vascular G-protein-coupled receptor. Inactivation is by cellular uptake and fatty acid amide hydrolase. Endocannabinoids relax coronary and other arteries and decrease cardiac work but seem not to be involved in tonic regulation of cardiovascular function. They act as a stress response system, which is activated, for example, in myocardial infarction and circulatory shock. Endocannabinoids are largely protective; they decrease tissue damage and arrhythmia in myocardial infarction and may reduce progression of atherosclerosis (CB2 receptor stimulation inhibits lesion progression), and fatty acid amide hydrolase knockout mice (which have enhanced endocannabinoid levels) show decreased cardiac dysfunction with age compared with wild types. However, endocannabinoids may mediate doxorubicin-induced cardiac dysfunction. Their signaling pathways are not fully elucidated but they can lead to changed expression of a variety of genes, including those involved in inflammatory responses. There is potential for therapeutic targeting of endocannabinoids and their receptors, but their apparent involvement in both protective and deleterious actions on the heart means that careful risk assessment is needed before any treatment can be introduced.
The actions of the anandamide-like mono-unsaturated fatty acid oleoylethanolamide (OEA) were first linked to satiety and control of food intake and recently reported to relax resistance vessels. This ...study characterizes its vasorelaxant mechanisms. Vasorelaxation to OEA were assessed in third order branches of rat superior mesenteric artery using a wire myograph. The roles of the endothelium, KCa channels, perivascular sensory nerves, NO, cannabinoid receptors, and the phospholipase C (PLC)/inositol trisphosphate (InsP3) and RhoA/ROCK signalling pathways, were assessed. OEA caused concentration- and endothelium-dependent vasorelaxation (pEC50=6.7±0.1, Rmax=93.1±2.5%). L-NAME greatly reduced the response (residual relaxation of only 24.6±12.8%). Capsaicin and pertussis toxin significantly reduced the vasorelaxation. Precontraction with KCl abolished the response. TRAM-34 had no effect, but both iberiotoxin and apamin+charybdotoxin markedly shifted the OEA concentration–response curve to the right (∼5-fold). O-1918 but not rimonabant attenuated the vasorelaxation. Both the CB1 receptor antagonist, AM251 and the CB2 receptor antagonist, AM630, given alone or in combination, reduced the response to OEA. Inhibition of PLC by U73122, ROCK by Y-27632 and antagonism of inositol trisphosphate (InsP3) receptors by 2-APB abolished OEA vasorelaxation. OEA vasorelaxation involves an endothelial site of action but not the known cannabinoid receptors. It involves Ca2+ released from InsP3-sensitive endothelial stores by mechanisms involving RhoA kinase and phospholipase C. It is likely that the released Ca2+ causes NO generation and opening of mainly large-conductance KCa channels. This study demonstrates a possible novel endothelial target that might be important in the control of regional blood flow induced by this lipid molecule.
High-skilled and recreational rugby players were placed in a semi-immersive CAREN Lab environment to examine susceptibility to, and detection of, deception. To achieve this, a broad window of seven ...occlusion times was used in which participants responded to life-size video clips of an opposing player ‘cutting’ left or right, with or without a deceptive sidestep. Participants made full-body responses to ‘intercept’ the player and gave a verbal judgement of the opponent's final running direction. Response kinematic and kinetic data were recorded using three-dimensional motion capture cameras and force plates, respectively. Based on response accuracy, the results were separated into deception susceptibility and deception detection windows then signal detection analysis was used to calculate indices of discriminability between genuine and deceptive actions (d’) and judgement bias (c). Analysis revealed that high-skilled and low-skilled players were similarly susceptible to deception; however, high-skilled players detected deception earlier in the action sequence, which enabled them to make more effective behavioural responses to deceptive actions.
•Full-body physical responses in a semi-immersive environment.•Both expert and recreational players were susceptible to deception.•Experts detected deception earlier in the action sequence than recreational players.•Earlier detection of deception enabled experts to make more effective physical responses.
The possible role of the endothelium in modulating responses to human urotensin‐II (U‐II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior ...descending coronary artery and basilar artery.
Human U‐II was a potent vasoconstrictor of endothelium‐intact isolated rat thoracic aorta (EC50=3.5±1.1 nM, Rmax=103±10% of control contraction induced by 60 mM KCl and 1 μM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L‐NAME (100 μM). Human U‐II did not cause relaxation of noradrenaline‐precontracted, endothelium‐intact rat aortae.
Human U‐II contracted endothelium‐intact rat isolated left anterior descending coronary arteries (EC50=1.3±0.8 nM, Rmax=20.1±4.9% of control contraction induced by 10 μM 5‐HT). The contractile response was significantly enhanced by removal of the endothelium (Rmax=55.4±16.1%). Moreover, human U‐II caused concentration‐dependent relaxation of 5‐HT‐precontracted arteries, which was abolished by L‐NAME or removal of the endothelium.
No contractile effects of human U‐II were found in rat small mesenteric arteries. However the peptide caused potent, concentration‐ and endothelium‐dependent relaxations of methoxamine‐precontracted vessels. The relaxant responses were potentiated by L‐NAME (300 μM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium‐derived hyperpolarizing factor).
The present study is the first to show that human U‐II is a potent endothelium‐dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U‐II which are likely to be important in determining the overall cardiovascular activity of this peptide.
British Journal of Pharmacology (2000) 130, 1865–1870; doi:10.1038/sj.bjp.0703513
Oleamide (cis‐9‐octadecenoamide) exhibits some cannabimimetic responses despite its low affinities at the currently known cannabinoid receptors. Here we have investigated whether or not it is a ...vasorelaxant in rat small mesenteric arteries.
Oleamide elicited vasorelaxation (EC50=1.2±0.2 μM, Rmax=99.1±3.9%, n=8) which was reduced by endothelial removal. Nitric oxide synthase inhibition reduced the response (EC50=5.3±1.6 μM, Rmax=59.2±7.7%, n=7; P<0.01) as did blockade of Ca2+‐sensitive K+ channels (KCa) with apamin plus charybdotoxin (both 50 nM) (EC50=2.1±0.2 μM, Rmax=58.4±1.9%, n=5; P<0.05). Desensitisation of vanilloid receptors with capsaicin (10 μM for 30 min) shifted the oleamide concentration–response curve ∼30‐fold to the right (n=7; P<0.01). Pertussis toxin (400 ng ml−1 for 2 h) caused a two‐fold shift in the response curve (EC50=2.2±0.4 μM, Rmax=66.8±4.5%, n=6; P<0.01).
Rimonabant (CB1 cannabinoid receptor antagonist; SR141716A; 3 μM) significantly inhibited relaxation induced by oleamide (EC50=3.5±0.3 μM, Rmax=75.1±1.9%; n=8; P<0.05). In contrast, neither the more selective CB1 receptor antagonist, AM251 (1 μM), nor the CB2 antagonist, SR144528 (1 μM), had significant effects. O‐1918 (10 μM), a putative antagonist at a novel endothelial cannabinoid receptor (abnormal‐cannabidiol site), markedly reduced the relaxation to oleamide (n=7; P<0.01).
It is concluded that oleamide responses in the rat isolated small mesenteric artery are partly dependent on the presence of the endothelium, activation of Ca2+‐sensitive K+ channels (KCa) and involve capsaicin‐sensitive sensory nerves. Oleamide may share a receptor (sensitive to rimonabant and O‐1918, and coupled to KCa and Gi/o) with anandamide in this vessel. This might be distinct from both of the known cannabinoid receptors and the novel abnormal‐cannabidiol site.
British Journal of Pharmacology (2006) 147, 560–568. doi:10.1038/sj.bjp.0706643
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