Min Period Of Hypoxia Research Articles

Protective Effect of DHQ-11 against Hypoxia-induced Vasorelaxation

Hypoxia, or the lack of oxygen, has multiple impacts on the vascular system. The major molecular sensors for hypoxia at the cellular level are hypoxia inducible factor and heme oxygenase. Hypoxia also acts on the vasculature directly conveying its damaging effects through disruption of the control of vascular tone, particularly in the coronary circulation, enhancement of inflammatory responses and activation of coagulation pathways. These effects could be particularly detrimental under pathological conditions such as obstructive sleep apnea and other breathing disorders. Introduction: The effect of conjugate 2-(3,4-Dihydroxyphenyl)-6-{[1-(2’-bromo-3’,4’-dimethoxyphenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H )-yl]methyl}-3,5,7-trihydroxychroman-4-one (DHQ-11) on hypoxia-induced vasorelaxation was investigated in rat aortic rings using standard organ bath techniques. Materials and methods: Hypoxia was stimulated by a superfusion of aortic rings with a glucose-free Krebs solution bubbled with 95 % N2/5 % CO2. The effect of conjugate DHQ-11 was assessed after a 60- min period of hypoxia on aortic rings precontracted with 50 mm KCl or 1µM phenylephrine (PE). The conjugate DHQ-11 significantly attenuated hypoxia-induced vasorelaxation in the endothelium-intact aortic rings precontracted with KCl or PE in a concentration-dependent manner. Results and discussion: This effect of conjugate DHQ-11 was more potent in aortic rings precontracted with PE than those with KCl where it maximally reduced hypoxia-induced vasorelaxation from 44.7 ± 3.7 to 5.4 ± 3.7 and 33.9 ± 3.4 to 10.8 ± 4.2 %, respectively. The removal of the endothelium attenuated the effect of conjugate DHQ-11 on hypoxia-induced vasorelaxation. Similarly, pretreatment of endothelium-intact aortic rings with L-NAME and methylene blue also attenuated the effect of conjugate DHQ-11 on hypoxia-induced vasorelaxation. Furthermore, the blockade of the ATP-sensitive KATP channel with glibenclamide and the calcium-activated large conductance BKCa channel with TEA also significantly attenuated the effect of conjugate DHQ-11 on hypoxia-induced vasorelaxation. Collectively, these results indicated that conjugate DHQ-11 attenuated the hypoxia-induced vasorelaxation suggesting that it alleviated the oxidative damage of vasculature. Conclusions: This effect of conjugate DHQ-11 possible is mediated through several mechanisms including the blockage of the extracellular Ca2+ entry via the voltage-dependent and receptor-operative Ca2+ channels, as well as inhibition of sarcoplasmic reticulum Ca2+ release via the inositol triphosphate pathway. In addition, endothelium and NO/sGC/cGMP/PKG pathway, as well as KATP and BKCa channels most likely participate in protection by conjugate DHQ-11 against hypoxia-induced vasorelaxation.

Transport and metabolism of exogenous fumarate and 3-phosphoglycerate in vascular smooth muscle.

The keto (linear) form of exogenous fructose 1,6-bisphosphate, a highly charged glycolytic intermediate, may utilize a dicarboxylate transporter to cross the cell membrane, support glycolysis, and produce ATP anaerobically. We tested the hypothesis that fumarate, a dicarboxylate, and 3-phosphoglycerate (3-PG), an intermediate structurally similar to a dicarboxylate, can support contraction in vascular smooth muscle during hypoxia. To assess ATP production during hypoxia we measured isometric force maintenance in hog carotid arteries during hypoxia in the presence or absence of 20 mM fumarate or 3-PG. 3-PG improved maintenance of force (p < 0.05) during the 30-80 min period of hypoxia. Fumarate decreased peak isometric force development by 9.5% (p = 0.008) but modestly improved maintenance of force (p < 0.05) throughout the first 80 min of hypoxia. 13C-NMR on tissue extracts and superfusates revealed 1,2,3,4-(13)C-fumarate (5 mM) metabolism to 1,2,3,4-(13)C-malate under oxygenated and hypoxic conditions suggesting uptake and metabolism of fumarate. In conclusion, exogenous fumarate and 3-PG readily enter vascular smooth muscle cells, presumably by a dicarboxylate transporter, and support energetically important pathways.

Cardiac output distribution in response to hypoxia in the chick embryo in the second half of the incubation time.

1. The fetus develops cardiovascular adaptations to protect vital organs in situations such as hypoxia and asphyxia. These include bradycardia, increased systemic blood pressure and redistribution of the cardiac output. The extent to which they involve maternal or placenta influences is not known. The objective of the present work was to study the cardiac output distribution in response to hypoxia in the chick embryo, which is independent of the mother. 2. Fertilized eggs were studied at three incubation times (10-13 days, 14-16 days and 17-19 days of a normal incubation time of 21 days). Eggs were placed in a Plexiglass box in which the oxygen concentration could be changed. Eggs were opened at the air cell and a chorioallantoic vein was catheterized. Cardiac output distribution was measured with 15 micron fluorescent microspheres injected during normoxia, during the last minute of a 5 min period of hypoxia and after 5 min of subsequent reoxygenation. 3. Hypoxia caused a redistribution of the cardiac output in favour of heart (+17 to +160 % of baseline) and brain (+21 to +57 % of baseline) at the expense of liver (-3 to -65 % of baseline), yolk-sac (-46 to -77 % of baseline) and carcass (-6 to -33 % of baseline). 4. The magnitude of the changes in cardiac output distribution to the heart, brain, liver and carcass in response to hypoxia increased with advancing incubation time. 5. The data demonstrate the development of a protective redistribution of the cardiac output in response to hypoxia in the chick embryo from day 10 of incubation.

Postnatal development of the pattern of respiratory and cardiovascular response to systemic hypoxia in the piglet: the roles of adenosine.

1. In 3-day-old and 3-week-old spontaneously breathing piglets anaesthetized with Saffan, we have studied ventilatory and cardiovascular responses evoked by 5 min periods of hypoxia (breathing 10 and 6% O2). 2. In 3-day-old piglets both 10 and 6% O2 evoked an increase followed by a secondary fall in ventilation, a gradual tachycardia and a renal vasoconstriction, with an increase in femoral blood flow that was attributable to femoral vasodilatation. Arterial blood pressure rose initially but fell towards control values by the 5th minute of hypoxia. 3. The stable adenosine analogue 2-chloroadenosine (2-CA; 30 mg kg(-1) i.v.) evoked bradycardia and renal vasoconstriction, but had no effect on femoral vasculature. These responses were blocked by the adenosine receptor antagonist 8-phenyltheophylline (8-PT; 8 mg kg(-1) i.v.). 8-PT also abolished the secondary fall in ventilation evoked by 10 and 6% O2 and the renal vasoconstriction evoked by 10% O2, but had no effect on the tachycardia, or on the femoral vascular response. 4. By contrast, in 3-week-old piglets both 10 and 6% O2 evoked a sustained increase in ventilation, tachycardia and a rise in arterial pressure with renal vasoconstriction, but no change in renal blood flow and substantial femoral vasodilatation with an increase in femoral blood flow. 2-CA evoked bradycardia and renal vasoconstriction, as in 3-day-old piglets, but also evoked pronounced femoral vasodilatation. 8-PT blocked these responses and the hypoxia-induced femoral vasodilatation, but had no significant effect on other components of the hypoxia-induced response. 5. We propose that there is postnatal development of the ventilatory and cardiovascular responses evoked by systemic hypoxia and of the role of locally released adenosine in these responses: at 3 days, adenosine released within the central nervous system and within the kidney is a major contributor to the secondary fall in ventilation and renal vasoconstriction respectively, whereas at 3 weeks, adenosine makes little contribution to the ventilatory response, or renal vasoconstriction, but is largely responsible for hypoxia-induced vaso-dilatation in skeletal muscle.

Increased hypoxic ventilatory sensitivity during exercise in man: are neural afferents necessary?

1. The acute ventilatory response to 3 min periods of hypoxia (AHR) was examined in nine patients with clinically complete spinal cord transection (T4-T7) during (a) rest and (b) electrically induced leg exercise (EEL). 2. EEL was produced by surface electrode stimulation of the quadriceps muscles so as to cause the legs to extend at the knee against gravity. End-tidal PCO2 was held constant 1-2 mmHg above resting values throughout both protocols. 3. On exercise, the average increase in metabolic CO2 production (VCO2 +/- S.E.M.) was 41 +/- 5 ml min-1. Venous lactate levels did not rise with exercise. 4. Baseline euoxic ventilation did not increase significantly with EEL, but there was a consistent and highly significant increase in the ventilatory response to hypoxia during EEL (mean delta AHR +/- S.E.M. of 1.6 +/- 0.21 min-1). 5. We conclude that an increase in hypoxic sensitivity during exercise can occur in the absence of volitional control of exercise and in the absence of afferent neural input from the limbs.

Measurement of rat plasma adenosine levels during normoxia and hypoxia

A stop solution containing EDTA, EGTA, dipyridamole, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and d, l-α-glycerophosphate has been used to prevent adenosine formation and loss from rat femoral arterial blood samples prepared for measurement of plasma adenosine levels. The femoral anterial plasma adenosine concentration in normoxic rats was 79.2 ± 12.7 nM. During a 5 min period of hypoxia (8% oxygen) plasma adenosine increased to 190.2 ± 32.2 nM. A resting plasma adenosine level of circa 80 nM, which is 10X lower than most previous estimates, approximates the threshold levels of adenosine required for arterial dilation.

Prostaglandins in the control of blood flow in canine skeletal muscle.

SUMMARY1. The effects of systemic hypoxia, arterial occlusion and muscle exercise on blood flow and oxygen uptake of the hind limb of anaesthetized areflexic dogs were assessed. The control responses were compared to those elicited after administration of meclofenamic acid (2 mg/kg, i.v.).2. Meclofenamic acid reduced resting blood flow by approximately 20%.3. The increase in blood flow during 6 min periods of hypoxia was inversely related to arterial oxygen saturation and this relationship was not altered significantly by meclofenamic acid.4. The magnitude of the reactive hyperaemias following arterial occlusion for 5‐40 s was dependent on the occlusion time. The peak changes in vascular conductance relative to the resting values were similar before and after administration of meclofenamic acid.5. Direct stimulation of the muscles of the hind limb with 0.5‐5 Hz produced frequency‐dependent increases in blood flow and oxygen uptake to the limb. Although these responses were depressed after meclofenamic acid, the relationship between blood flow and oxygen uptake was not changed. The responses to stimulation with 10 Hz were not affected by meclofenamic acid.6. An isolated chick rectum, superfused with re‐oxygenated venous blood from the hind limb during muscle stimulation at 10 Hz showed an initial relaxation, followed by contraction. The contraction was abolished after administration of meclofenamic acid.7. From these results it appears that the release of prostaglandins is not essential for hyperaemais associated with vessel occlusion, systemic hypoxia or muscle exercise.