The Effect of Intracerebroventricular Dopamine Administration on the Respiratory Response to Hypoxia.

Abstract

Acute hypoxia produces an increase in ventilation. When the hypoxia is sustained, the initial increase in ventilation is followed a decrease in ventilation. The precise mechanism of this decline in ventilation during sustained hypoxia is unknown. Recent studies hypothesized that the accumulation of dopamine in the central nervous system might have a major role in production of hypoxic respiratory depression. The purpose of this study was to examine whether dopamine has an effect on occurance of central ventilatory depression which is seen in acute hypoxia in peripheral chemoreceptors denervated animals. The experiment were conducted in rabbits anesthetized with Na-pentobarbital (25 mg x kg(-1) i.v.). For intracerebroventricular (i.c.v.) injections of dopamine (1 microg) in each animal, canula was placed in left lateral cerebral ventricle by stereotaxic method. Respiratory frequency (f x min(-1)), tidal volume (V(T)) ventilation minute volume (V(E)) and systemic arterial blood pressure (BP) were recorded during air and 3 minutes hypoxic gas mixture (8%O2-92%N2) breathing. I.c.v. administration of dopamine during normoxia decreased V(T), f, V(E) and BP, significantly. When rabbits were injected with an i.c.v. dopamine on hypoxic gas mixture breathing in control animals, there was depression of hypoxic ventilatory responses. After i.c.v. administration of dopamine antagonists haloperidol (0.1 mg) and domperidone (0.07 mg) in chemodenervated rabbits, the significant increases in V(T), V(E) and BP were observed. On the breathing of hypoxic gas mixture of chemodenervated and i.c.v. dopamine antagonists administrated rabbits, hypoxic depression was completely abolished. These results of this study show that accumulation of dopamine in the brain seems to reduce the response of the central control mechanisms to chemoreceptor impulses during normoxia and hypoxia. In conclusion present study suggests important role played by central dopaminergic pathways in the occurence of acute hypoxic ventilatory depression.

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

“…Initially, it was believed that the heterogeneity of this response was due primarily to the state of arousal within any given species since in some animals HVD is only observed in the anesthetized state; however, in many species HVD is observed in both anesthetized/asleep and also in awake animals, calling this definition into question. For example, HVD has been observed in awake humans (155,167,350,351), awake and anesthetized cats (405), awake rats (229,382), anesthetized rats, as a decline in phrenic nerve activity (156,375), and in anesthetized rabbits (136), but is not observed in awake dogs (44, 60). Perhaps more confounding, in awake goats some groups detect HVD (120,121,229,382), while others do not (2,76,285).…”

“…Indirect support for this hypothesis comes from studies in which DA administered to awake humans or anesthetized rabbits prevents the acute HVR and STP, which in turn prevents the occurrence of HVD (62, 136). This suggests that upregulating inhibitory dopaminergic input during hypoxia opposes the excitation of the NTS mediated by excitatory inputs from the carotid body, which would in turn limit the release of glutamate at the NTS.…”

Remediation of Cellular Hypoxic Damage by Pharmacological Agents

“…Several agents can be classified in this group: (1) substances of central action: dopamine antagonists and other pharmacological agents that increase lung ventilation [54][55][56]; (2) inhibitors of carbo anhydrase [57,58], which lead to the accumulation of carbon dioxide in the blood and chemoreceptor stimulation of ventilation (Fig. (5)); mixtures of sodium and potassium salts [59] and other pharmacological agents.…”

Effects of Intravenous and Intracerebroventricular Theophylline on Hypoxic Ventilatory Depression in Anesthetized Cats

“…Artificial perfusion studies have also shown that the functioning of respiratory neurons in the brain stem is unaltered during moderate central hypoxemia (PaO 2 50 mm Hg) [9]. On the other hand, hypoxia influences the rate of synthesis or release of neurotransmitters and modulators [12,13], leading to accumulation of adenosine, dopamine and Á-aminobutyric acid in the brain [2,14,15]. Administration of long-acting analogues of adenosine, either systemically or directly into the third cerebral ventricle, decreases phrenic nerve activity in peripherally chemodenervated air breathing cats while theophylline, a specific antagonist of adenosine, prevents and reverses the decrease of phrenic activity [16] as reported by Javaheri et al [17].…”