Ventilatory stimulation by dopamine-receptor antagonists in the mouse.
Ventilation was measured by a plethysmographic method in awake mice before and after intraperitoneal injection of neuroleptic drugs to test the hypothesis that dopaminergic mechanisms modulate control of breathing in this species. Dose-dependent augmentation of ventilation at rest and during hypoxia, and reduced ventilation during hypercapnia was demonstrated for haloperidol, droperidol, prochlorperazine and chlorpromazine (P less than 0.05 or less for each drug). Doses of drugs causing maximal increase of the ventilatory response to hypoxia were linearly related (r = 0.98, P less than 0.001) to in vitro affinity of the drugs for dopamine receptors. Despite presumed equal dopamine-receptor blockade, the drugs had unequal effects on the ventilatory response to hypoxia. Droperidol augmented hypoxic ventilation to 290% of the control value, chlorpromazine to 250% control, prochlorperazine to 190% control and haloperidol to 120% control. These differences in efficacy were in the same order as the affinities of the drugs for alpha-adrenoceptors. The effect of combined haloperidol (90 nmol kg-1) and varying doses of phentolamine (175-900 nmol kg-1) was assessed to test the hypothesis that alpha-antagonism was a factor in determining the increase in ventilation following dopamine blockade. Phentolamine caused dose-dependent augmentation of the ventilatory effects of haloperidol (P less than 0.01) but had no ventilatory effect when given alone. Carotid body resection in anaesthetized mice abolished the stimulation of hypoxic ventilation caused by droperidol. It is concluded that dopaminergic mechanisms in the carotid body modulate ventilatory control in the awake mouse. The drugs most effective in augmenting hypoxic ventilation are those that block both dopamine and alpha-adrenoceptors.
Olson
L G
LG
Saunders
N A
NA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D002344:Carotid Body / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D018492:Dopamine Antagonists; D004329:Droperidol / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010646:Phentolamine / Q000494:pharmacology; D011346:Prochlorperazine / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects*; D013268:Stimulation, Chemical
D000317:Adrenergic alpha-Antagonists; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D006220:Haloperidol; D004329:Droperidol; D002746:Chlorpromazine; D011346:Prochlorperazine; D010646:Phentolamine