Interdependence of respiratory and cardiovascular changes induced by systemic hypoxia in the rat: the roles of adenosine.

Abstract

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

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

“…On the other hand, the lung stretch receptors with vagal afferents do contribute to the tachycardia, but not to the peripheral vasodilatation (62). Indeed, when ventilation was kept constant by artificial ventilation, then hypoxia induced bradycardia, but with substantial vasodilatation in skeletal muscle (60). By considering these results together with the effects of various antagonists of the sympathetic nervous system, we have concluded that the primary bradycardia of hypoxic stimulation of carotid chemoreceptors is opposed both by the secondary effects of hyperventilation on lung stretch receptors and by the ability of central nervous hypoxia to increase cardiac sympathetic activity (56,60,62).…”

“…Thus, when ventilation begins to fall, this exacerbates the fall in PaO 2 and the peripheral vasodilatation and bradycardia that are caused by the local effects of hypoxia, so potentiating the fall in arterial pressure. Once the arterial pressure is below the autoregulatory range, then cerebral blood flow falls, the O 2 supply to the brain is further reduced and the central neural hypoxia is exacerbated so that the central respiratory neurones are further depressed (60).…”

“…Indeed, when ventilation was kept constant by artificial ventilation, then hypoxia induced bradycardia, but with substantial vasodilatation in skeletal muscle (60). By considering these results together with the effects of various antagonists of the sympathetic nervous system, we have concluded that the primary bradycardia of hypoxic stimulation of carotid chemoreceptors is opposed both by the secondary effects of hyperventilation on lung stretch receptors and by the ability of central nervous hypoxia to increase cardiac sympathetic activity (56,60,62). The late bradycardia that occurs when hypoxia is prolonged can be attributed not only to the primary bradycardia of carotid chemoreceptor stimulation, but also to the local effects of hypoxia on the heart (60,63), while the late decrease in ventilation towards or below the baseline reflects the central effect of hypoxia on respiratory neurones (63).…”

Release of ATP in the Ventral Medulla during Hypoxia in Rats: Role in Hypoxic Ventilatory Response

“…Adenosine has been implicated as a potential mediator (Runold et al, 1989;Thomas and Marshall, 1994;Schmidt et al, 1995;Chau and Koos, 1999;Johansson et al, 2001). However, we recently demonstrated that adenosine release in the medullary regions involved in respiratory control, nucleus tractus solitarii and rostral ventrolateral medulla (VLM), occurs too late to be responsible for the initiation of hypoxia-induced depression of the respiratory activity .…”

“…Several lines of evidence implicate adenosine as a mediator for hypoxia-induced depression of respiration. Hypoxic respiratory depression is reduced by the administration of adenosine receptor antagonists (Runold et al, 1989;Thomas and Marshall, 1994;Schmidt et al, 1995;Chau and Koos, 1999) or in mice lacking adenosine A 1 receptor (Johansson et al, 2001). During hypoxia, adenosine levels rise in the VLM in the cat (Richter et al, 1999).…”