1. In anaesthetized rats, systemic hypoxia evoked hyperventilation, tachycardia, a fall in arterial pressure, vasodilatation in skeletal muscle and increases in K+ concentration measured in arterial plasma ([K+]a), venous efflux from muscle ([K+]v) and in right atrial plasma ([K+]at). The ATP-sensitive potassium (K+ATP) channel inhibitor glibenclamide (10 or 20 mg kg-1 i.v.) reduced the muscle vasodilatation and increase in [K+]v, but had no significant effect on the other changes. 2. The adenosine receptor antagonist, 8-phenyltheophylline (8-PT, 10 mg kg-1 i.v.) had similar effects to glibenclamide. 3. Glibenclamide reduced the muscle vasodilatation evoked by the adenosine analogue, 2-chloroadenosine given i.v. (30 micrograms kg-1). 4. Infusion of adenosine (0.3 mg kg-1 min-1 for 5 min) into the hindlimb evoked muscle vasodilatation and an increase in [K+]v, both of which were abolished by 8-PT. 5. We propose that during systemic hypoxia, part of the muscle vasodilatation that can be attributed to adenosine is due to the action of K+, which is released from skeletal muscle fibres through glibenclamide-sensitive K+ channels (possibly K+ATP channels) that are activated by adenosine. This may be a general mechanism for the vasodilator influence of adenosine.

Transcripts for P2X(2) and P2X(6) subunits are present in rat CNS and frequently colocalize in the same brainstem nuclei. When rat P2X(2) (rP2X(2)) and rat P2X(6) (rP2X(6)) receptors were expressed individually in Xenopus oocytes and studied under voltage-clamp conditions, only homomeric rP2X(2) receptors were fully functional and gave rise to large inward currents (2-3 microA) to extracellular ATP. Coexpression of rP2X(2) and rP2X(6) subunits in Xenopus oocytes resulted in a heteromeric rP2X(2/6) receptor, which showed a significantly different phenotype from the wild-type rP2X(2) receptor. Differences included reduction in agonist potencies and, in some cases (e.g., Ap(4)A), significant loss of agonist activity. ATP-evoked inward currents were biphasic at the heteromeric rP2X(2/6) receptor, particularly when Zn(2+) ions were present or extracellular pH was lowered. The pH range was narrower for H(+) enhancement of ATP responses at the heteromeric rP2X(2/6) receptor. Also, H(+) ions inhibited ATP responses at low pH levels (

1. In ten spontaneously breathing, Saffan-anaesthetized rats (group I), respiratory and cardiovascular responses evoked by 10 min periods of hypoxia (arterial partial pressure of 02, Pa,02, 33 mmHg) were recorded before and after the administration of the adenosine receptor antagonist 8-phenyltheophylline (8-PT, 10 mg kg-' i.v.). Similar experiments were performed on nine constantly ventilated rats (group II; Pa02, 29 mmHg) with arterial partial pressure of CO2 (Pa,co2) held constant.2. In group I, hypoxia induced an initial increase and a secondary fall in ventilation (VE) with an accompanying secondary fall in heart rate (HR), arterial pressure (ABP) fell and cerebral vascular conductance (CVC) increased progressively. Cerebral blood flow (CBF) tended to fall with time during hypoxia. 8-PT abolished the secondary falls in VE and HR and reduced the fall in ABP and increase in CVC, while CBF was better maintained. 3. In group II, hypoxia induced a similar cardiovascular response to that in group I, but at the 1st minute of hypoxia, the HR was lower and the increase in CVC was greater. 8-PT did not affect the hypoxia-induced changes in HR, ABP, CVC or CBF. 4. These results indicate specific ways in which the ventilatory and cardiovascular responses induced by hypoxia in the spontaneously breathing rat are interdependent.They also indicate that the influences of 8-PT on the cardiovascular changes induced by hypoxia during spontaneous ventilation are mainly a consequence of its ability to block the centrally mediated contribution of adenosine to the secondary fall in ventilation.In the anaesthetized rat, 3 or 5 min periods of systemic hypoxia produce hyperventilation which wanes after the 2nd minute of hypoxia, tachycardia which wanes to bradycardia, a pronounced fall in arterial pressure and vasodilatation in hindlimb skeletal muscle; similar cardiovascular-changes were recorded in the conscious rat

A role for P2 purinoceptors in the chemosensory response of respiratory neurones localised in the ventrolateral medulla to changes in arterial CO2 levels was investigated in the anaesthetised rat. Extracellular recordings were made from different classes of respiratory neurone and the effects of P2 receptor blockade on CO2‐evoked changes in activity investigated. Increasing inspired CO2 excited 85 % of inspiratory neurones in the pre‐Bötzinger complex. In all cases, CO2‐evoked excitation was blocked by ionophoretic application of the P2receptor antagonists suramin (0·02 M) and pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS; 100 μM), but not the adenosine receptor antagonist 8‐phenyltheophylline (8‐PT; 100 μM). Suramin and PPADS often reduced ongoing activity, and blocked the excitatory effects of ATP. Inspiratory neurones were also excited by the P2X receptor agonist αβ‐methyleneATP, suggesting a specific role for P2X receptors. Sixty‐six per cent of pre‐inspiratory neurones were also excited by CO2. This effect was reduced or abolished by prior application of P2 receptor antagonists. Although post‐inspiratory and expiratory neurones were excited by increasing levels of CO2, and also by ionophoretically applied ATP, the CO2‐evoked effects were unaffected by P2 receptor blockade. We suggest that ATP, possibly acting via P2X purinoceptors localised within the ventral respiratory group, is involved in central chemoreception. Specifically, these distinctive CO2‐P2X‐mediated actions were observed only in inspiratory neurones (incrementing inspiratory neurones and pre‐inspiratory neurones), which appear to have purinoceptors with pH sensitivity that can account for the actions of CO2 in modifying ventilatory activity.