Contribution of pre- and post-synaptic components to heightened central cholinergic activity in spontaneously hypertensive rats

doi:10.1016/0028-3908(89)90033-6

Neuropharmacology

Volume 28, Issue 4, April 1989, Pages 379-386

https://doi.org/10.1016/0028-3908(89)90033-6 Get rights and content

Abstract

In several models of essential hypertension in the rat, the pressor response to central cholinergic stimulation is enhanced with respect to age-matched normotensive controls. Neurochemical evidence is available from previous studies to suggest that both pre- (transmitter synthesis and release) and post-synaptic (muscarinic receptors) components of cholinergic transmission may be enhanced in hypertensive rats and that such alterations might be responsible for the exaggerated pressor response to centrally-acting cholinergic agonists. The present study, employing pharmacological approaches, was designed to determine whether pre- or post-synaptic components of central cholinergic transmission were more important in this regard. The pressor response to intravenous injection of the indirect-acting agonist, physostigmine, but not to that of the direct-acting agonist, arecoline, was significantly reduced by pretreatment with hemicholinium-3 (to deplete acetylcholine in brain). The pressor response to physostigmine, but not to arecoline, was enhanced in adult, spontaneously-hypertensive rats, with respect to their normotensive controls. The pressor response to oxotremorine was partially inhibited by pretreatment with hemicholinium-3, but was only partially effective at inducing an exaggerated pressor response in spontaneously hypertensive rats. These results are consistent with the hypothesis that heightened cholinergic activity in spontaneously hypertensive rats is derived primarily through altered pre-synaptic mechanisms, and that the actions of oxotremorine may involve a multi-synaptic cholinergic pathway.

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We examined whether the altered rostral ventrolateral medulla (RVLM) cholinergic function in spontaneously hypertensive rats (SHR) results from enhanced presynaptic cholinergic tone. Male 12-to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY) were anesthetized, paralyzed and artificially ventilated. Unilateral microinjection of cholinergic agents into the RVLM produced a pressor response. The pressor response to physostigmine was greater in SHR than that of WKY whereas the response to ACh and carbachol was the same in WKY and SHR. Bilateral microinjection of scopolamine produced a decrease in blood pressure. The depressor response was greater in SHR than that of WKY. When a microdialysis probe was placed in the RVLM, ACh release in the RVLM was greater in SHR than that of WKY. Choline acetyltransferase (CAT) activity was increased only in the rostro-ventral part of the medulla, which contained the RVLM, but not in other parts of the medulla oblongata. Physostigmine (0.5 mg/kg, i.p.)-induced increases in ACh content were also enhanced only in the rostro-ventral part of the medulla. These results provide direct evidence that ACh release in the RVLM is enhanced in SHR. It appears that the enhanced cholinergic activity in the RVLM of SHR results from an increase in cholinergic impulse flow in the RVLM of SHR. This abnormality may play a role in the maintenance of hypertension in SHR.
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Cholinomimetic agents increase blood pressure and heart rate via central muscarinic cholinoceptors in various aspects. It was reported that i.c.v. injection of the muscarinic M₁ and M₃ cholinoceptor selective antagonist, 4-DAMP (4-diphenylacetoxy-N-methyl-piperidine methiodide, inhibited the pressor response to physostigmine, while the M₁ selective antagonist, pirenzepine, was ineffective. In the present study, the involvement of muscarinic M₂ cholinoceptors in central cholinergic hypertension and tachycardia was investigated. Physostigmine (10–80 μg/kg i.v.), a cholinesterase inhibitor, and oxotremorine (20–40 μg/kg i.v.), a direct muscarinic cholinoceptor agonist, caused a dose-dependent increase in blood pressure. Additionally, physostigmine induced dose-dependent tachycardiac responses. I.c.v. administration of the muscarinic M₂ cholinoceptor antagonists, AF-DX 116 and methoctramine, inhibited both physostigmine (60 μg/kg) and oxotremorine (20 μg/kg)-induced pressor responses at their lower doses used in this study (100 nmol/rat and 10 nmol/rat, respectively). These findings indicate the partial involvement of postsynaptic muscarinic M₂ cholinoceptors. The higher doses of the antagonists (AF-DX 116 300 nmol/rat and methoctramine 30 nmol/rat) potentiated the blood pressure increase due to physostigmine but did not affect that due to oxotremorine. The physostigmine-induced tachycardiac responses were influenced similarly by these antagonists. These results suggest the presence and tonic influence of presynaptic inhibitory muscarinic M₂ cholinoceptors.
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The discovery of the antipsychotic action of chlorpromazine in the early 1950s and its usage in the treatment of schizophrenia heralded the beginning of modern psychopharmacology. Inquiries into the mechanism of action of this important compound led to the dopamine hypothesis of schizophrenia, a tenet that continues to provide one of the few durable models of brain dysfunction. This chapter focuses on the mechanism(s) by which clonidine produces its prominent pharmacological actions. Clonidine and related drugs may continue to be examined for potential antidementia effects. Despite the disappointing initial results in Alzheimer's patients, clonidine may exhibit beneficial actions in certain categories of human dementia. The possibility that combined treatment with clonidine and physostigmine may produce an added benefit fits with the observation of multiple neurotransmitter alterations in Alzheimer's disease. Several studies indicate that clonidine can inhibit many of the pharmacological effects produced by cholinesterase inhibitors, but this does not imply incompatibility for their use in dementia. A combination of physostigmine and clonidine is required to restore the beneficial effects of central cholinergic stimulation in the lesioned animals.
Cholinergic hyperactivity in the lateral septal area of spontaneously hypertensive rats: Depressor effect of hemicholinium-3 and pirenzepine
1991, Neuropharmacology
In the lateral septal area of spontaneously hypertensive rats, but not in Wistar-Kyoto rats, the selective M₁ antagonist, pirenzepine, and the depletion of acetylcholine storage, by hemicholinium-3 (HC-3), decreased blood pressure. The selective M₁ agonist McNeil-A-343, produced a pressor response only after treatment of the lateral septal area with HC-3 in spontaneously hypertensive rats. Carbachol, at doses that mainly affect M₂ muscarinic receptors, caused no cardiovascular changes in either strain, pointing to the main intervention of the M₁ subtype of muscarinic receptor in the hypertensive condition. In addition, increases in the density of binding sites for [³H]QNB and in V_max of sodium-dependent, HC-3-inhibitable, high affinity uptake of choline were demonstrated, without significant changes of the activity of choline acetyltransferase in the lateral septal area of spontaneously hypertensive rats. These results suggest that a hyperactivity of the cholinergic system of this area could play a role in the development and/or maintenance of hypertension in spontaneously hypertensive rats.

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^∗: Present address: Institute of Pharmacology, University of Messina, Piazza XX Settembre, 4, 98100 Messina, Italy.

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Contribution of pre- and post-synaptic components to heightened central cholinergic activity in spontaneously hypertensive rats

Abstract

Neuropharmacology

Eur. J. Pharmac.

Life Sci.

Eur. J. Pharmac.

Brain Res.

Life Sci.

Dev. Brain Res.

Brain Res.

Brain Res.

Cardiovascular control by cholinergic mechanisms in the central nervous system

Ann. Rev. Pharmac. Toxic.

The hypertensive response to injection of physostigmine into the hypothalamus of the unanesthetized rat

Clin. exp. Hypertension

Brain neurotransmitters and the development and maintenance of experimental hypertension

Prog. Drug Res.

Role of central cholinergic neurons in experimental hypertension

J. Cardiovasc. Pharmac.

Reflex regulation of sympathetic activity in the spontaneously hypertensive rat

Circ. Res.

Regulation of blood pressure by sympathetic nerve fibers and adrenal medulla in normotensive and hypertensive rats

Circ. Res.

Uber die blutdrucksteigernde Wirkung von Esterasaeblockern (E605, Eserin und Prostigmin)

Naunyn -Schmiedebergs Arch. exp. Path. Pharmak.