Muscarinic Receptor Subtype Involvement in Brain Cholinergic Stimulation by Intracerebroventricular Neostigmine in Sinoaortic Denervated Rats

Abstract

1. The present studies evaluated the participation of central muscarinic receptors in the cardiovascular effects of centrally injected neostigmine, a quaternary anticholinesterase, in conscious, sham-operated rats and in sinoaortic denervated animals. 2. The dose-dependent pressor effect of neostigmine (0.1 to 1 μg ICV) was greater in sinoaortic denervated rats than in sham-operated animals, but only a dose-dependent bradycardic effect was seen in sham-operated rats. 3. Doses of 3.3 nmol (ICV) of both the M 1 muscarinic antagonist, pirenzepine, and the M 3 muscarinic antagonist, 4-DAMP, prevented the pressor response to 1 μg of neostigmine in sham-operated rats and in sinoaortic denervated animals; however, the M 2 muscarinic antagonist, AF-DX116, partially blocked this response in sham-operated rats while failing to do so in sinoaortic denervated rats. In sham rats, doses of 3.3 nmol (ICV) of both pirenzepine and 4-DAMP prevented the bradycardic response to 1 μg (ICV) of neostigmine, whereas AF-DX116 induced a partial blockade. 4. 4-DAMP, at the dose of 0.3 nmol (ICV), but not pirenzepine at the same dose, prevented the pressor effect of neostigmine (0.1 to 1 μg ICV) in both groups of rats. Both muscarinic antagonists at this dose prevented the bradycardia elicited by the anticholinesterase (0.1 to 1 μg ICV), but 4-DAMP showed a greater antagonistic action on this cardiac effect than pirenzepine. In sham-operated rats, ICV injection of 0.3 nmol of AF-DX116 failed to modify the cardiovascular responses to 0.3 μg of neostigmine. 5. Results suggest mainly an involvement of brain M 3-subtype muscarinic receptors in the cardiovascular effect of intracerebroventricular administration of anticholinesterase neostigmine in both groups of rats.