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Aims Intermittent early reperfusion (ischaemic postconditioning; PostC) reduces ischaemia–reperfusion (IR) injury. Using an in vivo model of endothelial IR injury in humans, we sought to determine the role of KATP channels in PostC and whether inhibition of the mitochondrial permeability transition pore (mPTP) at the onset of reperfusion protected against endothelial IR injury. Methods and results Endothelial function (EF) in healthy volunteers was assessed using vascular ultrasound to measure the percentage increase in the diameter of the brachial artery in response to reactive hyperaemia [flow-mediated dilatation (FMD)]. In resistance vessels, venous occlusion plethysmography was used to measure the dilator response to acetylcholine (ACh) [area under ACh dose–response curve (ACh AUC)]. Measurements were made before and after IR injury. Ischaemic postconditioning consisted of three 10 s cycles of alternating ischaemia and reperfusion in the first minute of reperfusion. Oral glibenclamide and glimepiride were used to determine the role of KATP channel subtypes in PostC. Intra-arterial cyclosporine was used to determine the role of mPTP in endothelial IR injury. Ischaemia–reperfusion reduced EF in the brachial artery (FMD 7.1 ± 0.9% pre-IR, 2.8 ± 0.4% post-IR; P < 0.001) and resistance vessels [ACh AUC (×104) 2.1 ± 0.4 pre-IR, 1.5 ± 0.2 post-IR; P < 0.05]. Ischaemic postconditioning preserved EF in the brachial artery [FMD 6.8 ± 0.9% (P < 0.001 vs. post-IR)] and resistance vessels [ACh AUC (×104) 1.9 ± 0.2 (P < 0.001 vs. post-IR)]. Protection by PostC was abolished by glibenclamide in the brachial artery [FMD 3.3 ± 0.2% (P < 0.001 vs. post-IR + PostC)] and in resistance vessels [ACh AUC (×104) 1.1 ± 0.2 (P < 0.001 vs. post-IR + PostC)], whereas glimepiride had no effect. Cyclosporine preserved EF after IR injury in the resistance vessels [ACh AUC (×104) 1.4 ± 0.2 post-IR vs. 2.2 ± 0.3 post-IR + cyclosporine; P < 0.05]. Conclusion Protection by PostC against endothelial IR injury in humans depends on KATP channel activation and is mimicked by inhibition of the mPTP at reperfusion. [ABSTRACT FROM PUBLISHER]

Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans.Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial NG-monomethyl-l-arginine (l-NMMA) and bradykinin, respectively. The effects of supplementation with l-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion.Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and l-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with l-arginine had no effect.Inflammation causes widespread endothelial dysfunction, reduces vascular NO bioavailability and increases oxidative stress. These actions are partially reversible with local anti-oxidants. These findings suggest a role for reactive oxygen species in inflammation-induced endothelial dysfunction. [Copyright &y& Elsevier]

Objectives: Responses to EDHF are usually characterised in the presence of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibitors. The contribution of NO to endothelium-dependent relaxation in the presence of NOS inhibitors was assessed using NO scavengers with the objective of testing (i) whether any residual NO produces endothelium-dependent relaxation in a manner similar to EDHF and (ii) to identify the source of the residual NO. Methods: Small rat hepatic and mesenteric arteries were mounted in a tension myograph for either isometric or membrane potential measurements. Results: Relaxation to ACh was unaffected by pre-treatment with NG-nitro-l-arginine methyl ester (l-NAME, 300 μM), and indomethacin (Indo, 5 μM) in the absence or presence of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 μM), nitro-l-arginine (300 μM) or l-nitro-mono-methyl-arginine (l-NMMA, 300 μM). Addition of OxyHb (20 μM) or carboxy-PTIO (300 μM) produced a significant suppression of ACh-induced relaxations (&ap;40%). In l-NAME+Indo treated arteries ACh-induced hyperpolarisation (Δ16.3±2.1 mV, n=8) was significantly suppressed with the addition of OxyHb (Δ10.2±1.6 mV, n=12). ACh-induced relaxation, in the presence of l-NAME+Indo+OxyHb, was abolished by raised extracellular K+, or the combination of charybdotoxin (CTX, 100 nM)+apamin (100 nM). In contrast whilst l-NAME+indo+barium+ouabain suppressed ACh-induced relaxation, the presence of OxyHb had no additional effect. Ultraviolet light induced a relaxation in arteries treated with l-NMMA+Indo (37.0±5.2%, n=9) which was sensitive to OxyHb (15.2±10.9%, n=4), and barium+ouabain (6.39±2.7%, n=4), but not CTX+apamin (37.8±2.4%, n=4). Conclusions: These findings suggest that NO contributes significantly to the “EDHF-like” response seen in rat small arteries and that the source of this NO may be preformed vascular stores. [Copyright &y& Elsevier]

Objective: Aging is associated with endothelial dysfunction. We studied the acute and longer-term effects of vitamin C compared to a ‘Mediterranean-type’ diet on endothelial function in healthy older subjects. Methods: Bilateral venous occlusion plethysmography was used to measure forearm blood flow in subjects aged 57–80 years. Responses to cumulative intra-arterial doses of the endothelium-dependent dilator bradykinin (BK; n=56; 20, 40, 80 pmol/min) and the nitric oxide donor glyceryl trinitrate (GTN; n=54; 4, 8, 16 nmol/min), were determined alone and in the presence of vitamin C (25 mg/min). We then randomised 54 subjects to a ‘healthy’ diet (n=18), vitamin C (1 g/day; n=18) or placebo for 6 weeks and reassessed endothelial and smooth muscle function. Results: Acute intra-arterial vitamin C did not alter dilatation to BK or GTN. Similar increases in plasma vitamin C occurred on oral vitamin C (83±4 to135±8 μmol/l) and ‘healthy’ diet (84±5 to135±27 μmol/l; P<0.01 for both), with no change seen on placebo. Treatment with a ‘healthy’ diet but not oral vitamin C improved endothelium-dependent (P=0.043) and endothelium-independent dilatation (P=0.011). Conclusions: A ‘Mediterranean-type’ diet rich in vitamin C improves vascular function. Neither acute intra-arterial nor sustained administration of oral vitamin C improves vascular function in healthy older subjects. [Copyright &y& Elsevier]

Background. Circulating inhibitors of endothelial function have been implicated in the pathogenesis of vascular disease in chronic renal failure. The aim of this study was to determine if lowering the plasma concentration of these and other dialysable toxins improves endothelial function. To do this we compared the acute effects on endothelial function of single episodes of haemodialysis with automated peritoneal dialysis. We hypothesized that endothelial function would improve after dialysis, with a greater effect seen after haemodialysis due to more substantial clearance of endothelial toxins per‐treatment. [ABSTRACT FROM PUBLISHER]

Objective: Nitric oxide (NO) is a vasodilator and inhibitor of platelet function. The clinical use of NO donors as inhibitors of platelet activation is limited by their concomitant hypotensive effect. S-nitroso-glutathione (GSNO) has a significant antiplatelet effect at doses that cause only a small decrease in blood pressure in rats. The aim of this study was to examine the antiplatelet and vasodilator properties of this nitrosothiol in the human forearm. Methods: Forearm blood flow was measured by forearm occlusion plethysmography in five healthy males. Ex vivo platelet aggregation to ADP was performed in a platelet ionised calcium lumi-aggregometer. Results: Intra-arterial infusion of GSNO (0.2, 1, and 5 nmol·min−1) resulted in inhibition of ADP (1-10 μM) induced platelet aggregation. This inhibition was submaximal for 0.2 and maximal for 1 and 5 nmol·min−1. However, the antiaggregatory effect observed at the lowest dose of GSNO was accompanied only by a threshold increase in forearm blood flow. Conclusions: These results show that GSNO is more effective as an inhibitor of platelet activation than as a vasodilator, suggesting that it is possible to achieve selective antiplatelet and potentially antithrombotic effects with NO donors.Cardiovascular Research 1994;28:691-694 [ABSTRACT FROM PUBLISHER]