Search

New Findings: What is the topic of this review? This review considers how local dilator mechanisms and increased sympathetic nerve activity interact during acute systemic hypoxia and then reviews current understanding of some of the modifications induced by chronic hypoxia. What advances does it highlight? During acute hypoxia, local levels of hypoxia determine the release of vasodilators and magnitude of arteriolar dilatation, as well as the extent to which sympathetically evoked vasoconstriction is blunted, so maximizing distribution of O2 to muscle fibres. Chronic hypoxia in adult life and fetal programming induced by chronic hypoxia in utero lead to increased responsiveness to acute hypoxia and further blunting of sympathetic vasoconstriction, but are also associated with hypertension. In resting skeletal muscle, acute systemic hypoxia evokes vasodilatation, while vasoconstriction evoked by increased muscle sympathetic nerve activity is blunted, referred to herein as hypoxic sympatholysis. This review considers the contributions of adenosine, prostaglandin I2 , nitric oxide, ATP and endothelium-derived hyperpolarizing factors to the muscle vasodilatation, with particular attention being given to the release and actions of adenosine, which plays a dominant role. It is argued that the dilator substances are released in proportion to the local level of hypoxia, notably, allowing terminal arterioles to regulate O2 distribution through the capillaries. Correspondingly, hypoxic sympatholysis can be attributed to the ability of local hypoxia to blunt vasoconstriction evoked by noradrenaline acting on α1 - and α2 -adrenoceptors. The synergistic actions of ATP as cotransmitter may be depressed in parallel, but the actions of neuropeptide Y persist. Consideration is also given to the changes induced by chronic hypoxia in adult life and to the consequences in adult life of fetal programming induced by chronic hypoxia during pregnancy. In both conditions, dilator responsiveness to acute hypoxia is maintained, but the action or release of adenosine is altered in ways that are not yet understood. Both conditions are also accompanied by blunted sympathetically evoked vasoconstriction, tonically raised muscle sympathetic nerve activity, and increased muscular vascular tone and arterial blood pressure. With hypoxia-induced fetal programming, arterial pressure is increased in young adults and increases with age. The mechanisms underlying these changes are discussed, and it is argued that chronic hypoxia in adult life or in utero may facilitate development of hypertension., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)

Little is known of the role of O(2)-dependent mechanisms in the hyperaemia associated with static muscle contraction or recovery from fatigue. Thus, in recreationally active, young, male subjects, forearm contraction was performed twice at 100% maximal voluntary effort until exhaustion, with a 7 min recovery period, whilst 40% O(2) (hyperoxia) was breathed during the contractions only, or during recovery only, or room air (normoxia) was breathed throughout. When hyperoxia was limited to the contractions, postcontraction increases in forearm blood flow, measured by venous occlusion plethysmography, were ∼25% lower (P < 0.05, n = 10) than during normoxia throughout. Furthermore, the postcontraction increase in venous lactate and fall in pH were attenuated (P < 0.05, n = 8). However, there was no effect on fatigue; time to voluntary exhaustion of contraction 2 was ∼25% less than for contraction 1 in both conditions. By contrast, when hyperoxia was limited to recovery (n = 10), there was no effect on postcontraction increases in forearm blood flow, but fatigue was ameliorated; time to voluntary exhaustion of contraction 2 was comparable to that of contraction 1. These results allow the novel conclusions that, even during static forearm contraction at 100% maximal voluntary effort, additional O(2) dissolved in plasma can attenuate the contribution made by O(2)-dependent dilator substances to postcontraction hyperaemia and that these substances may be released from the muscle fibres or blood vessel wall. Furthermore, they indicate that even in recreationally active individuals, recovery from fatigue can be improved by additional O(2) made available during recovery, and the O(2)-dependent mechanisms that contribute to fatigue are different from those that induce postcontraction hyperaemia.

Muscle vasodilatation evoked by systemic hypoxia is adenosine mediated and nitric oxide (NO) dependent: recent evidence suggests the increased binding of NO at complex IV of endothelial mitochondria when O(2) level falls leads to adenosine release. In this study on anaesthetised rats, the increase in femoral vascular conductance (FVC) evoked by systemic hypoxia (breathing 8 % O(2) for 5 min) was reduced by oxypurinol which inhibits xanthine oxidase (XO): XO generates O(2)(-) from hypoxanthine, a metabolite of adenosine. By contrast, infusion of superoxide dismutase (SOD), which dismutes O(2)(-) to hydrogen peroxide (H(2)O(2)), potentiated the hypoxia-evoked increase in FVC. However, NO synthesis inhibition reduced the hypoxia-evoked increase in FVC and it was not further altered by SOD. In other studies, the spinotrapezius muscle was pre-loaded with hydroethidine (HE), or dihydrorhodamine (DHR) which fluoresce in the presence of O(2)(-) and H(2)O(2), respectively. In muscle loaded with HE, systemic hypoxia increased fluorescence in endothelial cells of arterioles, whereas in muscle loaded with DHR, fluorescence was diffusely located in and around arteriolar endothelium. We propose that in systemic hypoxia, O(2)(-) generated by the XO degradation pathway from adenosine released by endothelial cells, and released by endothelial mitochondria by increased binding of NO to complex IV, is dismuted to H(2)O(2), which facilitates hypoxia-induced dilatation.

Comparisons were made between responses evoked by noradrenaline (NA) in iliac artery rings from normoxic (N) rats and chronically hypoxic (CH) rats kept in 12 % O(2) for 3-4 weeks. At P(O(2)) of 100 mmHg, cumulative concentration-response curves (CCRC) to NA were greatly depressed in endothelium-intact (E+) rings, but not endothelium-denuded (E-) rings, of CH rats relative to N rats. However, CCRCs evoked by NA in E+ and E- rings during nitric oxide (NO) synthase inhibition were similar in N and CH rats. Reducing P(O(2)) to 55 mmHg depressed CCRCs to NA in E+ and E- rings of CH and N rats in the absence and presence of NO synthase inhibition. At P(O(2)) of 100 mmHg, CCRCs evoked by phenylephrine were comparable in E+ and E- rings of N and CH rats as were CCRCs for the relaxation evoked by isoprenaline, which were similarly rightward shifted by NO synthase inhibition. However, CCRCs evoked by the NO donor sodium nitroprusside were leftward shifted in E- rings of CH rats relative to N rats. Further, in the presence of the alpha(2) adrenoceptor inhibitor rauwolscine, CCRCs to NA were comparable in E+ rings of CH and N rats. Thus, the depressive effects of chronic hypoxia on NA-evoked contractions of iliac artery are additional to those of acute hypoxia. We propose that they reflect a facilitation of the contribution of NO to alpha(2) adrenoceptor-evoked relaxation that includes an increased sensitivity of the vascular smooth muscle of arteries from CH rats to NO.

1. The present review is concerned with the effects of acute systemic hypoxia on the gross vascular conductance of skeletal muscle (MVC) and on the behaviour of muscle microcirculation. 2. On the basis of experiments performed in the rat, it is argued that adenosine released from the vascular endothelium plays a major role in dilating muscle vasculature by acting on adenosine A1 receptors. 3. The dilatation of the proximal arterioles is primarily important in increasing MVC and in limiting the fall in O(2) delivery to muscle. It is suggested that the action of adenosine on proximal arterioles is dependent on nitric oxide (NO) rather than mediated by NO, such that adenosine dilates the proximal arterioles via other mechanisms when synthesis of NO is blocked. 4. In contrast, dilatation of terminal arterioles, particularly in regions within muscle where the hypoxia is most severe, helps to improve the distribution of available O(2), allowing muscle O(2) consumption to be maintained by increased O(2) extraction. It is concluded that the action of adenosine on terminal arterioles is mainly mediated by NO arising from stimulation of endothelial A1 receptors. 5. Therefore, adenosine plays a major role in coordinating the behaviour of muscle vasculature such that the relationship between O(2) supply and O(2) demand can be optimized even when the O(2) content of the arterial blood is greatly reduced.

Skeletal muscle capillarity and fibre cross-sectional area were investigated within and between diaphragm (Diaph), extensor digitorum longus (EDL), soleus (SOL) and tibialis anterior (TA) muscles of control and chronic hypoxic (12 % O(2) for 6 weeks) adult male Wistar rats (final body mass approximately 355 g). Cryostat sections were stained for alkaline phosphatase activity to depict all capillaries, and for succinic dehydrogenase to demonstrate regional differences in oxidative capacity within the muscles. Hypoxia-induced angiogenesis occurred in all muscles (P < 0.01), with capillary-to-fibre ratio (C:F) being higher in the more active and oxidative muscles, Diaph (27 %) and SOL (26 %), than phasically active and glycolytic muscles, TA (21 %) and EDL (15 %). Diaph, SOL and EDL maintained fibre size, and hence showed an increased capillary density (CD) and reduced intramuscular diffusion distance (DD), whereas TA showed fibre hypertrophy and maintained CD and DD compared to control muscles. The extent of angiogenesis among different regions of muscle varied so as to suggest that muscle fibre size has an additional influence on capillary growth during chronic systemic hypoxia, which is progressive over an extended period of systemic hypoxia.

In rings of rat iliac artery, contractions were evoked by noradrenaline (NA), the selective alpha(1) adrenoceptor agonist phenylephrine (PE), and K(+), which causes depolarisation-induced contraction. There was no evidence of alpha(2) adrenoceptor-evoked contraction. Hypoxia, induced by reducing P(O(2)) in the bath from 100 mmHg to 70, 55 or 40 mmHg, had similar effects on rings with (E+) and without (E-) endothelium. In E- rings, the NA concentration-response curve was biphasic, whereas that for PE was monophasic. Hypoxia reduced maximum contractions in response to NA and PE (NA(max) and PE(max), respectively) without affecting the concentrations that evoked 50 % of maximum contraction (EC(50)). At P(O(2)) of 70 mmHg, NA(max) of the high affinity alpha(1) receptor for NA (NA(maxh)) and PE(max) were reduced by approximately 15 %, but at P(O(2)) of 55 and 40 mmHg, NA(maxh) was severely attenuated while PE(max) fell by 45 and 75 %, respectively. Similarly, the Ca(2+) channel blocker nicardipine depressed NA(maxh) and PE(max), but P(O(2)) of 55 mmHg further reduced NA(max) and PE(max). Hypoxia also reduced contractions evoked by NA, PE or K(+) at the concentrations required to produce 80 % of the maximum contraction (EC(80)), receptor-mediated contractions being more affected. Ca(2+)-free conditions reduced the contractions evoked by NA and PE, at the EC(80), to approximately 10 % of control. The K(+) channel inhibitors glibenclamide and tetraethylammonium did not prevent hypoxia-induced depression of PE-evoked contraction. Thus, contractions evoked in iliac artery by the high affinity subtype of alpha(1) adrenoceptor for NA, which may respond to circulating levels of NA, and by the single alpha(1) adrenoceptor subtype for PE, are especially vulnerable to P(O(2)) levels less-than-or-equal 55 mmHg. We propose that this reflects hypoxia-induced inhibition of Ca(2+) influx through L-type and receptor-operated Ca(2+) channels; K(+) channel opening makes little contribution.

The aims of the present study were to evaluate how acute systemic hypoxia affects O2 delivery to skeletal muscle and muscle O2 consumption (VO2) of the rat and to establish how these relationships are altered by chronic systemic hypoxia. Thus, the effects of breathing different concentrations of O2 (air, 12% and 8% O2) upon oxygen delivery and VO2 were studied in hindlimb muscles of control, normoxic (N) rats and of rats that had been made chronically hypoxic in a chamber at 12% O2 for 3-4 weeks (CH) rats. Under anaesthesia, arterial blood pressure, femoral blood flow (FBF), arterial O2 content (Ca,O2) and venous O2 content in the efflux from hindlimb were measured. In N rats, changing the inspirate from air to 12% and 8% O2 for 5 min each, reduced Ca,O2 from 20 +/- 0.3 ml (100 ml)-1 in air to 13 +/- 1.0 ml (100 ml)-1 in 8% O2. FBF did not change significantly (1.7 +/- 0.1 ml min-1 in air) so that O2 delivery to hindlimb muscles fell from 0.28 +/- 0.07 to 0.16 +/- 0.02 ml min-1 in 8% O2. Nevertheless, the VO2 of hindlimb muscle was well maintained: 0.06 +/- 0.02 ml min-1 in air and 0.08 +/- 0.02 ml min-1 in 8% O2. In CH rats breathing 12% O2, Ca,O2 (23 +/- 1.0 ml (100 ml)-1) was comparable to that of N rats breathing air, due to an increase in haematocrit, as were FBF (1.6 +/- 0.2 ml min-1) and O2 delivery (0.39 +/- 0.05 ml min-1). However, VO2 was 2.5-fold greater in CH rats (0.16 +/- 0.03 ml min-1). As in N rats, FBF was well maintained at 1.7 +/- 0.2 and 1.6 +/- 0.2 ml min-1 in 8% O2 and air, respectively. Further, VO2 was also well maintained, at 0.17 +/- 0.02 and 0.12 +/- 0.02 ml min-1 in 8% O2 and air, respectively. These results suggest that, contrary to previous reports, muscle VO2 of the rat is independent of O2 delivery over a wide range of O2 delivery values. They also suggest that muscle VO2 of CH rats is similarly independent of O2 delivery. The novel finding that muscle VO2 has a greater absolute value in CH rats can, we propose, be explained by an increase in VO2 of the vasculature rather than of the skeletal muscle fibres and reflects increased biosynthetic activity of the vessel walls and/or vascular remodelling.

In two groups of Saffan-anaesthetized, spontaneously breathing rats we have attempted to identify the peripheral influences of adenosine in mediating the responses evoked by hypoxia by using an adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT, 20 mg kg-1 i.v., Group 1) and adenosine deaminase (ADA, 500 units in 0.04 ml infused into the tail artery for 10 min, Group 2); neither of these drugs crosses the blood-brain barrier. Recordings were made of respiration, heart rate, arterial pressure, blood flow and vascular conductance in the femoral artery, with ankle ligated (FBF and FVC, respectively) and in the carotid artery with all branches except the internal carotid ligated (CBF and CVC, respectively, Group 1 only) in order to indicate responses in skeletal muscle and cerebral vasculature. Hypoxia (breathing 8 or 10% O2 for 10 min) evoked an increase followed by a secondary decrease in respiration, tachycardia followed by secondary bradycardia, a fall in arterial pressure, an increase in FVC and CVC and an increase, followed by a decrease, in CBF. Neither 8-SPT nor ADA had any significant effect on the secondary decrease in respiration. The secondary bradycardia was unaffected by 8-SPT, but abolished by ADA. Both drugs reduced the fall in arterial pressure and the increase in FVC; 8-SPT had no significant effect on the increase in CVC, but CBF no longer fell with arterial pressure. We propose that adenosine contributes to the hypoxia-induced fall in arterial pressure by causing vasodilatation in skeletal muscle and possibly by causing bradycardia by a direct action on the heart; other evidence suggests that adenosine contributes to the secondary decrease in respiration by acting on central respiratory neurones. The possibility that the fall in arterial pressure and the secondary falls in CBF, respiration and heart rate, can become interdependent in a positive feedback manner is discussed.

We have examined the surface ultrastructure and morphological characteristics of leucocytes obtained from control rats breathing air and rats made acutely hypoxic (breathing 6% O2, for 30 min). Striking ultrastructural and morphological changes occurred in the leucocytes of hypoxic rats. These changes included the appearance of crater-like holes, a reduction in granule size and disruption of the cell membrane. The implications of these findings are discussed.

In nine artificially ventilated rats anaesthetized with Saffan, systemic hypoxia induced a tachycardia followed by a bradycardia, a fall in systemic arterial pressure and an increase in pulmonary artery pressure (PPA) indicating pulmonary vasoconstriction. This increase in PPA was abolished by the adenosine receptor antagonist 8-phenyltheophylline (8-PT, 10 mg kg-1 I.V.). Further, in seven rats the Pa,O2 achieved during hypoxia was greater after 8-PT than before (38 vs. 40 mmHg). We suggest that adenosine makes a major contribution to hypoxia-induced pulmonary vasoconstriction in the rat. The better maintenance of Pa,O2 during hypoxia may reflect improved perfusion of well-ventilated alveoli.

In spontaneously breathing anaesthetized rats, both moderate and severe hypoxia caused increases in [K+] in venous efflux from hindlimb muscle, from 4.3 to 4.6 and from 3.8 to 4.4 mM respectively; the increases were accentuated to 5.2 and 5.7 mM after beta 2-receptor blockade with I.V. sotalol. Sotalol also potentiated the vasodilatation evoked in hindlimb muscle by moderate hypoxia, but reduced that evoked by severe hypoxia. We propose that K+ released from muscle during hypoxia contributed to the local vasodilatation. Further, we suggest that this effect was enhanced in moderate hypoxia by blockade of the beta 2-mediated uptake mechanism for K+ in skeletal muscle, but outweighed in severe hypoxia by blockade of the beta 2-mediated dilator action of circulating catecholamines on vascular muscle.

1. Contractions and electrical activity were recorded from isolated segments of longitudinal (L) and circular (C) myometrium from rats on gestation days 16-17 and 21 before and during parturition. 2. The segments were arranged so that the activity of the two layers could be monitored simultaneously and independently. 3. Out of the 15 preparations from days 16-17, 13 showed no co-ordination of activity between the layers. In the other two preparations a large contraction of C occasionally initiated a contraction of L. Surgical separation of the layers disrupted the co-ordination and L then developed its independent rhythm. 4. On day 21 before delivery, eight of 10 preparations exhibited 1:1 co-ordination of activity between the two layers, but C did not consistently pace L. The pacing shifted from one layer to the other several times during an experiment. 5. During parturition there was a 1:1 co-ordination of activity in all 10 preparations examined. In nine of these L initiated the activity of the C. Surgical separation of the layers disrupted the co-ordination and C developed its independent rhythm. In one the pacing shifted from one layer to the other several times during the experiment. 6. In all cases where co-ordination between the layers was observed it was myogenic and apparently related to the spread of action potentials between the two muscles.