Roger Bloch

The nucleus reticularis lateralis: A region highly sensitive to clonidine

Slow bilateral microinjections of a low dose of clonidine (75 ng/kg) in the cats nucleus reticularis lateralis (NRL) lead to significant hypotension and bradycardia. This finding confirms the existence of a ventromedullary highly sensitive site of action of clonidine. It is suggested that clonidine inhibits some vasopressive and cardioacceleratory structures within the NRL region.

evidence for a neuromodulatory role of GABA at the first synapse of the baroreceptor reflex pathway

SummaryMicroinjections of GABA and of the specific agonist of GABA receptors, muscimol, in the intermediate nucleus tractus solitarii (NTS) of pentobarbitone anaesthetized cats produced hypertension and tachycardia. The GABA receptor antagonist, bicuculline, had opposite effects and prevented those of muscimol. Therefore, a GABAergic system appears to modulate the cardiovascular regulation within the NTS. d,l-Baclofen also increased blood pressure and heart rate when injected into the same region, but this effect was not antagonized by bicuculline. The mechanism of this action of baclofen is discussed.

Role of the ventral surface of the brain stem in the hypotensive action of clonidine

The areas S of the ventral surface of the brain stem and the immediately surrounding zone were superficially destroyed by the means of electro-coagulation, in 14 cats. This destruction produced a drop in blood pressure, which was transient in 9 and definitive in 4 animals; in one cat only the arterial pressure did not change after the destruction. In 6 animals which have been sham-operated, clonidine (15 mug/kg, i.v.) always induced a marked fall in blood pressure whereas in 10 animals which had maintained or recovered a normal blood pressure after the destruction of the area S, clonidine (15 mug/kg) injected intravenously no longer produced any decrease of the arterial pressure. These results suggest that the integrity of the areas S is necessary for the development of the hypotensive action of clonidine. This hypotensive drug may act, at least at the level of the ventral surface of the brain stem, through inhibition of a vasopressive structure.

The central hypotensive action of baclofen in the anaesthetized cat.

In the pentobarbital-anaesthetized cat, the intracerebroventricular administration of 20 microgram/kg d,1-baclofen led to marked hypotension and bradycardia, whereas the same dose of d-baclofen (i.c.v.) had no cardiovascular effect. When the drug was prevented from reaching the brain stem structures by collecting perfusate through a catheter lodged in the Aqueduct of Sylvius, the efficacy of d,1-baclofen was increased. Bicuculline did not antagonize the central cardiovascular effects of d,1-baclofen at doses which inhibit the cardiovascular effects of GABA agonists. However, both glutamic acid and kainic acid prevented and reversed the central hypotension and bradycardia produced by d,1-baclofen. These effects of baclofen may therefore be mediated by a selective inhibition of the release of the excitatory neurotransmitter, glutamate, within forebrain structures involved in central cardiovascular regulation.

Medullary cardiovascular effects of tetrodotoxin in anaesthetized cats

Tetrodotoxin injected in the cat nucleus tracus solitarii produced hypertension without bradycardia, whereas in the nucleus reticularis lateralis it led to hypotension and bradycardia. Tetrodotoxin acts by blocking neuronal activity; it is a useful tool for studying the central organization of cardiovascular regulation. The present data confirm that the nucleus reticularis lateralis is a vasopressive centre.

Tag antagonises the central cardiovascular effects of taurine

The taurine antagonist TAG was examined for its blocking activity towards the central cardiovascular effects of taurine and muscimol. Intracerebroventricular (i.c.v.) injections of taurine (1-1000 micrograms/kg) and muscimol (0.1-3 micrograms/kg) in the anesthetised cat led to hypotension and bradycardia. Pretreatment with TAG (1 mg/kg i.c.v.) antagonised the blood pressure effects of taurine. The selectivity of this antagonism is discussed since TAG also shifted to the right the blood pressure dose-response curve obtained with muscimol.

Pharmacological analysis of the central cardiovascular effects of four GABA analogues

SummaryThe central cardiovascular effects of 4 structural analogues of GABA were investigated. The drugs were injected intracerebroventricularly (i.c.v.) in cumulative doses into pentobarbital-anaesthetized normotensive rats. Muscimol (0.01–10 μg/kg), THIP (0.01–100μg/kg), kojic amine (0.1–100 μg/kg) and isoguvacine (0.1–100μg/kg) produced dose-dependent hypotension and bradycardia. The maximal fall in the mean blood pressure was of about 35% of the initial values. These effects appears to be of central origin since the intravenous (i.v.) injection of the same doses of the drugs did not produce any similar cardiovascular modifications. The hypotensive effects of muscimol and kojic amine were antagonized partly by i.c.v. bicuculline. The combination of bicuculline and kainic acid almost completely prevented the blood pressure lowering effects of muscimol, kojic amine and isoguvacine. THIP however was only slightly antagonized by bicuculline and kainic acid. Atropine i.v. also prevented partly the cardiovascular effects of all these drugs.Thus, the mechanisms of the central cardiovascular actions of GABA analogues appear to be more complex than expected and variable from one drug to another.The involvement of GABA receptors of the A and B types and of cholinergic mechanisms in the hypotensive effect of the drugs is discussed.

Cardiovascular effects of intracerebroventricular injections of baclofen in the conscious rabbit.

Baclofen [~-(4-chlorophenyl)-y-aminobutyric a id] is a lipophilic analogue of y-aminobutyric acid (GABA) that penetrates the blood brain barrier. It is effective in the treatment of spasticities of spinal origin. During trials with baclofen in spastic patients, Pinto et al(l972) described hypotensive side effects. In the anaesthetized cat, Stanovnik et a1 (1978), Olpe et al(l978) and Sweet et al(l979) reported a hypotensive effect of intravenous and intracisternal baclofen. Recently, we observed a marked hypotensive and bradycardic effect of baclofen in the anaesthetized cat. The origin of this action appeared to be located mainly within the forebrain and may be related to the inhibition of glutamate release (Bousquet et a1 1981). However, Persson & Henning (1980) observed that baclofen administered intraperitoneally or intracisternally to the conscious rat produced a sustained hypertension and tachycardia reversed by pentobarbitone anaesthesia. We have investigated the central cardiovascular actions of baclofen in the conscious rabbit and present evidence that the drugs direct intracerebroventricular (i.c.v.) administration into the central nervous system results in a marked hypotension and bradycardia.

HYPOTENSIVE EFFECT OBTAINED BY APPLICATION OF DRUGS TO THE VENTRAL SURFACE OF THE MEDULLA: A MEMBRANE STABILISING MECHANISM?

The hypotensive response which can be obtained in cats by application of some beta-blockers or dextroenantiomers, on the clonidine-sensitive ventromedullary area, is probably due to a membrane-stabilising mechanism. This approach led us to discuss the mechanism of the hypotensive action of centrally acting drugs.