Caudal ventrolateral medulla. A region responsible for the mediation of vasopressin-induced pressor responses

We localized glutamate-sensitive sites in the ventrolateral medulla of the rat with the spinal cord cut at C. When unilaterally injected into a circumscribed region of the caudal ventrolateral medulla, L-glutamate (30-300 ng) elicited a dose-dependent increase in arterial pressure. The pressor response was accounted for by an increased release of vasopressin because it was abolished by the intravenous injection of a vasopressin antagonist. Bilateral microinjections of kainic acid (50 ng) into the ventrolateral glutamate-sensitive area markedly reduced a vasopressin-induced pressor response to kainic acid (30 ng), injected bilaterally into the nucleus tractus solitarii. It is concluded that the glutamate-sensitive neurons in the caudal ventrolateral medulla are involved in mediation of the vasopressin-induced pressor response arising from the nucleus tractus solitarii.     

Caudal ventrolateral medulla

Summary We localized glutamate-sensitive sites in the ventrolateral medulla of the rat with the spinal cord cut at C₁. When unilaterally injected into a circumscribed region of the caudal ventrolateral medulla,l-glutamate (30–300 ng) elicited a dose-dependent increase in arterial pressure. The pressor response was accounted for by an increased release of vasopressin because it was abolished by the intravenous injection of a vasopressin antagonist. Bilateral microinjections of kainic acid (50 ng) into the ventrolateral glutamate-sensitive area markedly reduced a vasopressin-induced pressor response to kainic acid (30 ng), injected bilaterally into the nucleus tractus solitarii. It is concluded that the glutamate-sensitive neurons in the caudal ventrolateral medulla are involved in mediation of the vasopressin-induced pressor response arising from the nucleus tractus solitarii.     

Effect of overproduction of nitric oxide in the brain stem on the cardiovascular response in conscious rats

To examine the role of nitric oxide in the brain stem on cardiovascular response in vivo, we have developed and applied a technique of endothelial nitric oxide synthase gene transfer into the nucleus tractus solitarii or the rostral ventrolateral medulla of rats in vivo. The blood pressure and heart rate were monitored using a radiotelemetry system in the conscious state. As a marker of sympathetic nerve activity, we measured 24-h urinary norepinephrine excretion. We found that overexpression of endothelial nitric oxide synthase in the nucleus tractus solitarii as well as in the rostral ventrolateral medulla causes hypotension and bradycardia via a decrease in sympathetic nerve activity. Furthermore, in the case of the local increases in nitric oxide in the rostral ventrolateral medulla, we suggest that this effect is mediated by an increase in gamma-aminobutyric acid. Moreover, in the stroke-prone spontaneously hypertensive rat, the increase in nitric oxide production evoked by the overexpression of endothelial nitric oxide synthase in the rostral ventrolateral medulla caused greater depressor and sympatho-inhibitory responses than in normotensive Wistar-Kyoto rats, suggesting that an abnormality of the L-arginine-nitric oxide pathway may be involved in the central mechanisms of hypertension in this model.     

Alpha-methylnoradrenaline-induced hypotension in the nucleus tractus solitarii, of the rat: a localization study.

The sites in the nucleus tractus solitarii in the rat medulla oblongata where ( ? )-α-methyl-noradrenaline induced hypotension were determined using microinjections. The most effective area was found to extend from +500 to ?400 μm of the caudal tip of the area postrema (defined as zero plane). At these sites no effect was observed with the ( + ) stereoisomer of α-methylnoradrenaline or vehicle. Injections of ( ? )-methylnordrenaline in adjacent structures were ineffective.     

Responses to microinjections of endomorphin and nociceptin into the medullary cardiovascular areas

1. Cardiovascular effects of microinjections of nociceptin and endomorphin-2 into the following medullary areas were studied in urethane-anaesthetized rats: chemoreceptor projection site (CPS), intermediate portion of the nucleus tractus solitarius (I-NTS), caudal ventrolateral medullary depressor area (CVLM) and rostral ventrolateral medullary pressor area (RVLM). 2. Microinjections of nociceptin or endomorphin-2 (0.6 mmol/L each) into the CPS and RVLM elicited depressor and bradycardic responses, whereas similar injections into the I-NTS and CVLM elicited pressor and tachycardic responses. 3. The mechanism of cardiovascular responses to microinjections of these opioid peptides into different medullary areas involved in cardiovascular function can be postulated as follows: the direct effect of nociceptin and endomorphin-2 on neurons is usually inhibitory. Because the activation of CPS and RVLM by microinjections of L-glutamate results in pressor and tachycardic responses, inhibition of these areas by nociceptin and endomorphin-2 elicits depressor and bradycardic responses. Similarly, activation of neurons in the I-NTS and CVLM by microinjections of L-glutamate elicits depressor and bradycardic responses. Therefore, inhibition of these areas by microinjections of these opioid peptides elicits an increase in blood pressure and heart rate.     

Cardiorespiratory effects of inositol hexakisphosphate following microinjections into the nucleus tractus solitarii

Microinjections of inositol hexakisphosphate (IP6), a metabolite of inositol recently found to occur in high concentrations in the brainstem, were made into the caudal portion of the nucleus tractus solitarii (NTS) of spontaneously breathing rats and cardiorespiratory parameters recorded for a 30 min test period. Microinjections of IP6, in the dose range of 100-500 pmol/rat, produced significant dose-related reductions in mean arterial blood pressure and respiratory rate. The onset for hypotensive action and respiratory depression following microinjections of IP6 was very rapid and a transient apnea could be elicited at the higher doses. Moreover, the sodium and calcium salts of IP6 were relatively equipotent in depressing cardiorespiratory parameters, with the exception of heart rate wherein the sodium salt elicited a much more pronounced bradycardia. These results confirm and extend the findings of a previous study suggesting that IP6 and closely related metabolites may act on extracellular receptors. Taken together, these data provide further support to the notion that inositol lipid signalling pathways may generate both intracellular and extracellular signals in the brain.     

Rilmenidine lowers arterial pressure via imidazole receptors in brainstem C1 area.

We sought to determine the site of action and receptor type responsible for the antihypertensive actions of rilmenidine, an oxazoline analogue of clonidine. In anesthetized paralyzed rats decerebration did not alter the dose dependent reductions in arterial pressure and heart rate elicited by i.v. drug. Rilmenidine microinjected bilaterally into the C1 area of the rostral ventrolateral medulla (RVL), but not nucleus tractus solitarii (NTS) nor caudal ventrolateral medulla (CVL), elicited dose-dependent falls in arterial pressure and heart rate at doses an order of magnitude less than required systemically. Prior microinjection into the C1 area of the selective alpha 2-adrenoceptor antagonist SKF-86466, even at high doses, failed to modify the hypotension to i.v. rilmenidine. However, microinjection of 3- to 10-fold lower doses of idazoxan, a ligand for imidazole as well as alpha 2-adrenoceptors, blocked the effects. Rilmenidine also competed with the clonidine analogue [3H]p-aminoclonidine ([3H]PAC) at specific binding sites in membranes of bovine ventrolateral medulla and frontal cortex. In RVL rilmenidine competed with binding to imidazole and alpha 2-adrenergic binding sites with a 30-fold selectivity for the imidazole binding sites. In frontal cortex binding was of lower affinity and restricted to alpha 2-adrenergic sites. We conclude that rilmenidine, like clonidine, acts to lower arterial pressure by an action on imidazole receptors in the C1 area of RVL. The higher selectivity of rilmenidine for imidazole to alpha 2-adrenoceptors as compared to clonidine may explain the lower sedative effects of rilmenidine.     

Vasopressor and depressor areas in the rat medulla: Identification by microinjection of l-glutamate

l-Glutamate (in 0.1 μl of 0.9% NaCl) was injected via multibarrelled glass micropipettes into the ventrolateral medulla of urethane-anesthetized rats. This area, explored stereotaxically, extended from 2.2mm rostral (near trapezoid bodies) to 0.4mm caudal, with respect to the obex, 2.4mm lateral to the mid-line on each side and 2.4mm deep from the ventral surface of the medulla. Two types of responses were elicited by injection of l-glutamate. One type was a dose-related increase in arterial pressure and heart rate; these responses were elicited from the lateral portion of nucleus reticularis gigantocellularis, the medial aspect of nucleus reticularis parvocellularis and the dorsal-lateral reticular nucleus. The second type of response was a dose-related fall in arterial pressure with no change in heart rate; this response was localized caudal to pressure areas in the caudal ventrolateral part of nucleus reticularis gigantocellularis, ventrolateral nucleus reticularis ventralis, nucleus ambiguus and the A₁ region. Glutamic acid diethylester (GDEE), an antagonist of l-glutamate, blocked all the cardiovascular effects of l-glutamate. These results indicate the presence of receptors for glutamate in the pressor and depressor areas. Glutamic acid diethylester caused a fall in blood pressure when injected on its own into pressor sites suggesting the existence of a glutaminergic input to the pressor sites. Inhibition of neuronal activity in pressor sites produced by microinjection of muscimol (a potent neuroinhibitory analogue of GABA) caused a decrease in blood pressure. On the other hand, pressor responses resulted following similar inhibition in the depressor sites. These results indicate that the pressor and depressor sites identified in the ventral medulla of the rat may have an important role to play in central cardiovascular regulation.     

Ethanol inhibition of stress-related tachycardia involves medullary NMDA receptors

In rats, neurons in the perifornical area of the hypothalamus send descending projections to the commissural part of the nucleus tractus solitarii as demonstrated by an anterograde tracer study. In urethane-anaesthetised rats, stimulation of neurons in the perifornical area by microinjection of bicuculline or 6-OH-saclofen causes tachycardia and inhibits baroreflex bradycardia. The effects elicited from the perifornical area are similar in magnitude to those elicited from the adjacent dorsomedial nucleus, also called the hypothalamic defense area. Microinjection into the nucleus tractus solitarii of the NMDA (N-methyl- -aspartate) receptor antagonist, AP-7 (2-amino-7-phosphonoheptanoic acid), inhibits the tachycardic response to stimulation of the perifornical area. Injection of ethanol intravenously or into the nucleus tractus solitarii also inhibits this tachycardic response, but causes no further inhibition when combined with AP-7. We conclude that the perifornical area is part of the hypothalamic defense area, and it is under strong, tonic GABAergic inhibition mediated by both GABA_A and GABA_B receptors. Furthermore, descending input from the perifornical area to the nucleus tractus solitarii is via an NMDA synapse, and ethanol inhibits stress-related tachycardia by inhibiting these NMDA receptors in the nucleus tractus solitarii.     

Role of I1-imidazoline receptors within the caudal ventrolateral medulla in cardiovascular responses to clonidine in rats

Although it is recognized that imidazoline receptors play an important role in the central regulation of cardiovascular activities, little is known about their role in the caudal ventrolateral medulla. In male Sprague-Dawley rats anesthetized with urethane, we used antagonists of I1-imidazoline receptor or alpha2-adrenoceptor to assess the function of these receptors in the caudal ventrolateral medulla in controlling the cardiovascular effects of clonidine. Unilateral microinjection of clonidine (6 nmol/50 nl) into the caudal ventrolateral medulla significantly (P<0.01) increased blood pressure and the discharge of the rostral ventrolateral medulla presympathetic neurons, while heart rate remained unchanged. Microinjection of yohimbine (a selective alpha2-adrenoceptor antagonist, 500 pmol/50 nl) into the caudal ventrolateral medulla did not modify blood pressure, heart rate, or the discharge of the rostral ventrolateral medulla presympathetic neurons, and failed to attenuate the local caudal ventrolateral medulla clonidine-induced blood pressure elevation. However, unilateral microinjection of idazoxan (a mixed antagonist of imidazoline receptor and alpha2-adrenoceptor, 2 nmol/50 nl) into the caudal ventrolateral medulla significantly (P<0.01) decreased mean arterial pressure, heart rate, and the discharge of the rostral ventrolateral medulla presympathetic neurons, and completely abolished the pressor effect of clonidine. In addition, bilateral microinjection of idazoxan (4 nmol in 100 nl for each side) into the caudal ventrolateral medulla effectively (P<0.01) blocked the depressor effects of clonidine administered intravenously (5 and 50 microg/kg). These results confirm that I1-imidazoline receptors within the caudal ventrolateral medulla are involved in maintaining the tonic cardiovascular activities and in the pressor effect of clonidine in the caudal ventrolateral medulla. In addition, it seems that the caudal ventrolateral medulla plays an important role in the antihypertensive effects of systemically administered clonidine in rats.     

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

Summary Microinjections 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.     

Serotonin receptors in the rat nucleus tractus solitarii and cardiovascular regulation

The effects of local application in the nucleus tractus solitarii of different serotonin receptor agonists and antagonists were investigated in anesthesized rats. Unilateral microinjection of serotonin produced an acute and transient hypotension and bradycardia which could be totally blocked by antagonists acting preferentially upon 5-HT2 receptor binding sites: ketanserin and ritanserin. 5-HT1 receptor agonists such as RU-24969 and 8-hydroxy-2-(di-n-propylamino)tetralin failed to reproduce the acute cardiovascular effects of serotonin. Bilateral microinjection of 5-HT2 receptor antagonists produced an increase in the level and in the variability of arterial pressure but did not block the baroreceptor reflex arc. The data suggest that serotonin acting upon 5-HT2 receptors in the nucleus tractus solitarii plays an important role in the modulation of arterial pressure.     

Effects of medullary alpha2-adrenoceptor blockade in the rat

The effect of alpha2-adrenoceptor blockade in the medulla was studied in pentobarbital anesthetized rats in which arterial blood pressure, heart rate and renal sympathetic nerve activity were analysed. Three series of experiments were performed: (1) i.c. administration of alpha2-adrenoceptor antagonists with different subtype affinities; (2) i.v. administration of methoxy-idazoxan to study its effects on neuronal activity into the rostral ventral medulla; (3) microinjections of methoxy-idazoxan in rostral ventral medulla and nucleus tractus solitarii. Methoxy-idazoxan (0.1-3 microg x kg(-1) i.c., n=5), but not saline, rauwolscine, BRL 44408 (2-[2H-(1,3,dihydroisoindol)methyl]-4,5dihydroimidazol) or ARC 239 (2-[2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquilindione) (each at 10-100 microg x kg(-1) i.c., n=5-5-6-5, respectively), increased mean arterial blood pressure, heart rate and renal nerve activity (+19+/-6 mm Hg, +72+/-22 beats x min(-1), +43+/-9%) and blocked the sympatho-inhibitory action of clonidine (10 microg x kg(-1) i.v.). In further experiments, methoxy-idazoxan, BRL 44408 and the highest dose of rauwolscine i.c., reversed the clonidine-induced sympatho-inhibition (order of potency: methoxy-idazoxan>BRL4440>rauwolscine, n=6 each), whereas ARC 239 (n=5) or saline (n=7) did not. Methoxy-idazoxan i.v. (n=7, 10-100 microg x kg(-1)) increased the renal sympathetic nerve and rostral ventral medulla neuronal activity and the heart rate (+36+/-7%, +66+/-29% and +18+/-9 beats x min(-1)) without a significant effect on mean arterial blood pressure. Microinjection of methoxy-idazoxan (1 nmol/40 nl) into the rostral ventral medulla reversed the effect of clonidine microinjected into the same site (2 nmol/40 nl, n=5). In another group of rats (n=8), methoxy-idazoxan increased mean arterial blood pressure, heart rate and renal nerve activity (+16+/-2 mm Hg, +42+/-7 beats x min(-1), +24+/-5%) and blocked the effect of clonidine i.v. (10 microg x kg(-1)). Bilateral microinjections into the nucleus tractus solitarii (n=5) did not alter mean arterial blood pressure but decreased heart rate and sympathetic nerve activity (-30+/-16 beats x min(-1), -20+/-14%). Our results offer direct in vivo evidence for the main role of the alpha2A/D-adrenoceptors located in the ventral pressor area. The data show that the sympathy-excitatory effect of alpha2-adrenoceptor antagonists is due to the blockade of a tonic activation of these alpha2A/D-adrenoceptors present in the rostral ventral pressor area.     

The cardiovascular effects of quipazine are mediated by peripheral 5-HT2 and 5-HT3 receptors in anaesthetized rats

Quipazine (0.5-2 mg/kg i.v.) produced transient hypotension and bradycardia followed by sustained hypertension and variable effects on heart rate in anaesthetized rats. The hypotension, bradycardia and sympatho-inhibitory effects of quipazine were attenuated by bivagotomy. In bivagotomized rats, the hypertension produced by quipazine was not modified by hexamethonium or prazosin but was abolished by ritanserin (1 mg/kg i.v.). In ritanserin-treated rats, section of the carotid sinus nerves and vagus nerves or ICS 205.930 (0.1 mg/kg i.v.) abolished the hypotensive, bradycardic and sympatho-inhibitory effects of quipazine; the action of quipazine was not reproducible in these rats. Quipazine also inhibited the Bezold-Jarish reflex elicited by 5-HT (20 micrograms/kg i.v.). In ICS 205.930-treated rats, the hypertension evoked by quipazine was associated with a reduction in splanchnic nerve activity due to stimulation of baroreceptors. The renin-angiotensin system is not involved in the hypertensive response. The increase in heart rate produced by quipazine in bivagotomized rats was reduced by ritanserin and tertatolol (0.1 mg/kg i.v.) and abolished by a combination of both drugs. We conclude that the bradycardic and sympatho-inhibitory effects of quipazine result from activation of 5-HT3 receptors located in the cardiopulmonary area and of carotid body chemoreceptors. The hypertension and tachycardia are mediated by vascular and myocardial 5-HT2 receptors. No evidence was obtained for a central sympatho-excitatory effect.     

Respiratory effects produced by microinjection of l-glutamate and an uptake inhibitor of l-glutamate into the caudal subretrofacial area of the medulla

The purposes of our study were to determine the type of respiratory changes that would occur when either an excitatory amino acid receptor agonist or an uptake inhibitor was administered into the caudal subretrofacial area. This was done by microinjecting either l-glutamate or l-pyrrolidine-2,4-dicarboxylate (l-trans-2,4-PDC) into the caudal subretrofacial area while monitoring tidal volume, respiratory rate, mean arterial blood pressure and heart rate. Bilateral microinjection of 2.5 nmol of l-glutamate into the caudal subretrofacial area produced apnea in eight of eight animals tested, and the duration of apnea was 27 ± 2 s. To determine the type of l-glutamate receptor responsible for mediating the apneic response, antagonists of the N-methyl-d-aspartate (NMDA) and non-NMDA receptor, namely, 3-[(RS)-carboxypiperazin-4-yl]-propyl-phosphonic acid (CPP), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively, were tested. Neither antagonist in doses that blocked NMDA (in the case of CPP) and amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) (in the case of CNQX) blocked apnea elicited by l-glutamate. In addition, kynurenic acid, an antagonist of NMDA and non-NMDA ionotropic receptors, failed to block the effect of l-glutamate. Microinjection of the metabotropic receptor agonist drug, trans-l-1-amino-1,3-cyclopentone-dicarboxylic acid (l-trans-ACPD), into the caudal subretrofacial area failed to have any effect on respiratory activity. Because of the inability to block the effect of l-glutamate in the caudal subretrofacial area, and the lack of effect of l-trans-ACPD, the data suggest that the apneic response produced by l-glutamate is mediated by an as yet undefined receptor. Microinjection of the l-glutamate uptake inhibitor, l-trans-2,4-PDC, was found to produce apnea. Using the dose of 0.5 nmol of l-trans-2,4-PDC, we examined the type of excitatory amino acid receptor that mediated the response. Neither pretreatment with the NMDA receptor antagonist, CPP, nor the non-NMDA receptor antagonist, CNQX, affected l-trans-2,4-PDC-induced apnea. However, combined use of these two antagonists prevented l-trans-2,4-PDC-induced apnea. These data suggest that the effect of synaptically released exitatory amino acid at the caudal subretrofacial area on breathing is apnea, and that this effect is mediated by simultaneous activation of both NMDA and non-NMDA ionotropic receptors.     

Effect of lesions of the nucleus tractus solitarii on the cardiovascular actions of clonidine in conscious rats.

Clonidine has been postulated to produce cardiovascular effects, the most noticeable of which are hypotension and bradycardia, by interaction with the nucleus tractus solitarii (NTS), a cranial nucleus in the dorsal medulla. The experiments reported herein, examined the effects of clonidine (30 μg/kg, i.v.) prior to and following bilateral electrolytic lesioning of the NTS. The studies were performed in conscious, spontaneously hypertensive (SHR) and Wistar-Kyoto rats (WKY). Clonidine produced marked hypotension and bradycardia in conscious, NTS-intact SHR. Intact WKY exhibited a biphasic response to clonidine with an initial hypertension preceeding a moderate decrease in blood pressure. Heart rate responded similarly to the SHR. Lesioning of the NTS, in both SHR and WKY, induced hypertension. Virtual abolition of the hypotension and bradycardia to clonidine was noted in lesioned SHR upon subsequent administration of clonidine. Nucleus tractus solitarii lesioning in WKY did not significantly alter clonidine-induced hypotension; however, the initial hypertensive phase was abolished following lesioning and bradycardia was blunted. These results indicate that the NTS plays an important role in the mediation of both the hypotension and bradycardia seen with clonidine in SHR. The differing responses of SHR and WKY to clonidine after NTS lesions may also indicate altered functional roles for the NTS in these two strains.     

The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression

Our objective was to identify the sites of interaction of cannabinoids with cardiovascular sympathetic regulation in the rat. Effects on sympathetic tone were first determined in anaesthetised animals following i.v. administration of the drugs. Central effects were evaluated in anaesthetised rats receiving microinjections of cannabinoids into brain stem nuclei. Peripheral effects were identified in pithed rats with electrically stimulated sympathetic outflow.In anaesthetised and artificially ventilated rats, i.v. injection of the cannabinoid agonists WIN55212-2 and CP55940 decreased mean arterial pressure, heart rate and the plasma noradrenaline concentration. These effects were antagonized by the CB(1) cannabinoid receptor antagonist SR141716A. The bradycardia was abolished by the muscarinic acetylcholine receptor antagonist methylatropine. The decreases in mean arterial pressure and heart rate caused by cannabinoids in ventilated rats were much less pronounced than in spontaneously breathing rats. Microinjection of WIN55212-2 into the nucleus tractus solitarii had no effect. Microinjected into the rostral ventrolateral medulla oblongata, WIN55212-2 lowered mean arterial pressure slightly without changing other parameters. In pithed rats, WIN55212-2 inhibited the increases in mean arterial pressure, heart rate and the plasma noradrenaline concentration evoked by electrical stimulation of the sympathetic outflow.Our results show that activation of CB(1) cannabinoid receptors induces sympathoinhibition and enhancement of cardiac vagal tone, leading to hypotension and bradycardia. Presynaptic inhibition of noradrenaline release from terminals of postganglionic sympathetic neurons is the major component of the sympathoinhibition, but an effect in the rostral ventrolateral medulla oblongata may also contribute. The cannabinoid-evoked cardiovascular depression depends strongly on the respiratory state of the animals.     

Microinjections of 5-HT1A agonists into the dorsal motor vagal nucleus produce a bradycardia in the atenolol-pretreated anaesthetized rat.

1. The effects of microinjections (100 nl) into the dorsal motor vagal nucleus of the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and flesinoxan, the 5-HT2 receptor agonist (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), the 5-HT3 receptor agonist phenylbiguanide (PBG), the alpha 2-adrenoceptor agonist clonidine and the excitatory amino acid glutamate on heart rate, blood pressure, tracheal pressure and phrenic nerve activity were investigated in atenolol-pretreated rats anaesthetized with sodium pentobarbitone. 2. Microinjections of glutamate (2.5 nmol) caused decreases in blood pressure, heart rate and phrenic nerve activity. In contrast, microinjections of 5-HT (1.2 nmol), 8-OH-DPAT (1.2 nmol) and flesinoxan (1.3 nmol) all caused a bradycardia but had no effect on blood pressure. In addition, 8-OH-DPAT and flesinoxan caused an increase in phrenic nerve activity. 3. Microinjections of DOI, PBG and clonidine had no significant effect on any of the variables recorded. None of the drugs used had any significant effect on tracheal pressure. 4. These results support the hypothesis that activation of 5-HT1A receptors causes excitation of cardiac vagal motoneurones and suggest that these receptors are also important in the control of central respiratory drive.     

Microinjection of S-nitrosocysteine into the nucleus tractus solitarii of conscious rats decreases arterial pressure but L-glutamate does not.

Unilateral microinjection of L-glutamate into the nucleus tractus solitarii of conscious rats increased arterial pressure and caused bradycardia while microinjection of S-nitrosocysteine into the same site of these animals caused hypotension and bradycardia. The responses to S-nitrosocysteine were blocked by prior microinjection of methylene blue into the nucleus tractus solitarii. The bradycardia and fall in arterial pressure induced by S-nitrosocysteine resemble more the cardiovascular changes in response to activation of baroreceptor afferents than the bradycardia and increase in arterial pressure induced by microinjection of L-glutamate into the nucleus tractus solitarii of conscious rats.     

Site-dependent inhibition of neuronal c-jun in the brainstem elicited by imidazoline I1 receptor activation: role in rilmenidine-evoked hypotension

Clonidine (a mixed alpha2-adrenoceptor and imidazoline I1 receptor agonist)-evoked hypotension was associated with dissimilar reductions in c-jun gene expression in the rostral ventrolateral medulla (RVLM) and the nucleus tractus solitarius (NTS) in normotensive rats. In the present study, we investigated the relative contribution of the alpha2-adrenoceptor vs. the imidazoline I1 receptor to the reduction in c-jun gene expression in these two brainstem areas. In conscious spontaneously hypertensive rats (SHRs), equihypotensive doses of three centrally acting hypotensive drugs with different selectivity for the two receptors were administered intracisternally (4 microl) to limit their actions to the brain. As a control, a similar hypotensive response was elicited by i.v. hydralazine. Clonidine (0.5 microg), or alpha-methylnorepinephrine (alpha-MNE, 4 microg), a highly selective alpha2-adrenoceptor agonist, similarly reduced c-jun mRNA expression in the NTS and rostral ventrolateral medulla. In contrast, a similar hypotensive response (-37+/-3.5 mm Hg) caused by the selective imidazoline I1 receptor agonist rilmenidine (25 microg) was associated with reduction in c-jun mRNA expression in the rostral ventrolateral medulla, but not in the NTS. Further, intra-rostral ventrolateral medulla rilmenidine (40 nmol) reduced c-Jun protein expression in rostral ventrolateral medulla and blood pressure and both responses were antagonized by selective imidazoline I1 receptor (efaroxan, 4 nmol), but not alpha2-adrenoceptor (SK&F 86466, 10 nmol) blockade. These results suggest: (1) the c-jun containing neurons in the brainstem are involved in the centrally mediated hypotension elicited by centrally acting antihypertensive agents, and (2) the alpha2-adrenoceptor modulates c-jun gene expression in the NTS and rostral ventrolateral medulla implicated in centrally mediated hypotension, and (3) the imidazoline I1 receptor mediated inhibition of c-jun gene expression in the rostral ventrolateral medulla, but not in the NTS, contributes to the centrally mediated hypotension by the second generation drugs.