Objective-Statins may increase extracellular adenosine formation from adenosine monophosphate by enhancing ecto-5Ј-nucleotidase activity. This theory was tested in humans using dipyridamole-induced vasodilation as a read-out for local adenosine formation. Dipyridamole inhibits the transport of extracellular adenosine into the cytosol resulting in increased extracellular adenosine and subsequent vasodilation. In addition, we studied the effect of statin therapy in a forearm model of ischemia-reperfusion injury. Methods and Results-Volunteers randomly received rosuvastatin or placebo in a double-blind parallel design (nϭ21).The forearm vasodilator response to intraarterial dipyridamole was determined in the absence and presence of the adenosine antagonist caffeine. During a separate visit the vasodilator response to nitroprusside and adenosine was established. In addition, healthy men were randomly divided in 3 groups to receive either placebo (nϭ10), rosuvastatin (nϭ22), or rosuvastatin combined with intravenous caffeine (nϭ12). Subsequently, volunteers performed forearm ischemic exercise. At reperfusion, Tc-99m-labeled annexin A5 was infused intravenously and scintigraphic images were acquired, providing an early marker of cell injury. Rosuvastatin treatment significantly increased the vasodilator response to dipyridamole, which was prevented by caffeine. Rosuvastatin did not influence the response to either sodium nitroprusside or adenosine indicating a specific interaction between rosuvastatin and dipyridamole, which does not result from an effect of rosuvastatin on adenosine clearance nor adenosine-receptor affinity or efficacy. Rosuvastatin increased tolerance to ischemia-reperfusion injury, which was attenuated by caffeine. Conclusions-Rosuvastatin increases extracellular adenosine formation, which provides protection against ischemiareperfusion injury in humans in vivo. [1][2][3] This benefit of statins has been attributed to the lowering of plasma cholesterol. However, preclinical research indicates that HMG-CoA reductase inhibition has additional effects, including the activation of ecto-5Ј-nucleotidase which converses extracellular adenosine monophosphate into adenosine. 4 -6 Increased adenosine formation favorably influences cardiovascular disease by reducing platelet aggregation, 7 atherosclerosis formation, 8 and ischemia-reperfusion injury. 9 As statins possess similar properties, adenosine is a possible candidate to mediate these effects. 3,10 -12 To our knowledge, the role of extracellular adenosine formation in the benefit of statins has not been explored in humans.Here, we report on the results of 3 studies which addressed the effect of rosuvastatin on adenosine formation and its potential relevance in humans in vivo. For this purpose, we used the adenosine receptor antagonist caffeine and the nucleoside transport inhibitor dipyridamole, as pharmacological tools to assess the involvement of endogenous adenosine in statin-induced effects. Dipyridamole reduces clearance of extracellular adenosi...
BackgroundIn patients with type 1 diabetes mellitus (T1DM), cardiovascular events are more common, and the outcome following a myocardial infarction is worse than in nondiabetic subjects. Ischemic or pharmacological preconditioning are powerful interventions to reduce ischemia reperfusion (IR)-injury. However, animal studies have shown that the presence of T1DM can limit these protective effects. Therefore, we aimed to study the protective effect of ischemic preconditioning in patients with T1DM, and to explore the role of plasma insulin and glucose on this effect.Methods99mTechnetium-annexin A5 scintigraphy was used to detect IR-injury. IR-injury was induced by unilateral forearm ischemic exercise. At reperfusion, Tc-annexin A5 was administered, and IR-injury was expressed as the percentage difference in radioactivity in the thenar muscle between the experimental and control arm 4 hours after reperfusion. 15 patients with T1DM were compared to 21 nondiabetic controls. The patients were studied twice, with or without ischemic preconditioning (10 minutes of forearm ischemia and reperfusion). Patients were studied in either normoglycemic hyperinsulinemic conditions (n = 8) or during hyperglycemic normoinsulinemia (n = 7). The controls were studied once either with (n = 8) or without (n = 13) ischemic preconditioning.ResultsPatients with diabetes were less vulnerable to IR-injury than nondiabetic healthy controls (12.8 ± 2.4 and 11.0 ± 5.1% versus 27.5 ± 4.5% in controls; p < 0.05). The efficacy of ischemic preconditioning to reduce IR-injury, however, was lower in the patients and was even completely abolished during hyperglycemia.ConclusionsPatients with T1DM are more tolerant to forearm IR than healthy controls in our experimental model. The efficacy of ischemic preconditioning to limit IR-injury, however, is reduced by acute hyperglycemia.Trial RegistrationThe study is registered at www.clinicaltrials.gov (NCT00184821)
Abstract-3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are effective in the primary and secondary prevention of cardiovascular events. Although originally developed to improve lipid profile, statins have demonstrated a surplus of beneficial pleiotropic effects, including improved endothelial function, reduced inflammation, and increased tolerance to ischemia-reperfusion injury. In preclinical studies, increased ecto-5Ј-nucleotidase activity, the key enzyme in extracellular adenosine formation, plays an important role in these effects. Because human data are absent, we explored the effects of rosuvastatin on ecto-5Ј-nucleotidase activity and the clinical relevance of increased extracellular adenosine during ischemia in humans in vivo. The forearm vasodilator responses to 3 increasing periods of forearm ischemia (2, 5, and 13 minutes) were determined during placebo and caffeine (an adenosine receptor antagonist) infusion into the brachial artery. At the end of an 8-day treatment period with rosuvastatin (20 mg per day), this whole procedure was repeated. During both experiments, ecto-5Ј-nucleotidase activity was determined. Vasodilator responses are expressed as the percentage increase in forearm blood flow ratio from baseline. Rosuvastatin increased ecto-5Ј-nucleotidase activity by 49Ϯ17% and enhanced the vasodilator response after 2, 5, and 13 minutes of ischemia in the absence (146Ϯ19, 330Ϯ26, and 987Ϯ133 to 312Ϯ77, 566Ϯ107, and 1533Ϯ267) but not in the presence of caffeine ( Key Words: adenosine Ⅲ ecto-5Ј-nucleotidase Ⅲ caffeine Ⅲ ischemia Ⅲ reactive hyperemia 3 -Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are effective in the primary and secondary prevention of cardiovascular events. 1,2 Although originally developed to improve lipid profile, statins have demonstrated a surplus of beneficial pleiotropic effects, including improved endothelial function, reduced inflammation, and increased tolerance to ischemia-reperfusion injury. [3][4][5][6][7] These effects are independent of plasma cholesterol lowering and improve outcome after cardiovascular events. 8,9 Increased extracellular adenosine formation has been implicated as one of the underlying mechanisms. This is supported by several preclinical studies demonstrating the activation of ecto-5Ј-nucleotidase (CD73) activity, increased stimulation of adenosine receptors, and adenosine-mediated protection against ischemia-reperfusion injury by statins. 10 -12 The enzyme CD73 dephosphorylates extracellular AMP, which forms the rate-limiting step in the formation of extracellular adenosine. 13 We recently demonstrated increased extracellular adenosine formation in healthy human volunteers after a 1-week treatment with rosuvastatin using a pharmacological approach. In addition, we demonstrated rosuvastatin-induced augmentation of postocclusive reactive hyperemia (PORH). 5 However, we did not assess CD73 activity as a potential source of extracellular adenosine, nor did we investigate the role of adenosine in rosuvasta...
Background and purpose: Dipyridamole enhances post-occlusive reactive hyperaemia (PORH) in the human forearm vascular bed. We hypothesize that this effect is completely mediated by increased adenosine receptor stimulation. To test this hypothesis, the effect of caffeine (an adenosine receptor antagonist) on dipyridamole-induced augmentation of PORH was explored. Experimental approach: The forearm vasodilator responses to three increasing periods of forearm ischaemia (2, 5 and 13 min) were determined during placebo infusion. Forty minutes after the last reperfusion period, this procedure was repeated during intra-arterial infusion of dipyridamole (7.4 nmol min À1 per 100 ml forearm). At least 2 weeks later, this whole procedure was repeated, but now in the presence of caffeine (90 mg min À1 per 100 ml volume). Key results: After 2, 5 and 13 min of ischaemia, the average forearm blood flow increased to 5.6 ± 0.7, 9.7 ± 1.3 and 34.5±2.1 ml min À1 per 100 ml. After infusion of dipyridamole into the brachial artery, these numbers were significantly increased to 7.7 ± 0.8, 12.5 ± 1.5 and 41.6 ± 3.1 ml min À1 per 100 ml. This response was abolished by the concomitant infusion of caffeine (6.6 ± 0.5, 10.2 ± 0.6, 35.1 ± 2.2 (caffeine) versus 7.4 ± 0.4, 10.5 ± 0.6, 33.7 ± 2.2 ml min À1 per 100 ml (caffeine/dipyridamole)). Conclusions and implications: Caffeine prevented the augmenting effect of dipyridamole on PORH. This indicates that dipyridamole-induced augmentation of PORH is mediated via increased adenosine receptor stimulation as a result of elevated extracellular formation of adenosine during ischaemia.
1 The purine nucleotide adenosine-5 0 -triphosphate (ATP) exerts pronounced effects on the cardiovascular system. The mechanism of action of the vasodilator response to ATP in humans has not been elucidated yet. The proposed endothelium-derived relaxing factors (EDRFs) were studied in a series of experiments, using the perfused forearm technique. 2 Adenosine 5 0 -triphosphate (0.2, 0.6, 6 and 20 nmol dl À1 forearm volume min À1 ) evoked a dosedependent forearm vasodilator response, which could not be inhibited by separate infusion of the nonselective COX inhibitor indomethacin (5 mg dl À1 min À1 , n ¼ 10), the blocker of Na þ /K þ -ATPase ouabain (0.2 mg dl À1 min À1 , n ¼ 8), the blocker of K Ca channels tetraethylammonium chloride (TEA, 0.1 mg dl À1 min À1 , n ¼ 10), nor by the K ATP -channel blocker glibenclamide (2 mg dl À1 min À1 , n ¼ 10). All blockers, except glibenclamide, caused a significant increase in baseline vascular tone. The obtained results might be due to compensatory actions of unblocked EDRFs. Combined infusion of TEA, indomethacin and L-NMMA (n ¼ 6) significantly increased the baseline forearm vascular resistance. The ATP-induced relative decreases in forearm vascular resistance were 4875, 6773, 8872, and 9272% in the absence and 2377, 6274, 8972, and 9371% in the presence of the combination of TEA, indomethacin and L-NMMA (Po0.05, repeated-measures ANOVA, n ¼ 6). A similar inhibition was obtained for sodium nitroprusside (SNP, Po0.05 repeated-measures ANOVA, n ¼ 6), indicating a nonspecific interaction due to the blocker-induced vasoconstriction. 3 ATP-induced vasodilation in the human forearm cannot be inhibited by separate infusion of indomethacin, ouabain, glibenclamide or TEA, or by a combined infusion of TEA, indomethacin, and L-NMMA. Endothelium-independent mechanisms and involvement of unblocked EDRFs, such as CO, might play a role, and call for further studies.
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