The role of adenosine in the early respiratory and cardiovascular changes evoked by chronic hypoxia in the rat

Abstract

Experiments were performed on anaesthetized normoxic (N) rats and chronically hypoxic rats that had been exposed to 12% O 2 for 1, 3 or 7 days (1, 3 or 7CH rats). The adenosine A 1 receptor antagonist DPCPX did not affect the resting hyperventilation of 1-7CH rats breathing 12% O 2 and increased resting heart rate (HR) in 1CH rats only. DPCPX partially restored the decreased baseline arterial pressure (ABP) and increased femoral vascular conductance (FVC) of 1 and 3CH rats, but had no effect in N or 7CH rats. DPCPX also attenuated the decrease in arterial blood pressure (ABP) and increase in FVC evoked by acute hypoxia in N and 1-7CH rats. The non-selective adenosine receptor antagonist 8-SPT had no further effect on baselines or cardiovascular responses to acute hypoxia, but attenuated the hypoxia-evoked increase in respiratory frequency in 1-7CH rats. In N, and 1 and 3CH rats, the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine had no effect on baselines or increases in FVC evoked by acetylcholine. We propose: (i) that tonically released adenosine acting on A 1 receptors reduces HR in 1CH rats and stimulates endothelial NOS in 1 and 3CH rats to decrease ABP and increase FVC, the remaining NO-dependent tonic vasodilatation being independent of iNOS activity; (ii) that in 7CH rats, tonic adenosine release has waned; (iii) that in 1-7CH rats, adenosine released by acute hypoxia stimulates A 1 but not A 2 receptors to produce muscle vasodilatation, and stimulates carotid body A 2 receptors to increase respiration. Adenosine makes a major contribution to the cardiovascular and ventilatory responses evoked by acute systemic hypoxia. In human subjects and the rat, a major part of the vasodilatation evoked in hindlimb muscle (increase in femoral vascular conductance, FVC) is mediated by adenosine acting on A 1 receptors (Neylon & Marshall, 1991;Bryan & Marshall, 1999a;Leuenberger et al. 1999). Further, adenosine contributes to the secondary fall in tidal volume (V T ) and heart rate (HR) that occur during extended periods of acute hypoxia (Millhorn et al. 1984;. This accords with evidence that adenosine can decrease HR by acting on cardiac A 1 receptors (Evans et al. 1982;Belardinelli et al. 1989) and decrease V T and respiratory frequency (R F ) by acting on central neural A 1 receptors (Eldridge et al. 1985;Wessberg et al. 1985;Schmidt et al. 1995). Adenosine also stimulates A 2 receptors in the carotid body and so may contribute to the increase in R F of acute hypoxia (Monteiro & Ribeiro, 1987;Kobayashi et al. 2000).The adaptations that occur in ventilation and haematocrit (Hct) from the onset of chronic hypoxia have been extensively investigated (e.g. Olson & Dempsey, 1978;Dempsey & Forster, 1982;Ou et al. 1992). By contrast, relatively little is known of the cardiovascular adaptations. We have now confirmed (accompanying paper Walsh & Marshall, 2006) that resting hyperventilation is already present in rats exposed to chronic hypoxia (12% O 2 ) for 1, 3 and 7 days (1, 3 and 7CH rats), while an incr...

Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity

“…Exogenously applied adenosine increased CSN chemosensory discharges in the cat in vivo (24, 25) and in vitro (38), as well as in the rat (43). Adenosine and its analogs have been shown to stimulate ventilation in a dose-dependent manner in several species, including humans and rats (26,37,40,45,46), with the stimulatory effect reaching up to nearly 60% of the maximal asphyxic ventilation; this stimulation is abolished by CSN section and mediated by A 2 receptors (26; see 8). The physiological meaning of these pharmacological findings on CSN and ventilation became obvious when it was demonstrated that mild hypoxia augments adenosine release in an in vitro preparation of rat CB (2).…”

Effects of Euphylline on Breathing Pattern and Chemosensitivity of the Respiratory System after Activation of GABAb-Receptors

“…Adenosine receptor antagonists differently affected the response of the respiratory system to acute and chronic hypoxia and hypercapnia [13,14].…”

“…Adenosine, a product of degradation of macroergic compounds formed during brain hypoxia, acts as a tonic neuromodulator of respiration and may produce various effects depending on the site of its action and type of adenosine receptors to be activated [6,13]. The purinergic system considerably modulates respiration in not only fetuses and newborns [4], but also adults [7].…”

Enhanced adenosine A2b receptor signaling facilitates stimulus-induced catecholamine secretion in chronically hypoxic carotid body type I cells

“…Interestingly, a nonspecific Ado receptor antagonist [8-(psulfophenyl)theophylline hydrate] was shown to blunt the increase in respiratory frequency elicited by acute hypoxia in CHox rats (56). Walsh et al (56) concluded that the increased HVR in CHox rats was due to activation of A 2 receptors by endogenous Ado released in the CB.…”

“…Walsh et al (56) concluded that the increased HVR in CHox rats was due to activation of A 2 receptors by endogenous Ado released in the CB. Moreover, Ado A 2a and A 2b receptors are expressed in CB type I cells (10,17), and Ado signaling contributes to chemoexcitation via presynaptic and postsynaptic mechanisms involving A 2 receptors (9).…”