Supplementary oxygen is commonly administered in current medical practice. Recently it has been suggested that hyperoxia causes acute oxidative stress and produces prompt and substantial changes in coronary resistance in patients with ischemic heart disease. In this report, we examined whether the effects of hyperoxia on coronary blood velocity (CBV) would be associated with a reduction in myocardial function. We were also interested in determining if the postulated changes in left ventricular (LV) function seen with Tissue Doppler Imaging (TDI) could be reversed with intravenous vitamin C, a potent, acute anti-oxidant. LV function was determined in eight healthy subjects with transthoracic echocardiography and TDI before and after hyperoxia and with and without infusing vitamin C. Hyperoxia compared to room air promptly reduced CBV by 28 ± 3% (from 23.50 ± 2.31 cm/s down to 17.00 ± 1.79 cm/s) and increased relative coronary resistance by 34 ± 5% (from 5.63 ± 0.88 up to 7.32 ± 0.94). Meanwhile, LV myocardial systolic velocity decreased by 11 ± 6% (TDI). These effects on flow and function were eliminated by the infusion of vitamin C. This suggests that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation.
Obesity is a disease of oxidative stress (OS). Acute hyperoxia (breathing 100% O2) can evoke coronary vasoconstriction by the oxidative quenching of nitric oxide (NO). To examine if weight loss would alter the hyperoxia related-coronary constriction seen in obese adolescents, we measured the coronary blood flow velocity (CBV) response to hyperoxia using transthoracic Doppler echocardiography before and after a 4-week diet-and-exercise regimen in 6 obese male adolescents (age 13–17 yrs, BMI, 36.5 ± 2.3 kg/m2). Six controls of similar age and BMI were also studied. The intervention group lost 9 ± 1% body weight, which was associated with a reduced resting heart rate (HR), reduced diastolic blood pressure (BP), and reduced rate pressure product (RPP, all P<0.05). Before weight loss, hyperoxia reduced CBV by 33 ± 3%. After weight loss, CBV only fell by 15 ± 3% (P <0.05). In the control group, CBV responses to hyperoxia were unchanged during the two trials. Thus weight loss: 1) reduces HR, BP, and RPP; and 2) attenuates the OS related-coronary constrictor response seen in obese adolescents. We postulate that: 1) the high RPP before weight loss led to higher myocardial O2 consumption, higher coronary flow and greater NO production, and in turn a large constrictor response to hyperoxia; and 2) weight loss decreased myocardial oxygen demand and NO levels. Under these circumstances, hyperoxia induced vasoconstriction was attenuated.
Spilk S, Herr MD, Sinoway LI, Leuenberger UA. Endothelium-derived hyperpolarizing factor contributes to hypoxia-induced skeletal muscle vasodilation in humans. Am J Physiol Heart Circ Physiol 305: H1639 -H1645, 2013. First published September 16, 2013 doi:10.1152/ajpheart.00073.2013.-Systemic hypoxia causes skeletal muscle vasodilation, thereby preserving O 2 delivery to active tissues. Nitric oxide (NO), adenosine, and prostaglandins contribute to this vasodilation, but other factors may also play a role. We tested the hypothesis that regional inhibition of endothelium-derived hyperpolarizing factor with the cytochrome P-450 2C9 antagonist fluconazole, alone or combined with the NO synthase antagonist N G -monomethyl-L-arginine (L-NMMA), attenuates hypoxia-induced vasodilation. We compared forearm blood flow (FBF) and skin blood flow before and during brachial artery infusion of fluconazole (0.3 mg/min; trial 1) or fluconazole ϩ L-NMMA (50 mg over 10 min; trial 2) and during systemic hypoxia (10 min, arterial PO 2 ϳ37 mmHg) in infused (experimental) and control forearms of 12 healthy humans. During normoxia, fluconazole and fluconazole ϩ L-NMMA reduced (P Ͻ 0.05) forearm vascular conductance (FVC) by ϳ10% and ϳ18%, respectively. During hypoxia and fluconazole (trial 1), FVC increased by 1.76 Ϯ 0.37 and 0.95 Ϯ 0.35 units in control and experimental forearms, respectively (P Ͻ 0.05). During hypoxia and fluconazole ϩ L-NMMA (trial 2), FVC increased by 2.32 Ϯ 0.51 and 0.72 Ϯ 0.22 units in control and experimental forearms, respectively (P Ͻ 0.05). Similarly, during hypoxia with L-NMMA alone (trial 3; n ϭ 8) FVC increased by 1.51 Ϯ 0.46 and 0.45 Ϯ 0.32 units in control and experimental forearms, respectively (P Ͻ 0.05). These effects were not due to altered skin blood flow. We conclude that endotheliumderived hyperpolarizing factor contributes to basal vascular tone and to hypoxia-induced skeletal muscle vasodilation and could be particularly relevant when other vasodilator systems are impaired.hypoxia; vasodilation; endothelium-derived hyperpolarizing factor; fluconazole; nitric oxide UNDER BASAL CONDITIONS and during physiological stress, skeletal muscle blood flow is closely matched to metabolic demand. Accordingly, in healthy humans, systemic hypoxia is accompanied by skeletal muscle vasodilation, which serves to maintain O 2 homeostasis (20,27,29). Because hypoxia raises sympathetic vasoconstrictor nerve traffic and norepinephrine spillover (14, 31), vasodilation results from release of systemic or local vasodilator factors. In agreement with studies in rodents (22,24,26), it has been reported that nitric oxide (NO) (7,9,16,35) and adenosine (15, 18) contribute to hypoxiainduced vasodilation in humans. In addition, some reports (6, 35), but not others (27), support a role for an increase in circulating epinephrine, and one recent report (19) suggests that vasodilator prostaglandins also contribute to the skeletal muscle vasodilation elicited by systemic hypoxia. Thus multiple endogenous vasodilator mechanisms ...
Prior studies suggest that adenosine, nitric oxide and prostaglandins contribute to skeletal muscle vasodilation induced by systemic hypoxia in humans. However, pharmacological blocking studies suggest that other vasodilator systems such as for example endothelium‐derived hyperpolarizing factor (EDHF) may be involved. Fluconazole, an antifungal agent with cytochrome P450 2C9 inhibitor properties can be used to block EDHF. We exposed healthy humans (n=8) to systemic hypoxia (inspired O2 fraction 0.1 for 10 min; arterial pO2 ~38 mmHg) and measured forearm blood flow (FBF, plethysmography) during brachial artery infusion of fluconazole (0.33 mg/min) and of fluconazole and NG–monomethyl‐L‐arginine (L‐NMMA; 50 mg) in the infused and opposite forearms. Forearm vascular conductance (FVC) was calculated as FBF/mean blood pressure. During normoxia, fluconazole had no effect on FVC and failed to attenuate the rise in FVC during hypoxia (P=NS). However, during co‐infusion of fluconazole and L‐NMMA, the hypoxia‐induced increase in FVC was markedly reduced (experimental vs. control: 0.11±0.23 vs. 1.65±0.66 units; P<0.05). Because L‐NMMA induces an experimental NO‐deficient state, these data suggest that EDHF may be uniquely important when bioavailability of NO is diminished. This could have broad implications in conditions characterized by oxidative stress. Supported by NIH P01 HL077670, and M01 RR010732.
In healthy humans, short‐term intermittent hypoxia (IH) raises sympathetic nerve activity mirroring the sympathetic activation seen in patients with obstructive sleep apnea. To explore the role of oxidative stress, we measured blood pressure (BP), sympathetic activity (microneurography) and flow‐mediated brachial artery dilation before and following IH (30 episodes, O2 saturation nadir ~82%) with and without the antioxidant ascorbic acid (50 mg/kg iv) in healthy subjects (age 26±1 yrs; n=13). During saline infusion, IH produced a sustained increase in sympathetic activity (pre vs. post 20.0±1.8 vs. 25.2±1.8 bursts/min; P<0.05) and a small rise of mean BP (pre vs. post 86±2 vs. 89±3 mmHg; P<0.05). In contrast, on a separate day during infusion of ascorbic acid, IH did not raise sympathetic activity (pre vs. post 20.2±2.1 vs. 20.5±2.6 bursts/min; P=NS) or BP (pre vs. post 88±2 vs. 89±2 mmHg; P=NS). Moreover, whereas during saline infusion IH reduced flow‐mediated dilation (pre vs. post 6.8±1.3 vs. 3.2±1.6%; P<0.05), with ascorbic acid this effect was not seen (pre vs. post 6.0±1.2 vs. 6.1±1.4%; P=NS, n=8). These data suggest indirectly that oxidative stress may play a role in the sympathetic activation and vascular dysfunction induced by IH.Supported by P01 HL077670 and UL1 RR033184.
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