Endogenously and exogenously increased noradrenaline exerts sex-different responses in human.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
M Wolzt
Publications and source records attributed to M Wolzt.
Endothelin ETA receptor-subtype specific antagonism does not mitigate the acute systemic or renal effects of exogenous angiotensin II in humans.
BACKGROUND: Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin-1 (ET-1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ET(A)-receptor blockade. DESIGN: The study design was balanced, randomized, placebo-controlled, double blind, two-way cross-over, in 10 healthy male subjects. METHODS: Subjects received stepwise increasing intravenous doses of Ang II (0.65, 1.25, 2.5, 5 ng kg(-1) min(-1) for 15 min per dose level) in the presence or absence of BQ-123 (60 microg min(-1)), a specific ETA-receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow. RESULTS: Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0.001 vs. baseline, for all parameters). BQ-123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ-123 had no significant haemodynamic effect under baseline conditions. CONCLUSIONS: Short-term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA-receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET-1.
Adult↗
Effect of inhalation of different mixtures of O(2) and CO(2) on retinal blood flow.
AIM: To determine the effects of various mixtures of O(2) and CO(2) on retinal blood flow in healthy subjects. METHODS: A randomised, double masked, four way crossover trial was carried out in 12 healthy male non-smoking subjects. Gas mixtures (100% O(2), 97.5% O(2) + 2.5% CO(2), 95% O(2) + 5% CO(2), and 92% O(2) + 8% CO(2)) were administered for 10 minutes each. Two non-invasive methods were used: laser Doppler velocimetry (LDV) for measurement of retinal blood velocity and fundus imaging with the Zeiss retinal vessel analyser (RVA) for the assessment of retinal vessel diameters. Arterial pH, pCO(2), and pO(2) were determined with an automatic blood gas analysis system. Retinal blood flow through a major temporal vein was calculated. RESULTS: Retinal blood velocity, retinal vessel diameter, and retinal blood flow decreased during all breathing periods (p <0.001 each). Administration of 92% O(2) + 8% CO(2) significantly increased SBP, MAP, and PR (p <0.001 each, versus baseline), whereas the other gas mixtures had little effect on systemic haemodynamics. Addition of 2.5%, 5%, and 8% CO(2) to oxygen caused a marked decrease in pH and an increase in pCO(2) (p <0.001 versus pure oxygen). CONCLUSIONS: Breathing of pure oxygen and oxygen in combination with carbon dioxide significantly decreases retinal blood flow. Based on these data the authors speculate that hyperoxia induced vasoconstriction is not due to changes in intravascular pH and cannot be counteracted by an intravascular increase in pCO(2).
Adult↗
Train your endothelium.
Explore the source record for details and available documents.
Arteriosclerosis↗
Health related quality of life in patients with long-standing insulin dependent (type 1) diabetes mellitus: benefits of regular physical training.
BACKGROUND AND AIMS: Regular exercise is recommended to diabetic patients in addition to dietary restrictions and drug therapy. We have studied whether health related quality of life (HRQOL) can be improved by a regular physical training program. METHODS: 23 otherwise healthy patients with history of type 1 diabetes for 20 +/- 10 years were included. 15 patients (age: 41 +/- 2 years) participated in an aerobic physical training program over 4 months and 8 patients (33 +/- 11 years) served as a control group. HRQOL was assessed by a validated questionnaire (MOS SF-36). Tests were carried out at baseline and after 4 months. RESULTS: Physical training increased peak oxygen uptake (VO2max) by 27 +/- 13% after 4 months (p = 0.04) in the training group. There was no significant change in hand or leg isometric muscle strength. All HRQOL scales improved in the training group with significantly higher (p < 0.04) Social Functioning and Vitality scores, respectively. Moreover, insulin requirements decreased during physical training program (p < 0.05). CONCLUSIONS: Our data indicate that physical exercise training in patients with type I diabetes mellitus improves metabolic control and various aspects of HRQOL. Besides enhanced cardiorespiratory capacity, this is an important subjective benefit in patients with longstanding insulin dependent (type 1) diabetes mellitus.
Adult↗
The renal and systemic hemodynamic effects of a nitric oxide-synthase inhibitor are reversed by a selective endothelin(a) receptor antagonist in men.
There is evidence for an interaction between nitric oxide (NO) and endothelin (ET) at the level of the renal vasculature. We hypothesized that acute renal effects of systemic NO synthase inhibition (NG-monomethyl-l-arginine, L-NMMA) may be blunted by coadministration of a specific ET(A) receptor antagonist (BQ-123) in healthy humans. Fifteen healthy young male subjects participated in this randomized, double-blind, placebo-controlled 3-way crossover study. These sodium-repleted volunteers received L-NMMA alone, or BQ-123 alone, or L-NMMA with a subsequent coinfusion of BQ-123. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined with the PAH and inulin clearance method, respectively. Mean arterial pressure (MAP) and pulse rate were measured noninvasively at baseline and every 15 min after the start of the study period. L-NMMA alone reduced RPF (-22%, P < 0.001) and GFR (-8%, P < 0.009) and increased MAP (+10%, P < 0.001). BQ-123 alone did not affect these parameters. However, coinfusion of BQ-123 blunted the effects of L-NMMA on RPF (P < 0.001), GFR (P < 0.001), and MAP (P = 0.006). Peripheral and renal hemodynamic effects of acute systemic NO synthase inhibition are at least partially reversed by ET(A) receptor blockade with BQ-123. This indicates a functional antagonism between specific ET(A) receptor antagonist and NO synthase inhibitors at the level of the renal vasculature.
Adult↗
Glucose and insulin exert additive ocular and renal vasodilator effects on healthy humans.
AIMS/HYPOTHESIS: There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy. METHODS: We carried out two different 3-way crossover studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/ 1, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively. RESULTS: Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions. CONCLUSIONS/INTERPRETATION: Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed.
Adult↗
A double masked placebo controlled study on the effect of nifedipine on optic nerve blood flow and visual field function in patients with open angle glaucoma.
AIMS: To investigate whether nifedipine affects ocular perfusion or visual fields in open angle glaucoma patients. METHODS: In a parallel group study nifedipine or placebo was administered for 3 months (n = 30). Ocular fundus pulsation amplitude (FPA), cup blood flow (Flowcup) and visual field mean deviation (MD) were measured. RESULTS: Five patients receiving nifedipine discontinued due to adverse events. Nifedipine did not affect FPA [difference: 0.3 microm (95% CI -0.3,0.9); P = 0.70], Flowcup: [difference: -9 rel.units (95% CI -133,114); P = 0.99], or MD [difference: 0.2dB (95% CI -2.2,2.7); P = 0.51] vs placebo. CONCLUSIONS: Systemic nifedipine is not well tolerated in glaucoma patients and exerts no effect on visual fields or ocular perfusion.
Administration, Oral↗
Free fatty acids/triglycerides increase ocular and subcutaneous blood flow.
Elevated plasma free fatty acids (FFA) induce skeletal muscle insulin resistance and impair endothelial function. The aim of this study was to characterize the acute hemodynamic effects of FFA in the eye and skin. A triglyceride (Intralipid 20%, 1.5 ml/min)/heparin (bolus: 200 IU; constant infusion rate: 0.2 IU. kg(-1). min(-1)) emulsion or placebo was administered to 10 healthy subjects. Measurements of pulsatile choroidal blood flow with laser interferometry, retinal blood flow with the blue field entoptic technique, peak systolic and end diastolic blood velocity (PSV, EDV) in the ophthalmic artery with Doppler sonography, and subcutaneous blood flow with laser Doppler flowmetry were performed during an euglycemic somatostatin-insulin clamp over 405 min. Plasma FFA/triglyceride elevation induced a rise in pulsatile choroidal blood flow by 25 +/- 3% (P < 0.001) and in retinal blood flow by 60 +/- 23% (P = 0.0125). PSV increased by 27 +/- 8% (P = 0.001), whereas EDV was not affected. Skin blood flow increased by 149 +/- 38% (P = 0.001). Mean blood pressure and pulse rate remained unchanged, whereas pulse pressure amplitude increased by 17 +/- 5% (P = 0.019). Infusion of heparin alone had no hemodynamic effect in the eye or skin. In conclusion, FFA/triglyceride elevation increases subcutaneous and ocular blood flow with a more pronounced effect in the retina than in the choroid, which may play a role for early changes of ocular perfusion in the insulin resistance syndrome.
Adult↗
Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia.
BACKGROUND: Previous studies have suggested that statins exert beneficial effects beyond their favorable lipid lowering effect. Particularly, the modification of thrombus formation and degradation, alteration in inflammatory response, plaque stabilization and improved endothelial function are thought to be responsible for additional reduction of morbidity and mortality due to cardiovascular events. To date, however, it is still unclear whether these effects are elicited by all statins. METHODS AND RESULTS: We set out to compare in a controlled, randomized, double-blind study design the effects of almost equieffective cholesterol lowering doses of three chemically and pharmacokinetically different statins (atorvastatin, simvastatin, pravastatin) on hemostatic and inflammatory markers in 99 hypercholesterolemic patients. At entry and 3 months after onset of statin therapy plasma cholesterol and von Willebrand factor antigen (vWf-Ag), fibrinogen, d-dimer, prothrombin fragment 1+2 (F1.2) and C-reactive protein (CRP) were measured. The effect on plasma values of F1.2, vWf-Ag, d-dimer and CRP was not significantly different between the three treatment groups. The effect of simvastatin on fibrinogen (p = 0.005) was more pronounced than the effects of atorvastatin (p = 0.48 n.s.) and pravastatin (p = 0.15 n.s.). Plasma levels of F1.2 and vWf-Ag (when data of all statins were pooled) were significantly reduced by 7% and 10% versus baseline, respectively. No significant reduction was observed for d-dimer (p = 0.26) and CRP (p = 0.5). Total plasma cholesterol levels decreased significantly (p < 0.0001 in all groups) between 22% and 29% compared to baseline. CONCLUSION: The present study shows similar short-term (3 months) effects of atorvastatin, simvastatin and pravastatin on selected hemostatic and inflammatory parameters in plasma in patients with hypercholesterolemia. Thus, chemical and pharmacological differences between statins appear to exert no major influence on these parameters.
Adult↗
Effects of insulin on retinal and pulsatile choroidal blood flow in humans.
BACKGROUND: Insulin induces vasodilation in several tissues, including skeletal muscle and kidneys. OBJECTIVE: To investigate whether insulin may contribute to ocular blood flow regulation. METHODS: The study was performed in a balanced, randomized, placebo-controlled, single-masked, 3-way, crossover design in 9 healthy male subjects. Each subject received 2 doses of insulin (1.5 or 3 mU/kg per minute) or placebo on 3 different study days. Measurements of fundus pulsation amplitude with laser interferometry to assess pulsatile choroidal blood flow, of retinal blood flow with the blue-field entoptic technique, and of mean blood flow velocity in the ophthalmic artery with Doppler sonography were performed under euglycemic clamp conditions over 120 minutes. RESULTS: Hyperinsulinemia significantly increased fundus pulsation amplitude (1.5 mU/kg per minute: 8.7% +/- 1.1% vs baseline; 3 mU/kg per minute: 13.2% +/- 2.3% vs baseline; P<.001 vs placebo [analysis of variance]) and mean blood flow velocity (1.5 mU/kg per minute: 10.0% +/- 4.3% vs baseline; 3 mU/kg per minute: 6.6% +/- 3.5% vs baseline; P = .03 vs placebo). Retinal blood flow did not increase during administration of insulin (1.5 mU/kg per minute: 6.4% +/- 8.0% vs baseline; 3 mU/kg per minute: 8.0% +/- 5.1% vs baseline; P = .99 vs placebo). Neither the effect in the choroid nor that in the ophthalmic artery was dose-dependent. CONCLUSION: Hyperinsulinemia significantly increases choroidal blood flow and mean blood flow velocity in the ophthalmic artery. By contrast, retinal blood flow was not influenced by hyperinsulinemia. The maximum effective dose of insulin for ocular hemodynamics is likely to be within the physiological range.
Adult↗
A comparison between laser interferometric measurement of fundus pulsation and pneumotonometric measurement of pulsatile ocular blood flow. 2. Effects of changes in pCO2 and pO2 and of isoproterenol.
PURPOSE: We have shown in the companion paper that, under baseline conditions, there is a high degree of association between laser interferometrically measured fundus pulsation amplitude (FPA) and pneumotonometrically measured pulse amplitude (PA) and pulsatile ocular blood flow (POBF). The present study investigated the effect of high pCO2, of high pO2 and of isoproterenol on POBF as assessed with laser interferometry and pneumotonometry. METHODS: Pneumotonometry and laser interferometry were performed in young healthy subjects during breathing of 100% O2 (n = 10; hyperoxia) and of 5% CO2 + 95% air (n = 8; hypercapnia). In addition these parameters were studied during stepwise increasing doses of isoproterenol, a beta-receptor agonist (n = 8). RESULTS: Inhalation of 5% CO2 + 95% air increased FPA (24 +/- 12%, p < 0.001), PA (26 +/- 13%, p < 0.001) and POBF (15 +/- 8%, p = 0.002). Inhalation of 100% O2 decreased FPA (-5 +/- 7%, p = 0.027), but did not change PA or POBF. The effect of 100% O2 inhalation on FPA in the optic disc was more pronounced (-11% to -20%) than in the macula. Isoproterenol caused a dose-dependent increase in FPA, PA and POBF (p < 0.001). The association between the induced changes in FPA and PA or POBF was highly significant. CONCLUSIONS: The present study shows that FPA can be taken as a valid relative measure of pulsatile choroidal blood flow. Our results in the optic disc indicate that FPA at the neuroretinal rim and at the cup is influenced by retinal and choroidal circulation.
Adrenergic beta-Agonists↗
A comparison between laser interferometric measurement of fundus pulsation and pneumotonometric measurement of pulsatile ocular blood flow. 1. Baseline considerations.
PURPOSE: Several methods have been proposed for the investigation of the human choroidal circulation. The aim of the present study was to compare laser interferometric measurements of cardiac synchronous fundus pulsations with pneumotonometric measurements of intraocular pressure pulse and pulsatile ocular blood flow in humans. METHODS: The association between fundus pulsation amplitude as assessed with laser interferometry and pulse amplitude (PA) and pulsatile ocular blood flow (POBF) as assessed with pneumotonometry was investigated in 28 healthy subjects. Additionally, we investigated the distribution of fundus pulsation amplitude (FPA) in a region of -15 degrees to +15 degrees around the macula (n = 18) and the influence of accommodation paralysis with cyclopentolate on FPA (n = 10). RESULTS: There was a high association between FPA and PA (r = 0.86, p < 0.001) and FPA and POBF (r = 0.70, p < 0.001). Fundus pulsations in the macula were significantly smaller than in the optic disc, but significantly larger than those in peripheral regions of the retina. Administration of cyclopentolate did not influence FPA. CONCLUSIONS: On the basis of the strong correlation between laser interferometric measurements of FPA and pneumotonometric measurements of PA and POBF, we conclude that the FPA is a valid index of pulsatile choroidal perfusion in humans.
Adult↗
Ocular haemodynamics and colour contrast sensitivity in patients with type 1 diabetes.
BACKGROUND: There is evidence that altered ocular blood flow is involved in the development and progression of diabetic retinopathy. However, the nature of these perfusion abnormalities is still a matter of controversy. Ocular haemodynamics were characterised with two recently introduced methods. METHODS: The cross sectional study was performed in 59 patients with type 1 diabetes with a diabetes duration between 12 and 17 years and an age less than 32 years and a group of 25 age matched healthy controls. Scanning laser Doppler flowmetry and laser interferometric measurement of fundus pulsation amplitude were used to assess retinal and pulsatile choroidal blood flow, respectively. In addition, colour contrast sensitivity along the tritan axis was determined. RESULTS: Fundus pulsation amplitude, but not retinal blood flow, increased with the progression of diabetic retinopathy. Retinal blood flow was influenced by plasma glucose levels (r = 0.32), whereas fundus pulsation amplitude was associated with HbA(1c) (r = 0.30). In addition, a negative correlation between the colour contrast sensitivity along the tritan axis and retinal blood flow was observed. CONCLUSIONS: The present study indicates that pulsatile choroidal blood flow increases with the progression of diabetic retinopathy. Increased retinal blood flow appears to be related to loss of colour sensitivity in patents with type 1 diabetes.
Adolescent↗
Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans.
Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.
Adenosine Triphosphate↗
Endothelin-1 contributes to hyperoxia-induced vasoconstriction in the human retina.
PURPOSE: There is evidence that ocular blood flow strongly depends on arterial oxygen tension. Results from recent animal studies indicate that the vasoconstrictor response to hyperoxia may be mediated in part by an increased production of endothelin (ET)-1. In an effort to answer the question whether the retinal vasoconstrictive response to hyperoxia in humans is mediated through ET-1, changes in ocular hemodynamics induced by 100% O2 breathing were studied in the absence and presence of an ET(A) receptor antagonist (BQ-123). METHODS: The study was a randomized, placebo-controlled, double-masked, balanced, three-way crossover design. On separate study days 15 healthy male subjects received infusions of BQ-123 (either 60 microg/min or 120 microg/min) or placebo. The effects of BQ-123 or placebo on hyperoxia-induced (100% O2 breathing) changes in retinal and pulsatile choroidal blood flow were assessed with the blue-field entoptic technique and with laser interferometric measurement of fundus pulsation, respectively. RESULTS: During baseline conditions, hyperoxia caused a decrease in retinal blood flow between -29% and -34% (P<0.001) and a decrease in fundus pulsation amplitude between -7% and -8% (P<0.001). BQ-123 dose dependently blunted the response to hyperoxia in the retina (60 microg/min: -25%, 120 microg/min: -20%; P = 0.003), but not in the choroid. CONCLUSIONS: These results indicate that ET-1 contributes to hyperoxia-induced retinal vasoconstriction in the human retina.
Adult↗
Effects of systemic NO synthase inhibition on choroidal and optic nerve head blood flow in healthy subjects.
PURPOSE: There is evidence from animal studies that nitric oxide (NO) is a major determinant of ocular blood flow. In humans NO synthase inhibition reduces pulsatile choroidal blood flow, but no data on optic nerve head (ONH) vasculature are available yet. The goal of this study was to investigate the effects of NO synthase inhibition on human choroidal and ONH blood flow using laser Doppler flowmetry. METHODS: The study design was a randomized, placebo-controlled, double-masked, balanced three-way crossover. On separate study days 12 healthy male subjects received infusions of N:(G)-nitro-L-arginine (L-NMMA; either 3 mg/kg over 5 minutes followed by 30 microg/kg per minute over 55 minutes or 6 mg/kg over 5 minutes followed by 60 microg/kg per minute over 55 minutes) or placebo. The effects of L-NMMA or placebo on choroidal and ONH blood flow were measured with laser Doppler flowmetry. In addition, laser interferometric measurement of fundus pulsation was performed in the macula to assess pulsatile choroidal blood flow. RESULTS: L-NMMA reduced all outcome parameters in the choroid and the ONH. The higher dose of L-NMMA caused a significant decrease in blood flow in the choroid (-26% +/- 9%; P: < 0.001) and the ONH (-20% +/- 16%; P: < 0.001) as evidenced from laser Doppler flowmetry and a significant decrease in fundus pulsation amplitude (-26% +/- 5%; P: < 0.001). CONCLUSIONS: These results indicate that NO is continuously released in human choroidal and ONH vessels.
Adult↗
Biochemical characterization of S-nitrosohemoglobin. Mechanisms underlying synthesis, no release, and biological activity.
S-Nitrosohemoglobin (SNO-Hb) has been suggested to act as an endogenous NO donor and physiological regulator of blood pressure. However, the mechanisms responsible for the formation of SNO-Hb and those underlying the release of NO and subsequent biological activity have yet to be elucidated. In the present study, a number of nitrosated oxyhemoglobin (HbO(2)) derivatives have been synthesized and characterized. HbO(2) can be nitrosated at up to three distinct residues, one in the alpha-globin chain and two in the beta-chain. A beta-chain mononitrosated species (designated "SNO-Hb"), generated by the reaction of HbO(2) and S-nitrosoglutathione, released NO via a thiol-dependent mechanism involving nucleophilic attack at the nitrosated thiol functionality of SNO-Hb; in the case of glutathione, this process was associated with the formation of a mixed disulfide. In contrast, multinitrosated hemoglobin species released NO and relaxed vascular smooth muscle by a thiol-independent mechanism. HbO(2) scavenged potently NO released from SNO-Hb and inhibited its vasorelaxant properties. These data show that the predominant vasoactive species released from SNO-Hb is NO, with HNO a putative intermediate; the presence of a low molecular weight thiol is a prerequisite for this process. Such observations have important implications for the generation, metabolic fate, and biological activity of S-nitrosothiols.
2,3-Diphosphoglycerate↗