Contribution of non-endothelium-dependent substances to exercise hyperaemia: are they O(2) dependent?

Abstract

This review considers the contributions to exercise hyperaemia of substances released into the interstitial fluid, with emphasis on whether they are endothelium dependent or O(2) dependent. The early phase of exercise hyperaemia is attributable to K(+) released from contracting muscle fibres and acting extraluminally on arterioles. Hyperpolarization of vascular smooth muscle and endothelial cells induced by K(+) may also facilitate the maintained phase, for example by facilitating conduction of dilator signals upstream. ATP is released into the interstitium from muscle fibres, at least in part through cystic fibrosis transmembrane conductance regulator-associated channels, following the fall in intracellular H(+). ATP is metabolized by ectonucleotidases to adenosine, which dilates arterioles via A(2A) receptors, in a nitric oxide-independent manner. Evidence is presented that the rise in arterial achieved by breathing 40% O(2) attenuates efflux of H(+) and lactate, thereby decreasing the contribution that adenosine makes to exercise hyperaemia; efflux of inorganic phosphate and its contribution may likewise be attenuated. Prostaglandins (PGs), PGE(2) and PGI(2), also accumulate in the interstitium during exercise, and breathing 40% O(2) abolished the contribution of PGs to exercise hyperaemia. This suggests that PGE(2) released from muscle fibres and PGI(2) released from capillaries and venular endothelium by a fall in their local act extraluminally to dilate arterioles. Although modest hyperoxia attenuates exercise hyperaemia by improving O(2) supply, limiting the release of O(2)-dependent adenosine and PGs, higher O(2) concentrations may have adverse effects. Evidence is presented that breathing 100% O(2) limits exercise hyperaemia by generating O(2)(-), which inactivates nitric oxide and decreases PG synthesis.

Figure 1. Involvement of adenosine and NO in the vasodilator responses evoked by isometric twitch contractions in rat hindlimb muscle

A–C shows femoral vascular conductance (FVC; –▪–) for the control response in the 1 min before (baseline), 5 min during (S1–5) and 7 min after sciatic nerve stimulation at 40 Hz (R1–7). In A,FVC is shown after ZM241385 (–▴–) and after ZM241385 + 8-sulphophenyltheophylline (8-SPT)(…♦…). §P < 0.05, control S1–5 and/or R1–7 vs. stimulation after ZM241385 and stimulation after ZM241385 + 8-SPT. There was no significant difference between stimulation after ZM241385 and stimulation after ZM241385 + 8-SPT at any time point. In B, FVC is shown after l-NAME (–○–) and after l-NAME + ZM241385 (…▴…). *P < 0.05 vs. control; §P < 0.05 vs. l-NAME. In C, FVC is shown after l-NAME (–○–), after l-NAME + SNAP to restore baseline FVC (…▵…) and after l-NAME + SNAP + ZM241385 (–▴–). *P < 0.05 vs. control; §P < 0.05 vs. l-NAME; and †P < 0.05 vs. l-NAME + SNAP. All values are shown as means ± SEM. In A, n = 10; in B and C, n = 12 rats. Modified from Ray & Marshall (2009a,b). In D, the effects on FVC of breathing air or 40% O₂ without or with 8-SPT are compared. The FVC response to sciatic nerve stimulation (40 Hz) is shown when breathing air (–▪–) or 40% O₂ (–○–), as well as after 8-SPT when breathing air (–♦–) and after 8-SPT during 40%O₂ (…♦…). *P < 0.05 vs. control. All values are shown as means ± SEM; n = 10 rats. (CJ Ray, L Hargreaves, AM Coney, JM Marshall, unpublished observations).

Figure 2. Effects of breathing 40% O₂ during contraction (A and C) or during recovery (B) on responses evoked by isometric forearm contraction at 100% maximal voluntary effort (MVE) to exhaustion

A, effects of breathing 40% O₂ during contraction on forearm vascular conductance (FVC). B, FVC when 40% O₂ was breathed during recovery from contraction, recorded at 1 min intervals at rest and after contraction and, in addition, immediately (0) and at 15 s after contraction. Continuous and dashed lines join values recorded when air was breathed throughout and when 40% O₂ was breathed, respectively, for periods indicated by the bars below. C, effects of breathing 40% O₂ during contraction on venous lactate concentration and pH. Values were recorded when air was breathed throughout (open columns) and when 40% O₂ was breathed only during contraction (filled columns). All values are shown as means ± SEM. *,† Difference from baseline in the air and 40% O₂ conditions, respectively (P < 0.05). § Difference between values recorded when air and 40% O₂ were breathed (P < 0.05). Modified from Fordy & Marshall (2012).

Figure 3. Schematic diagram showing contribution to exercise hyperaemia of substances released into interstitial fluid during contraction

Shear stress, acting on endothelium, causes tonic activation of endothelial nitric oxide synthase (NOS), generating NO, which produces tonic dilatation of arterioles, upon which other influences are superimposed. Nitric oxide also competes with O₂ for the same binding site on cytochrome oxidase (cyta₃) in mitochondria, thereby regulating endothelial ATP synthesis. During exercise, K⁺ released from skeletal muscle fibres during their action potentials dilates arterioles by causing hyperpolarization of vascular smooth muscle. Even at rest, O₂ diffuses outwards along length of arterioles, but during exercise the periarteriolar stays virtually constant because arterial is well maintained. In contracting muscle fibres, capillaries and venules, however, falls due to increase in muscle oxygen consumption (). The fall in muscle and pH leads to release of ATP from muscle fibres through regulated channels; ATP is metabolized extracellularly to adenosine, which dilates arterioles via adenosine A_2A receptors. The fall in muscle and capillary and venular also leads to release of the prostaglandins PGE₂ and PGI₂ synthesized by cyclo-oxygenase (COX), which act on extraluminal EP and IP receptors for PGE₂ and PGI₂, respectively, to dilate arterioles. The release of ATP from red blood cells caused by haemoglobin unloading O₂ is also shown; ATP can act locally on P₂ receptors to cause dilatation. Breathing 40% O₂ during exercise limits the fall in tissue , which attenuates the generation of adenosine and prostaglandins, thereby attenuating exercise hyperaemia. The A₁ receptors on arterioles and A₁ and A_2A receptors on endothelium make little direct contribution to exercise hyperaemia.