Role of β-adrenergic and cholinergic systems in acclimatization to hypoxia in the rat

Abstract

The role of β-adrenergic and muscarinic cholinergic systems on maximal treadmill exercise performance and systemic O₂ transport during hypoxic exercise was studied in rats acclimatized to hypobaric hypoxia and in non-acclimatized littermates (NA rats). Untreated A rats had lower resting (fh) and maximal heart rate (fhmax) and cardiac output (Q̇), and higher maximal O₂ uptake than NA. The only effect of cholinergic receptor blockade with atropine (Atp) was an increase in pre-exercise fh to comparable levels in A and in NA. β₁-adrenergic receptor blockade with atenolol (Aten) lowered pre-exercise fh and (fhmax) to comparable values in A and in NA rats. However, since both pre-exercise fh and fhmax were lower in untreated A, the effect of Aten was relatively smaller in A. Aten reduced maximal exercise cardiac output (Q̇_max) in NA; however, tissue O₂ extraction increased such that was not affected. Aten did not influence Q̇_max or any other parameter of systemic O₂ transport in A. In conclusion the increased cholinergic tone may be responsible for the lower resting fh but not the lower fhmax of A; the integrity of the β-adrenergic system is not necessary to attain in hypoxia either in A or in NA; the decreased response to β-adrenergic stimulation in A limits the efficacy of this system on the mechanisms of systemic O₂ transport and reduces the effect of its blockade on these mechanisms.

Introduction

Humans and other mammals acutely exposed to environmental hypoxia show a decrease in maximal O₂ uptake that is correlated with the decrease in environmental P_O2 (Hartley et al., 1974; Cerretelli, 1976; Horstman et al., 1980; Bender et al., 1988). Hypoxia elicits several responses which appear to be directed to maintain tissue O₂ delivery under these conditions of restricted O₂ supply. One of these responses is an increase in sympathetic activity which is manifested early on and continues for several weeks (Cunningham et al., 1965; Johnson et al., 1983; Wolfel et al., 1994).

The increased activity of the β-adrenergic limb of the sympathetic system results in tachycardia which is apparent during the initial phase of hypoxia and which contributes to maintain cardiac output and tissue O₂ delivery (Stenberg et al., 1966; Reeves et al., 1967). As exposure to hypoxia continues, however, maximal exercise heart rate (fhmax) decreases with respect to the initial phase (Pugh, 1964; Cerretelli, 1976). The low fhmax contributes to reduce maximal cardiac output (Q̇_max) (Pugh, 1964) and offsets the effect of the elevation in blood O₂-carrying capacity that occurs in prolonged hypoxia. As a consequence of these opposing changes, tissue O₂ delivery during maximal exercise and change little, if at all, during acclimatization to hypoxia (Cerretelli, 1976; Bender et al., 1988; Gonzalez et al., 1993).

The decrease in fhmax observed during acclimatization to hypoxia occurs in spite of continued increased sympathetic activity and is thought to be due, at least in part, to down-regulation of myocardial β-adrenergic receptors which develops as a consequence of increased agonistic activity (Voelkel et al., 1981; Kacimi et al., 1992). These changes, together with an up-regulation of M2 muscarinic receptors (Wolfe and Voelkel, 1983; Kacimi et al., 1993) and down-regulation of A1 adenosinergic receptors (Kacimi et al., 1993) in the myocardium of hypoxia-acclimatized rats suggest a relative dominance of the cholinergic nervous system on the control of cardiac function in chronic hypoxia. However, the relevance of these changes observed in vitro to exercise performance and systemic O₂ transport during hypoxia has not been established.

The objective of these experiments was to determine the contribution of the β-adrenergic and cholinergic systems to the mechanisms of systemic O₂ transport and to maximal exercise performance in acute and chronic hypoxia. The approach taken was to study the effect of selective blockade of β₁-adrenergic and muscarinic cholinergic receptors on hemodynamics, O₂ transport and exercise performance before and after acclimatization to hypoxia. We hypothesized that if these systems have a critical role in O₂ transport in hypoxic exercise, blockade of the receptors should be reflected in changes in exercise performance. The animal model utilized was the rat, which shares with humans several traits of acclimatization to hypoxia (Gonzalez et al., 1991, Gonzalez et al., 1993).