Role of adenosine and its receptors in the vasodilatation induced in the cerebral cortex of the rat by systemic hypoxia

Abstract

1. In anaesthetized rats, we have examined the role of adenosine in vasodilatation evoked in the cerebral cortex by systemic hypoxia (breathing 8 % O2). Red cell flux was recorded from the surface of the exposed parietal cortex (CoRCF) by a laser Doppler probe, cortical vascular conductance (CoVC) being computed as CoRCF divided by mean arterial blood pressure. All agonists and antagonists were applied topically to the cortex. 2. Systemic hypoxia or adenosine application for 5 or 10 min, respectively, induced an increase in CoRCF and CoVC. These responses were substantially reduced by 8-phenyltheophylline (8-PT), an adenosine receptor antagonist which is non-selective between the adenosine A1 and A2A receptor subtypes. By contrast, the adenosine receptor antagonist 8-sulphophenyltheophylline (8-SPT) which is similarly non-selective, but unlike 8-PT, does not cross the blood-brain barrier, reduced the increases in CoRCF and CoVC induced by adenosine, but had no effect on those induced by hypoxia. 3. The A2A receptor agonist CGS21680 produced a substantial increase in CoRCF and CoVC, but the A1 receptor agonist 2-chloro-N6-cyclopentyladenosine had minimal effects. 4. The A2A receptor antagonist ZM241385 reduced the increase in CoRCF and CoVC induced by adenosine and reduced the increase in CoRCF induced by hypoxia. 5. We propose that exogenous adenosine that is topically applied to the cerebral cortex produces vasodilatation by acting on A2A receptors on the vascular smooth muscle. However, during systemic hypoxia, we propose that adenosine is released from endothelial cells and acts on endothelial A2A receptors to produce the major part of the hypoxia-induced dilatation in the cerebral cortex.

Figure 1. Responses evoked by systemic hypoxia (breathing 8 % O₂) before and after topical application of 8-PT to the cerebral cortex

Traces from above downwards are arterial blood pressure (ABP), heart rate (HR), carotid blood flow (CBF), carotid vascular conductance (CVC), cortical red cell flux (CoRCF) and cortical vascular conductance (CoVC). Continuous bars beneath traces indicate 5 min periods of hypoxia. 8-PT at 1 μM was given between A and B.

Figure 2. Effects of topical application of 8-PT to the cerebral cortex on responses induced by systemic hypoxia (breathing 8 % O₂)

Abbreviations as in Fig. 1 except MABP indicates mean arterial blood pressure. In each graph values are means ±s.e.m. during air breathing (time 0) and over 5 min of hypoxia as indicated by abscissa. ▪, before 8-PT; •, after 8-PT. CoRCF, CoVC, CBF and CVC are expressed as percentages of values recorded before hypoxic stimulus (time 0). *** Significant difference between response recorded before and after 8-PT; P < 0.001.

Figure 3. Effects of topical application of 8-PT to the cerebral cortex on responses induced by topically applied adenosine

Abbreviations and symbols as in Fig. 2.

Figure 4. Effects of topical application of 8-SPT to the cerebral cortex on responses induced by systemic hypoxia (breathing 8 % O₂)

Abbreviations and symbols as in Fig. 2.

Figure 5. Effects of topical application of 8-SPT to the cerebral cortex on responses induced by topically applied adenosine

Abbreviations and symbols as in Fig. 2; *P < 0.05.

Figure 6. Responses induced by topical application to the cerebral cortex of the A₁ and A₂ adenosine receptor agonists CCPA and CGS21680, respectively

Abbreviations as in Fig. 2. □, baseline values; shaded columns indicate values recorded at the end of 5 min topical application of the agonist (, CCPA; , CGS21680). Values for CoRCF and CoVC during agonist application are shown as percentage of baseline values. ** and * indicate a significant difference between values recorded at baseline and at the 5th minute of agonist application of P < 0.01 and P < 0.05, respectively.

Figure 7. Effects of topical application to the cerebral cortex of the A_2A adenosine receptor antagonist ZM241385 on responses induced by systemic hypoxia (breathing 8 % O₂)

Abbreviations and symbols as in Fig. 2. **P < 0.01.

Figure 8. Effects of topical application to the cerebral cortex of the A_2A adenosine receptor antagonist ZM241385 on responses induced by topically applied adenosine

Abbreviations and symbols as in Fig. 2.