Importance of spinal noradrenergic pathways in cardiovascular reflexes and central actions of clonidine and α-methyldopa in the rabbit

doi:10.1016/0006-8993(89)91133-5

Brain Research

Volume 499, Issue 1, 9 October 1989, Pages 39-52

https://doi.org/10.1016/0006-8993(89)91133-5 Get rights and content

Abstract

We have examined in conscious rabbits the chronic effects of 6-hydroxydopamine (6-OHDA)-induced local lesions of the spinal noradrenaline (NA) pathways on (i) resting mean arterial pressure (MAP) and heart rate (HR), (ii) the nasopharyngeal pressor response, (iii) the sympathetic component of the baroreceptor-heart rate reflex, (iv) the acute responses to intracisternal (i.c.) clonidine and α-methyldopa (α-MD), and (v) the acute NA release response produced by i.c. 6-OHDA. One month after injection of 6-OHDA (40 nmol in 4 μl) into the first cervical spinal cord segment (C₁), the NA content was reduced to 29% in C₂, 45% in T₄ and 61% in L₃ with little non-specific damage. Basal MAP was 14% higher (P < 0.05) than in sham-operated rabbits suggesting increased vasoconstrictor tone. Basal cardiac sympathetic tone was enhanced, but a corresponding increase in cardiac vagal tone resulted in little net effect on resting HR in the spinal NA-depleted group. Spinal NA lesions attenuated the nasopharyngeal pressor reflex by 27% in baroreceptor-intact rabbits and by 38% in sino-aortically denervated (SAD) animals. The lesion did not affect HR range, gain and BP₅₀ of the sympathetic baroreflex. In SAD rabbits, the acute MAP responses to i.c. 6-OHDA (early hypotension, late hypertension) were not affected by spinal NA depletion, but the early fall in HR (cardiac sympathetic inhibition) was abolished. The hypotension produced by i.c. clonidine or α-MD was not affected by the lesion, probably because many of the NA terminals in the lower thoracic and upper lumbar cord were still intact. Our results suggest that intraspinal NA fibers have a tonic inhibitory action on spinal preganglionic vasoconstrictor and cardiac motoneurons. The spinal NA neurons affecting vasomotor tone (but not cardiac sympathetic tone) are in turn inhibited by higher vasomotor centers receiving projections from the arterial and trigeminal afferents and thereby participate in vasoconstrictor reflexes.

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Imidazoline receptors associated with noradrenergic terminals in the rostral ventrolateral medulla mediate the hypotensive responses of moxonidine but not clonidine
2005, Neuroscience
We determined whether the cardiovascular actions of central anti-hypertensive agents clonidine and moxonidine are dependent on noradrenergic or serotonergic innervation of the rostral ventrolateral medulla (RVLM) in conscious rabbits. 6-Hydroxydopamine (6-OHDA) or 5,6-dihydroxytriptamine (5,6-DHT) was injected into the RVLM to deplete noradrenergic and serotonergic terminals respectively. One, 2 and 4 weeks later, responses to fourth ventricular (4V) clonidine (0.65 μg/kg) and moxonidine (0.44 μg/kg) were examined. Destruction of noradrenergic pathways in the RVLM by 6-OHDA reduced the hypotensive response to 4V moxonidine to 62%, 47% and 60% of that observed in vehicle treated rabbits at weeks 1, 2 and 4 respectively. The moxonidine induced bradycardia was similarly attenuated (to 46% of vehicle). Conversely, 6-OHDA had no effect on the hypotensive or bradycardic effects of 4V clonidine. Efaroxan (I₁-imidazoline receptor/α₂-adrenoceptor antagonist; 3.5, 11, 35 μg/kg) and 2-methoxyidazoxan (α₂-adrenoceptor antagonist; 0.3, 0.9, 3 μg/kg) equally reversed the hypotension to 4V clonidine, suggesting a mainly α₂-adrenoceptor mechanism. Efaroxan preferentially reversed responses to moxonidine in both vehicle and 5,6-DHT groups and in the 1st week after 6-OHDA, suggesting a mechanism involving mainly I₁-imidazoline receptors. This selectivity was subsequently lost in the 2nd and 4th weeks when the remaining hypotension was mainly mediated by α₂-adrenoceptors. Depletion of serotonergic terminals did not alter the responses to either agonist nor did it change the relative effectiveness of the antagonists. Western blots of RVLM tissues probed with imidazoline and α₂-adrenoceptor antisera showed a pattern of bands close to that reported in other species. The main effect of 6-OHDA was an 18% lower level of the 42 kDa imidazoline protein (P<0.05). We conclude that the hypotensive and bradycardic actions of moxonidine but not clonidine are mediated through imidazoline receptors and are dependent on intact noradrenergic pathways within the RVLM. Furthermore, the noradrenergic innervation may be associated with a 42 kDa imidazoline receptor protein.
The rostral ventrolateral medulla mediates sympathetic baroreflex responses to intraventricular angiotensin II in rabbits
2003, Autonomic Neuroscience: Basic and Clinical
The present study examined the role of the rostral ventrolateral medulla (RVLM) in mediating the pressor and renal sympathetic baroreflex effects of intraventricularly administered angiotensin II (Ang II) in urethane anaesthetised rabbits. Microinjection of Ang II over a wide range of medullary sites showed that pressor responses were observed only in the RVLM. Ang II was particularly potent in producing a transient pressor response at this site with a half maximal dose of 9 fmol. The administration of the Ang II antagonist Sar¹-Ile⁸-Ang II (10 pmol) bilaterally into the RVLM inhibited the pressor response to local and fourth ventricular Ang II, but not the pressor response to RVLM applied glutamate. To determine the contribution of the RVLM to the renal sympathetic baroreflex effects of Ang II, blood pressure–renal sympathetic nerve activity (RSNA) curves were constructed with intravenous infusion of phenylephrine or nitroprusside before and after Ang II, vehicle or glutamate infusions into the RVLM. Ang II infusion of 4 pmol/min into the RVLM increased blood pressure by 8±3 mm Hg and shifted the renal sympathetic baroreflex curve to the right. The maximum RSNA evoked by lowering blood pressure increased by 36±6%, similar to the effect seen with fourth ventricular Ang II and RVLM glutamate. These studies suggest that the major medullary pressor site of action of Ang II when injected into the hindbrain cerebro-spinal fluid of anaesthetized rabbits is the RVLM where it facilitates baroreflex control of RSNA.
Baroreflex failure syndrome: An uncommon observation of an excessive blood pressure variability
2001, Revue de Medecine Interne
Introduction. – Le baroréflexe à haute pression est opérant dans les conditions physiologiques et il enclenche des réponses sympathiques ou vagales qui modifient le tonus artériel et la fréquence cardiaque. Ces réponses adaptées font que la pression artérielle est une variable autorégulée, autrement dit qu’elle varie peu puisque ce réflexe la rectifie constamment alors que de nombreux facteurs tendraient à la modifier.
Exégèse. – L’ablation d’un chémodectome carotidien bilatéral génère une instabilité tensionnelle majeure chez le patient faisant l’objet de cet article. Les indices reflétant la mise en jeu spontanée du baroréflexe sont fortement altérés.
Conclusion. – Cette situation de dénervation sinoaortique met en relief l’importance du baroréflexe à haute pression dans la régulation tensionnelle.
Introduction. – The arterial baroreflex operates in physiological conditions. It induces sympathetic and vagal activity modulation resulting in arterial tone and heart rate changes. These appropriate responses limit blood pressure fluctuations and blood pressure is therefore regulated since the baroreflex constantly buffers the changes.
Exegesis. – Bilateral carotid body tumor excision resulted in excessive fluctuations of blood pressure. Indices of spontaneous baroreflex activity were markedly altered in the patient described herein.
Conclusion. – The excessive fluctuations of blood pressure due to the sinoaortic denervation demonstrate how powerful is this negative feedback control mechanism in control conditions.
Hypotensive and hypertensive effects of catecholamines intrathecally injected in anesthetized rats
1996, Journal of the Autonomic Nervous System
The cardiovascular effects of catecholamines intrathecally (i.t.) injected at the T₁₂−L₁ level were analyzed in pentobarbital anesthetized rats. Volumes of injection were not greater than 3 μ1. Noradrenaline in doses ranging from 0.03 to 0.3 μg (i.t.) did not alter the mean blood pressure (MBP) while higher doses (1, 3 and 10 μg, i.t.) caused a dose-dependent increase in MBP. Adrenaline induced hypotensive effects at low doses (0.03-0.3 μg, i.t.) and pressor effects at high doses (3 and 10 μg, i.t.). Neither adrenaline nor noradrenaline modified the heart rate. The pressor responses to both catecholamines were antagonized by the α₁-adrenoceptor blocker prazosin (0.05-1 μg, i.t.) and by the selective α_1A-adrenoceptor antagonist 5-methyl urapidil (10 and 15 μg, i.t.). In contrast, these pressor effects were not modified by the α_1B-adrenoceptor antagonist chloroethylclonidine (90 μg, i.t.). In animals pretreated with 1 μg prazosin (i.i.), low doses of noradrenaline (0.03 and 0.1 μg, i.t.) caused a hypotensive effect. Prazosin (1 μg, i.t.) failed to alter the hypotension caused by 0.1 μg adrenaline. The hypotensive response induced by either 0.1 μg noradrenaline (in the presence of prazosin) or 0.1 μg adrenaline was blocked by the α₂-adrenoceptor antagonist yohimbine (1 mg/kg, i.v.), by the GABA-A antagonists bicuculline (3.2 μg, i.t.) and picrotoxin (2.7 μg, i.t.), and by the GABA-B antagonist 2-hydroxy saclofen (30 μg, i.t.). The glycine-receptor antagonist strychnine (25 μg, i.t.) did not modify the hypotension induced by either noradrenaline (in the presence of prazosin) or adrenaline. These findings suggest that in the low thoracolumbar spinal cord of pentobarbital-anesthetized rats, noradrenaline and adrenaline have excitatory as well as inhibitory effects on the control of the BP. The pressor responses of high doses of i.t. injected catecholamines could be mediated by the activation of spinal α_1A-adrenoceptors, although the participation of α_1B-adrenoceptors cannot be rule out entirely. The hypotensive responses induced by low doses of i.t. injected catecholamines seem to involve the activation of spinal α_2A-adrenoceptors and the stimulation of an inhibitory GABAergic neuron in the spinal cord.
Neuropharmacologic and behavioral actions of clonidine: Interactions with central neurotransmitters
1992, International Review of Neurobiology
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.
Contribution of forebrain noradrenaline innervation to the central circulatory effects of α-methyldopa and 6-hydroxydopamine
1991, Brain Research
We studied the circulatory effects of chronic lesions of the ascending noradrenergic (NA) projections to the forebrain on the acute effects of intracisternal (i.c.) α-methyldopa (α-MD) and 6-hydroxydopamine (6-OHDA) on mean arterial pressure (MAP) and heart rate (HR) in conscious rabbits with arterial baroreceptors either intact or denervated (sinoaortic denervation, SAD). Both drugs acutely release neurotransmitter from central NA neurons. I.c. 6-OHDA produced acute hypertension and bradycardia while i.c. α-MD produced acute hypotension and bradycardia. The responses are qualitatively similar in SAD rabbits except that after 6-OHDA, HR increased. In another group we studied the effects of the drugs 3–4 weeks after localised injections of 6-OHDA in the midbrain dorsal and ventral NA bundles. Local 6-OHDA depleted forebrain regions of NA by 44–76%, and had no effects on basal values of MAP or HR. The pressor and depressor effects, of 6-OHDA and α-MD respectively, were little affected by the lesions in either intact or SAD rabbits. By contrast, in rabbits with intact baroreceptors, the lesion abolished the bradycardia produced by i.c. α-MD and 6-OHDA. The latter drug now produced a late tachycardia. In SAD rabbits, however, there was no effect on the α-MD-induced bradycardia, but the 6-OHDA tachycardia was enhanced. Since the major effects of the lesions were confined to the rabbits with intact baroreceptor afferents, it suggests that the ascending NA pathways are important for the cardiac responses dependent on baroreceptor input. In intact animals, both drugs produce bradycardia through facilitation of the vagal component of the baroreceptor-heart rate reflex. In SAD rabbits, almost all the changes to HR are mediated through the cardiac sympathetic and the lesions have little effect on HR.

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^*: Present address: De´partement de Pharmacologie, Faculte´de Me´decine, Necker Enfants Malades 156, Rue de Vaugirard, 75015 Paris, France.

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Importance of spinal noradrenergic pathways in cardiovascular reflexes and central actions of clonidine and α-methyldopa in the rabbit

Abstract

J. Neurosci. Meth.

Brain Research

J. Auton. Nerv. Syst.

Prog. Brain Res.

Eur. J. Pharmacol.

Brain Research

Brain Research

Brain Research

J. Auton. Nerv. Syst.

Brain Research

Neurosci. Lett.

Brain Research

Brain Research

Distribution of tyrosine hydroxylase and neuropeptide Y-like immunoreactive neurons in rabbit medulla oblongata, with attention to colocalization studies, presumptive adrenaline-synthesizing perikarya, and vagal preganglionic cells

J. Comp. Neurol.