Cellular mechanisms by which adenosine induces vasodilatation in rat skeletal muscle: significance for systemic hypoxia

Abstract

In previous studies we have provided evidence, by using adenosine receptor antagonists, that a major part of the vasodilatation induced in skeletal muscle of the rat during systemic hypoxia is mediated by adenosine (Neylon & Marshall, 1991). From the effects of glibenclamide, which inhibits ATP-sensitive K¤ (KATP) channels, we argued that a part of the hypoxia-induced muscle vasodilatation, particularly the early part, is dependent on the opening of KATP channels (Marshall et al. 1993). On the other hand, since ¬_NAME (nitro-¬_arginine methyl ester), which blocks the synthesis of nitric oxide (NO), greatly reduced both the hypoxia-induced muscle vasodilatation and that evoked by Journal of Physiology (1999) 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 ¬_NAME (nitro-¬_arginine methyl ester), or the ATP-sensitive K¤ (KATP) channel inhibitor glibenclamide, on responses evoked by systemic hypoxia (breathing 8% Oµ for 5 min) or i.a. infusion for 5 min of adenosine, the NO donor sodium nitroprusside (SNP), the adenosine A1 receptor agonist CCPA (2-chloro-N É-cyclopentyladenosine) or the adenosine A2A receptor agonist CGS 21680 (2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride). 2. ¬_NAME (10 mg kg¢ 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 FVC evoked by SNP. In addition, ¬_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 A1 receptor stimulation is entirely NO dependent while that induced by A2A receptors is largely NO dependent; dilatation may also be induced by direct stimulation of A2A receptors on the vascular smooth muscle. 3. Glibenclamide (10 or 20 mg kg¢ 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 FVC 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 KATP channel opening. They also indicate that NO does not induce muscle vasodilatation by opening KATP channels on the vascular smooth muscle, but indicate that the dilatation induced by adenosine and by A2A receptor stimulation is largely dependent on KATP channel opening, while that induced by A1 receptor stimulation is wholly dependent on KATP channel opening. 4. These results, together with previous evidence that hypoxia-induced vasodilatation in skeletal muscle is largely mediated by adenosine...

Multiple dilator pathways in skeletal muscle contraction-induced arteriolar dilations

“…The actions of Ado have been linked to K ATP channel activation in skeletal muscle (8,10) as well as in other tissues (18,22). However, we were unable to attenuate Ado-induced dilations with the concentration of glibenclamide that significantly attenuated both a pinacidil-induced local dilation (Fig.…”

“…Because both Ado and NO have been identified as playing a role in active hyperemia in hamster cremaster muscle, we explored their contributions to these dilations by using an Ado receptor antagonist [xanthine amine congener (XAC), an A 1 , A 2A , and A 2B membrane receptor antagonist] and a NO synthase inhibitor [N -nitro-L-arginine (L-NNA)]. The actions of Ado receptor activation (8,10,18,22) and NO dilator capacity (27,42) have been linked to ATP-sensitive potassium (K ATP ) channel function. At the microvascular level, K ATP channels are functional in arterioles at rest (18), and both Ado and K ATP channels have been identified as important in arteriolar dilations during muscle contraction (32,36).…”

Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators

“…Previous studies on the influence of adenosine on the splanchnic circulation, including the pancreas, have unequivocally demonstrated that the vasodilating effects are mediated by A 2 receptors (18,24). However, a vasodilator response mediated by A 1 receptors exists in other vascular beds, e.g., the diaphragm (14) and other skeletal muscle (8,9,38).…”

Vasopressin V1 receptors contribute to hemodynamic and sympathoinhibitory responses evoked by stimulation of adenosine A2a receptors in NTS

“…It is possible that both A 2a and V 1 receptors may act via stimulation of NOS because the activation of both of these receptors increases intracellular calcium (9,17,27,29). NO released from NTS neurons/synaptic terminals after activation of A 2a and V 1 receptors may activate pre-or postsynaptically those glutamatergic neurons that send their axons to the CVLM and finally inhibit RSNA (Fig.…”

“…It has been also demonstrated that central blockade of vasopressin V 1 receptors and nitric oxide (NO) synthase (NOS) attenuates posthemorrhagic hypotension (10,25). In addition, activation of both adenosine A 2a and vasopressin V 1 receptors may activate NOS because they both increase intracellular calcium levels (9,17,27,29). Therefore, adenosine, vasopressin, and NO may interact in creating the pattern of autonomic responses observed during hypotensive hemorrhage.…”