1. In anaesthetized rats, we recorded arterial blood pressure (ABP), heart rate (HR), femoral blood flow ((FBF) and femoral vascular conductance (FVC). We tested the effects of the nitric oxide (NO) synthesis inhibitor L-NAME (nitro-L-arginine methyl ester), or the ATP-sensitive K+ (K-ATP) channel inhibitor glibenclamide, on responses evoked by systemic hypoxia (breathing 8% O-2 for 5 min) or I.A. infusion for 5 min of adenosine, the NO donor sodium nitroprusside (SNP), the adenosine A(1) receptor agonist CCPA (2-chloro-N-6-cyclopentyladenosine) or the adenosine A(2A) receptor agonist CGS 21680 (2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride). 2. L-NAME (10 mg kg(-1) I.V.) greatly reduced the increase in FVC induced by hypoxia or adenosine, as we have shown before, but had no effect on the increase in PVC evoked by SNP. In addition, L-NAME abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that muscle vasodilatation induced by systemic hypoxia and infused adenosine are largely NO dependent. They also indicate that muscle dilatation induced by A(1) receptor stimulation is entirely NO dependent while that induced by A(2A) receptors is largely NO dependent; dilatation may also be induced by direct stimulation of A(2A) receptors on the vascular smooth muscle. 3. Glibenclamide (10 or 20 mg kg(-1) I.V.) reduced the increase in FVC induced by hypoxia, preferentially affecting the early part (< 1 min). In addition, glibenclamide greatly reduced the increase in PVC induced by adenosine, but it had no effect on that evoked by SNP. Further, glibenclamide abolished the increase in FVC evoked by CCPA and greatly reduced that evoked by CGS 21680. These results substantiate the view that hypoxia-induced muscle vasodilatation is initiated by K-ATP channel opening. They also indicate that NO does not induce muscle vasodilatation by opening K-ATP channels on the vascular smooth muscle, but indicate that the dilatation induced by adenosine and by A(2A) receptor stimulation is largely dependent on K-ATP channel opening, while that induced by A(1) receptor stimulation is wholly dependent on K-ATP channel opening. 4. These results, together with previous evidence that hypoxia-induced vasodilatation in skeletal muscle is largely mediated by adenosine acting on A(1) receptors, lead us to propose that adenosine is released from endothelium during systemic hypoxia and acts on endothelial A(1) receptors to open K-ATP channels on the endothelial cells and cause synthesis of NO, which then acts on the vascular smooth muscle to cause dilatation. During severe systemic hypoxia we propose that adenosine may also act on A(2A) receptors on the endothelium to cause dilatation by a similar process and may act on A(2A) receptors on the vascular smooth muscle to cause dilatation by opening K-ATP channels.
