Studies on the roles of ATP, adenosine and nitric oxide in mediating muscle vasodilatation induced in the rat by acute systemic hypoxia.

Abstract

1. In Saffan-anaesthetized rats, we have further investigated the mechanisms underlying the vasodilatation induced by adenosine in skeletal muscle by acute systemic hypoxia (breathing 8% O2 for 5 min). 2. In eleven rats the nitric oxide (NO) synthesis inhibitor nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1, i.v.) reduced the increase in femoral vascular conductance (FVC) induced by hypoxia by approximately 50%. L-NAME had similar effects on the increase in FVC induced by intra-arterial (I.A.) infusion of adenosine (at 1.2 mg kg-1 min-1 for 5 min via the tail artery) and by ATP (I.A., 1 mg kg-1 min-1 for 5 min). Subsequent administration of the adenosine receptor antagonist 8-sulphophenyl theophylline (8-SPT, 20 mg kg-1, i.v.) virtually abolished the adenosine- and ATP-induced increase in FVC. 3. In a further nine rats, 8-SPT reduced the increase in FVC induced by hypoxia by approximately 50%. This remaining increase in FVC was substantially reduced by L-NAME. 4. In an additional nine rats, alpha,beta-methyleneADP (160 micrograms kg-1, i.v.) which inhibits the 5'-ectonucleotidase that degrades AMP to adenosine, reduced the peripheral vasodilatation (fall in arterial blood pressure, ABP) induced by ATP infusion, but had no effect on the increase in FVC or decrease in ABP evoked by systemic hypoxia. 5. These results provide the first evidence that the muscle vasodilatation induced by adenosine during systemic hypoxia is mainly dependent on NO synthesis. They also suggest that adenosine is released as such rather than being formed extracellularly from AMP. Given evidence that extraluminal adenosine acts in an NO-independent fashion we propose that hypoxia releases adenosine from the endothelium. Our results also indicate that hypoxia induces muscle vasodilatation that is adenosine independent but NO dependent: they allow the possibility that this is partly mediated by ATP released from the endothelium.

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

“…Our experiments with nitro L-arginine methyl ester (L-NAME) which inhibits NO synthesis are consistent with this suggestion (94). For L-NAME greatly reduced both the muscle vasodilatation induced by systemic hypoxia and that induced by infusion of adenosine.…”

“…For L-NAME greatly reduced both the muscle vasodilatation induced by systemic hypoxia and that induced by infusion of adenosine. Thus, it seems that the great majority of the component of the hypoxia-induced dilatation that is mediated by adenosine is also dependent on NO synthesis by the endothelium (94). It could be that the K ATP channels that initiate the muscle vasodilatation are on the endothelium and coupled to adenosine receptors so that their activation triggers synthesis of NO by hyperpolarising the endothelial cells.…”

“…Firstly, we found that αß methylene ADP, which inhibits the action of 5'ectonucleotidase, had no significant influence on the dilatation induced in hind limb muscles of the rat by systemic hypoxia. This indicates that most of the adenosine that is vasoactive is released as such from the intracellular sites (94).…”

Lactate – a signal coordinating cell and systemic function

“…Hypoxia is known to stimulate systemic vasodilation via a host of neural, hormonal and local factors (Skinner and Marshall, 1996). Fattor et al (2005) have recently used the lactate clamp method to demonstrate an autoregulatory loop in sympathetic drive that is governed by lactate release.…”

Systemic Hypoxia Elevates Skeletal Muscle Interstitial Adenosine Levels in Humans

“…11 More recently, it has been shown that vasodilation in rats induced by adenosine during systemic hypoxia was dependent on nitric oxide synthesis. 17 However, it is unclear whether a similar interaction between adenosine and nitric oxide exists in human skeletal muscle. These findings illustrate that the mechanisms associated with hypoxia-induced vasodilation are complex and that although adenosine is a key mediator, other compounds may interact with adenosine and also contribute to increased peripheral blood flow.…”