Effect of chronic clonidine treatment on the turnover of noradrenaline and dopamine in various regions of the rat brain

Summary The turnover of noradrenaline (NA) and dopamine (DA) was estimated in various rat brain regions by measuring the depletion of the amines after inhibition of their biosynthesis by -methyltyrosine. Acute treatment with clonidine (0.1 mg/kg) reduced NA turnover in the brain stem, hypothalamus and rest of the brain but had no effect on DA turnover in the corpus striatum and rest of the brain. After chronic clonidine treatment (0.1 mg/kg, twice daily for 15 days), NA turnover was not affected by an additional injection of clonidine in the brain stem or in the hypothalamus but was still markedly reduced in the rest of the brain. In addition, DA turnover was reduced in the corpus striatum and rest of the brain, an effect which was also observed after a single injection of a high dose of clonidine (1 mg/kg). These findings suggest that a chronic administration of clonidine may cause regionally differential changes in the sensitivity of central NA receptors.     

Effect of prolonged clonidine treatment and its withdrawal on noradrenaline turnover in the cerebral cortex and medulla oblongata of the spontaneously hypertensive rat

Summary We have investigated the effect of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.5 mg-kg^–1 · 24 h^–1 for 10 days) and of withdrawal of this treatment on ingestive behaviour and on the cerebral turnover of noradrenaline in the adult spontaneously hypertensive rat (SHR). Clonidine amplified the fall in food and water intakes induced by minipump implantation. Ingestive behaviour returned to normal by the 4th to the 5th day in controls and by the 7th to the 8th day in clonidinetreated SHR. Clonidine withdrawal produced an increase in water intake above pre-implantation values. Body weight fell during clonidine treatment, then recovered slightly during withdrawal. After 5 days' treatment total DOPEG levels (an index of noradrenaline turnover) were reduced in cerebral cortex and medulla oblongata. The noradrenaline metabolite levels increased following withdrawal of drug treatment, the increase being more marked and faster in onset in cerebral cortex than in medulla oblongata. Thus prolonged treatment with clonidine decreases noradrenaline turnover and withdrawal of such treatment increases turnover. Send offprint requests to J. Atkinson at the above address     

Inhibition of noradrenaline uptake 2 in the isolated rat heart by steroids, clonidine and methoxylated phenylethylamines

Various steroids (corticosterone, testosterone, progesterone, β-oestradiol) produced a dose-dependent inhibition of the uptake of ³H-noradrenaline by the uptake₂ mechanism in the isolated perfused rat heart. These compounds were potent and selective inhibitors of uptake₂, with the exception of β-oestradiol which also inhibited noradrenaline accumulation in sympathetic nerves by the uptake₁ mechanism. The hypotensive drug, clonidine, was a moderately potent and highly selective inhibitor of uptake₂. Uptake was also inhibited by certain methoxylated phenylethylamine derivatives, but was unaffected by cocaine, desipramine, amitriptyline, angiotensin, histamine, ethanol or prostaglandins.     

Piperoxane reduces the effects of clonidine on aggression in mice and on noradrenaline dependent hypermotility in rats

Aggression in isolated male mice and hypermotility in rats produced by the noradrenaline releaser H 77/77 were studied after the s.c. administration of the alpha-adrenergic agonist clonidine and the alpha-antagonist piperoxane. Clonidine 0.005--0.5 mg/kg inhibited both behaviours while piperoxane showed a weak and short-lasting antiaggressive effect and no H 77/77 antagonism. Inactive doses of piperoxane reduced the inhibitory effects of clonidine. The results indicate that isolation-induced aggression in mice and H 77/77-induced hypermotility in rats are behavioural signs related to the availability of noradrenaline at the receptor.     

Inhibition of sympathetic transmission in rat heart by clonidine: The roles of stimulation frequency,endogenous feedback and noradrenaline re-uptake

Summary The inhibitory effects of clonidine were compared with other procedures which reduce the effector response to sympathetic cardioaccelerator nerve stimulation in the pithed rat. The effect of clonidine was most marked against responses to stimulation with relatively short trains of pulses and/or low frequencies of stimulation but a similar effect could be achieved by stimulating fewer fibres, by pretreating the rats with reserpine or by acute administration of guanethidine or propranolol. Unlike the other procedures, however, clonidine did not abolish responses. The effects of clonidine were similar whether or not endogenous -adrenoceptor-mediated feedback could be demonstrated. After blockade with cocaine of the neuronal re-uptake of transmitter noradrenaline, the inhibitory effect of clonidine was undiminished when the effect of cocaine on the frequency/response curve was taken into account. It is concluded that with frequencies and train lengths within the physiological range relative resistance to the inhibitory effect of clonidine is more dependent on post-junctional summation than on the development of pre-junctional facilitation or feedback mechanisms. Even with a single stimulus, however, the inhibitory effect of clonidine was limited suggesting that a portion of transmitter release is inaccessible to such blockade.     

Biochemical evidence that brainstem adrenaline-containing neurons are activated during clonidine withdrawal in the spontaneously hypertensive rat

Summary We have investigated the effects of prolonged treatment with clonidine (delivered intravenously via osmotic minipumps, 0.1 mg/kg/day for 7 or 10 days) and of withdrawal of such treatment on brainstem noradrenaline and adrenaline metabolism in the adult spontaneously hypertensive rat (SHR). After a seven day treatment with clonidine, noradrenaline and adrenaline turnovers were unchanged both in the A2-C2 and A1-C1 regions. During withdrawal, the noradrenaline turnover was also unchanged in these regions. However, the adrenaline turnover was significantly increased 16 h after withdrawal (p < 0.01) in the A2-C2 region and 16 h (p < 0.01) and 40 h (p < 0.05) after withdrawal in the A1-C1 region. These results show that noradrenaline metabolism is unchanged both during clonidine treatment and during its withdrawal in the brainstem catecholaminergic regions analyzed. In contrast, the increases in adrenaline turnover found in the A2-C2 and A1-C1 regions suggest that the adrenergic neurons of the brainstem could be activated during clonidine withdrawal. As the adrenergic CI neurons are a key element of the sympathetic vasopressor system, the increase in adrenaline turnover observed during withdrawal could be at the origin of the sympathetic hyperactivity found after cessation of prolonged treatment with clonidine. Send offprint requests to L. Lambás-Señas at the above address     

Effects of clonidine on the rate of noradrenaline turnover in discrete areas of the rat central nervous system

Turnover of noradrenaline in various regions of the rat brain was estimated by the decrease in noradrenaline content and/or formaldehyde-induced catecholamine fluorescence after inhibition of noradrenaline biosynthesis with alpha-methyl-p-tyrosine. Clonidine (0.1 and 0.3 mg/kg p.o.) decelerated the decrease in noradrenaline content of the locus coeruleus, the nucleus of the solitary tract, the intermediolateral cell column and the ventral horn of the thoracic spinal cord, as measured in tissue punches of the respective regions with a sensitive radioenzymatic method. In all these central regions the clonidine-induced decrease in noradrenaline turnover was antagonized by yohimbine, but not by phenoxybenzamine, indicating mediation through central alpha 2-adrenoceptors, similar to the cardiovascular effects of clonidine. When given alone, both yohimbine and phenoxybenzamine accelerated the disappearance of noradrenaline after inhibition of its biosynthesis. The combined results of radioenzymatic assay and fluorescence histochemistry determinations demonstrated that clonidine markedly reduced noradrenaline turnover in central noradrenaline-containing nerve terminals, but had no effect on the cell bodies of the A1 and A2 cell groups. Noradrenaline turnover was, however, decreased in projection areas of the A1 and A2 cell groups, namely the intermediolateral cell column of the spinal cord and nucleus of the solitary tract, respectively. This observation argues against the existence of a neuronal feedback loop running from the projection areas to the cell bodies of the A1 and A2 cell groups and mediating inhibition of noradrenaline turnover. The effect of clonidine on noradrenaline turnover is, therefore, most likely the result of a local feedback inhibition through presynaptic alpha-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of chronic administration of nicotine on the turnover and metabolism of noradrenaline in the rat brain

Chronic administration of nicotine (0.5 mg/kg, subcutaneously, 3 to 5 times a day for 6 weeks) accelerated the rate of disappearance of intraventricularly administered ³H-noradrenaline from rat brain. This was associated with normal levels of ³H-normetanephrine suggesting an increase in intraneuronal deamination.The rate constant of amine decline (k) in animals chronically treated with nicotine was significantly greater than that of controls, while the steady state level of brain noradrenaline was about equal in both groups of rats. Amphetamine, reserpine, acetylcholine, histamine, pheniprazine, pargyline, and nicotine affected the catecholamine levels in the rat brain treated with nicotine to the same degree as they did in the controls. It is concluded that chronic administration of nicotine may increase noradrenaline turnover in the brain and possibly increase the deamination of this amine.     

Clonidine but not nifedipine prevents the release of noradrenaline during naloxone-precipitated opiate withdrawal: an in vivo microdialysis study in the rat

In this study we have examined whether the ₂-adrenoceptor agonist clonidine and the calcium channel antagonist nifedipine firstly inhibit the naloxone-precipitated withdrawal syndrome in morphine-dependent rats and secondly reduce central noradrenaline release during withdrawal. We demonstrate that both clonidine (0.1 mg/kg) and nifedipine (10 mg/kg) attenuate the naloxone-precipitated withdrwal syndrome. Using in vivo microdialysis, we demonstrate that following naloxone the release of noradrenaline, as measured by perfusates from hippocampus, increases 300% in morphine-dependent rats. However, whilst pretreatment with clonidine inhibited this increased noradrenaline release, nifedipine did not. These findings suggest that whilst the action of clonidine in attenuating the morphine withdrawal syndrome may be mediated by decreasing central noradrenline release, this is not the mechanism by which nifedipine acts.     

Difference in the turnover of noradrenaline in rat heart during day and night

Summary In male Wistar rats (TNO W. 70), kept under constant conditions of illumination and darkness (12:12 h), the noradrenaline turnover in the heart was determined during the phases of illumination and darkness, respectively. With two different methods a significantly faster cardiac turnover of noradrenaline was found in animals studied during the 12 h of darkness. The experiments show that a circadian rhythm is of importance when one studies the effect of drugs on the turnover of noradrenaline.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

Chronic treatment of the spontaneously hypertensive rat with captopril attenuates responses to noradrenaline in vivo but not in vitro

Summary We have studied the attenuation by captopril of sympathetic neurotransmission in spontaneously hypertensive rats. Captopril (4 mg/kg for 15–17 days or 20 mg/kg for 4 days) was delivered i.v. by osmotic minipump. The higher dose lowered blood pressure, the lower dose did not. Both doses inhibited converting enzyme activity. In the pithed rat, both doses attenuated responses to exogenous noradrenaline and sympathetic nerve stimulation. In isolated tail arteries removed from captopril-treated rats, responses to sympathetic nerve stimulation and exogenous noradrenaline were the same as in controls. Perfusion of the tail artery of control rats with captopril, angiotensin I or angiotensin II had no effect on basal perfusion pressure or on vasoconstriction induced by exogenous noradrenaline or sympathetic nerve stimulation. Our results are consistent with the hypothesis that: 1. the attenuation of sympathetic neurotransmission by captopril depends upon the presence of an intact renin-angiotensin system, and 2. captopril has no direct postsynaptic effect in the isolated tail artery preparation. Send offprint requests to J. Atkinson at the above address     

Studies on the possible contribution of a peripheral presynaptic action of clonidine and dopamine to their vascular effects under in vivo conditions

Summary The functional consequences of drug-induced stimulation under in vivo conditions of -adrenoceptors and dopamine receptors at vascular adrenergic nerve endings (presynaptic receptors) was studied in the autoperfused hindquarters or hindlegs of cats anaesthetized with urethane. The changes in perfusion pressure in response to electrical stimulation of the lumbar sympathetic chain were taken as a measure of noradrenaline release from the vascular adrenergic nerves. Presynaptic inhibitory -adrenoceptors and dopamine receptors were activated by clonidine and dopamine, respectively. According to in vitro experiments these two drugs are more potent stimulants of peripheral presynaptic than postsynaptic receptors. The lowest frequency of stimulation of the lumbar sympathetic chain which yielded a reproducible pressor response was 4 Hz for the autoperfused hindquarters and 1 Hz for the hindlegs. Clonidine was tested over a wide dose range (1–100 g/kg i.v.). A reduction of the stimulation-induced pressor response in the autoperfused hindquarters or hindlegs was observed only after the rather high dose of 100 g/kg of clonidine. The inhibition was marked at low frequencies of stimulation (1–4 Hz) and weak or absent at high frequencies (16 and 32 Hz). The dose of clonidine (100 g/kg) which proved to be effective at presynaptic receptors produced a transient increase in blood pressure and in perfusion pressure of the hindquarters and hindlegs and virtually abolished spontaneous sympathetic nervous activity. In spinal cats, the clonidine-induced increases in blood pressure and perfusion pressure were very pronounced and of rather long duration. Thus, under in vivo conditions clonidine showed no selectivity for presynaptic -adrenoceptors in a blood-perfused vascular bed, and its presynaptic action was negligible as compared to its powerful central sympatho-inhibitory effect.Dopamine was constantly infused into the autoperfused hindquarters or hindlegs at increasing rates until a vasoconstriction due to stimulation of vascular (postsynaptic) -adrenoceptors occurred. The monoamine did not inhibit the stimulation-induced increases in perfusion pressure of the autoperfused hindquarters or hindlegs and, thus, an effect on presynaptic receptors was not found. The results underscore the importance of in vivo experiments for assessing the therapeutic significance of drug-induced stimulation of presynaptic receptors.Part of the results has been presented at the 16th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, 1975)     

Evidence that the dorsal raphe area is involved in the effect of clonidine against pentylenetetrazole-induced seizures in rats

Summary Injections of 5,7-dihydroxytryptamine (5,7-DHT) in the rat ventromedial tegmentum, which depleted forebrain serotonin, and of 6-hydroxydopamine in the dorsal noradrenergic bundle, which causes a marked reduction of forebrain noradrenaline, intensified pentylenetetrazol (PTZ)-induced seizures. Neither condition significantly modified the inhibitory effect of 0.5 mg/kg clonidine on PTZ-induced seizures, with the exception of the effect on mortality which was reduced in 5,7-DHT treated animals. Electrolytic lesions in the nucleus raphe medianus or dorsalis potentiated PTZ-induced seizures but only lesions in the nucleus raphe dorsalis significantly attenuated the effect of clonidine on tonic seizures and mortality. Both lesions reduced clonidine's effect on latency to the first convulsion.The results indicate that the dorsal raphe area plays a role in the inhibitory effect of 0.5 mg/kg clonidine on PTZ-induced seizures. Serotonin neurons other than those innervating diencephalic and telencephalic structures may also contribute, particularly to the effect of clonidine on tonic seizures.     

垂体中叶素对去甲肾上腺素诱导乳鼠心肌细胞凋亡的影响

目的 观察垂体中叶素(IMD)对去甲肾上腺素(NE)诱导的乳鼠心肌细胞凋亡的影响.方法 20孔原代培养的乳鼠心肌细胞完全随机分为5组,各4孔:正常对照组、NE组、IMD组、降钙素基因相关肽(CGRP)8-37组和肾上腺髓质素(ADM)22-52组.NE组加入1×10-6mol/L NE,IMD组在加NE前30 min加入1×10-8mol/L IMD,CGRP8-37组和ADM22-52组在加IMD前30 min分别加入1×10-7mol/L CGRP8-37与1×10-7mol/L ADM22-52.采用流式细胞仪检测心肌细胞凋亡率并测定半胱氨酸天冬氨酸蛋白酶(Caspase)-3活性.结果 与正常对照组比较,NE组心肌细胞凋亡率和Caspase-3活性均升高[分别为(31.95±6.33)%比(8.70±3.92)%,(2.97±0.20)%比(1.00±0.15)%,均P＜0.05];IMD组的凋亡率和Caspase-3活性[分别为(11.57±4.69)%、(1.34±0.18)%]比NE组明显降低(P＜0.05);CGRP8-37组和ADM22-52组细胞凋亡率[分别为(21.84±5.48)%、(23.43±6.54)%]和Caspase-3活性[分别为(2.15±0.23)%、(2.31±0.26)%]比IMD组明显增高(P＜0.05).结论 IMD通过与CGRP受体和ADM受体结合抑制乳鼠心肌细胞凋亡,对NE诱导的心肌细胞损伤具有防护作用.

Abstract：

Objective To investigate the effect of intermedin (IMD)on neonatal rat cardiomyocytes apoptosis induced by noradrenaline (NE). Methods Totally 20 cultured neonatal rats cardiomyocytes were randomly divided into S groups:control group, NE group, IMD group,calcitonin-gene-relatedpeptide(CGRP)8-37 group and adrenal medulla(ADM)22-52 group. Cultured cardiomyocytes were given 10-6 mol/L NE. At 30 min before administration of NE, IMD was added into the culture fluid in IMD group. CGRP8-37 or ADM22-52 were added at 30 min before IMD administration in CGRP8-37 group and ADM22-52 group respectively. Cardiomyocvte apoptotic rate (AR) and Caspase-3 activity were detected. Results Compared with control group, AR and Caspase-3 activity increased in NE group[(31.95±6.33)% vs (8.70±3.92)%,(2.97±0.20)% vs (1.00±0.15)% ,P＜0.05]. AR and Caspase-3 activity decreased significantly in IMD group compared with NE group(P＜0.05). AR and Caspase-3 activity were higher in CGRP8-37 group and ADM22-52 group than those in IMD group (P＜ 0. 05). Conclusion IMD can attenuate cardiomyocyte apoptosis induced by NE through CGRP receptor and ADM receptor.     

The action of trelibet, a new antidepressive agent on [H]noradrenaline release from rabbit pulmonary artery

Trelibet, a new antidepressant, used at 10⁻⁷–10⁻⁴ M failed to affect the [³H]noradrenaline ([³H]NA) release evoked from the isolated main pulmonary artery of the rabbit low frequency (2 Hz) nerve stimulation whether the neuronal uptake inhibitor cocaine (3 × 10⁻⁵ M) was present or not. Its metabolite (EGYT-2760) however, potentiated the nerve-evoked release of [³H]NA. In the absence of cocaine both the resting and the stimulation-evoked release of ³H increased in response to EGYT-2760. These effect were accompanied by muscle contraction. The EGYT-2760-potentiated transmitter release was inhibited either by exogenously applied 1-noradrenaline (10⁻⁶ M) or clonidine (10⁻⁶ M), preferential agonists of presynaptic ₂-adrenoceptors. The 1-noradrenaline-induced inhibition of transmitter release potentiated by EGYT-2760 was antagonized by 3 × 10⁻⁷ M yohimbine, a preferential ₂-adrenoceptor inhibitor. In the absence of cocaine, Ca²⁺ removal from the external medium failed to affect the ³H outflow-increasing effect of EGYT-2760 but abolished the nerve-evoked release-potentiating action of this compound. It is concluded that the metabolite of trelibet exerts a ‘yohimbine-like’ action, as well as a ‘tyramine-like’ effect in peripheral sympathetic nerve fibres.     

Diurnal rhythm in the central dopamine turnover in the rat

Summary Under controlled conditions of environmental light and darkness of 12:12 h the turnover of dopamine and noradrenaline in brain of male Wistar rats was studied at different times of the day. The turnover was calculated from the decline of the amine concentrations either after inhibition of the tyrosine-hydroxylase with H 44/68 (200 mg/kg, i.p.) or after inhibition of the dopamine--hydroxylase with FLA 63 (40 mg/kg s.c.). Whereas the noradrenaline turnover showed only slight but not significant variations within 24 h, the turnover of the central dopamine exhibited significant variations with increased turnover rates in the second half of the light and first half of the dark period. Thus, diurnal variations have to be taken into account when studying the effects of drugs on the turnover of biogenic amines in the central nervous system.Parts of this work were presented at the 16th Spring-Meeting of the German Pharmacological Society, Mainz 1975 (Lemmer and Berger, 1975a) and at the Int. Congr. on Rhythmic Function in Biological Systems, Vienna 1975 (Lemmer and Berger, 1975b)     

Effect of clonidine on heart rate in dogs with acute or chronic heart block

In chloralosed dogs with surgically induced heart block, clonidine provoked a slowing of the atrial and ventricular rhythms. In vagotomized dogs, a decrease in atrial rates was also observed after clonidine, but in this case, there was a higher degree of depression in the idioventricular rhythm than in animals with intact vagi. The depression in the idioventricular rhythm reflects a direct peripheral action of clonidine. The same ventricular slowing was observed in non-anesthetized dogs with chronic heart block. Atropine had no effect.     

The effects of acute administration of propranolol and practolol on the uptake,content, release,and turnover of noradrenaline in the rat heart in vivo

Summary The effect of the acute administration of (±)-, (+)-, and (–)-propranolol and practolol, respectively, on the cardiac turnover of noradrenaline was studied in male Wistar rats kept under controlled conditions of environmental lighting. Propranolol caused no or only minor effects on the turnover in concentrations of 0.001–0.1 mmoles/kg, whereas higher doses (0.2–0.4 mmoles/kg) decreased the noradrenaline turnover in rat hearts concomitantly with toxic signs from the CNS. The endogenous noradrenaline content was not changed by any concentration of propranolol. Practolol (0.1–0.4 mmoles/kg) did not influence the cardiac noradrenaline turnover, but, like an indirectly acting sympathomimetic drug, released noradrenaline.Supported by a grant of the Deutsche Forschungsgemeinschaft.     

Forskolin and the release of noradrenaline in cerebrocortical slices

Summary The role of adenosine 3,5-cyclic monophosphate (cAMP) in the release of noradrenaline from central neurones has been investigated by examining the effects of forskolin, 3-isobutyl-1-methylxanthine (IBMX), cis-6-(p-acetamidophenyl)-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methylbenzo[c] [1,6]-naphthyridine bis (hydrogenmaleinate) (AH21-132; a new phosphodiesterase inhibitor) and N⁶, O²-dibutyryl-adenosine 3,5-cyclic monophosphate (dibutyryl-cAMP) on the outflow of tritiated compounds from rat and rabbit cerebral cortex slices preincubated with [³H]-noradrenaline. Forskolin, IBMX, AH21-132 and dibutyryl-cAMP produced a concentration-dependent increase in both basal and electrically-evoked efflux of tritium from rat and rabbit cortex slices. The increase in basal tritium efflux from rabbit cortex slices elicited by forskolin and IBMX could be attributed mainly to an increase in [³H]-DOPEG although a small increase in [³H]-noradrenaline was also observed. Forskolin and (when combined with noradrenaline) IBMX and AH21-132 increased the cAMP content of rat cortex slices at similar or somewhat higher concentrations that they increased tritium efflux. Neither forskolin nor IBMX or AH21-132 had any effect on the cocaine-sensitive uptake of [³H]-noradrenaline into synaptosomes prepared from rat or rabbit cortex. The effects of forskolin, IBMX and dibutyryl-cAMP on electrically-evoked overflow of tritium from rat and rabbit cortex slices were reduced when cocaine (10 M) was present in the superfusion medium, although forskolin produced a similar increase in cAMP in the absence or presence of cocaine. It is suggested that cAMP may facilitate the normal process of noradrenaline release by nerve stimulation.     

Effects of clonidine on the baroreceptor-heart rate reflex and on single aortic baroreceptor fibre discharge

The effects of clonidine (Catapres^®) on the baroreceptor-heart rate reflex were studied in unanaesthetized rabbits, and its action on single aortic baroreceptor fibre discharge was examined under anaesthesia. Intravenous clonidine (bolus 2.5 to 10 μg/kg + infusion of 0.25 to 1.5 μg/kg/min) altered the mean arterial pressure (MAP) — heart period (HP; pulse interval) curve, reducing median blood pressure and increasing the gain and heart period range (HPR). At low dose increased HPR by enhancing both vagal excitation and sympathetic inhibition of HP during a rise in MAP, compared with control conditions. At high i.v. dose of drug sympathetic inhibition was complete even at low MAP, and HPR increased due to a rise in vagal output to 4–6 times control. Lateral ventricle injections of 0.5 to 1.5 μg/kg of clonidine altered MAP - HP curve parameters in a similar manner as i.v. infusion. High dose of clonidine i.v. enhanced single aortic baroreceptor fibre discharge at a given MAP in anaesthetized animals, but there was no effect at low dose. Clonidine alters heart rate mainly through its direct central action on the baroreceptor pathways; at high dose these effects are reinforced by peripheral baroreceptor resetting. Clonidine has only slight effects on cardiac motoneurones not receiving baroreceptor projections.