Central Adrenergic Mechanisms Research Articles

Altered urinary sodium excretion response after central cholinergic and adrenergic stimulation of adult spontaneously hypertensive rats.

In this study, we hypothesized that blunting of the natriuresis response to intracerebroventricularly (i.c.v.) microinjected cholinergic and adrenergic agonists is involved in the development of hypertension in spontaneously hypertensive rats (SHR). We evaluated the effect of i.c.v. injection of cholinergic and noradrenergic agonists, at increasing concentrations, and of muscarinic cholinergic and α1 and α2-adrenoceptor antagonists on blood pressure and urinary sodium handling in SHR, compared with age-matched Wistar Kyoto rats (WR). We confirmed that CCh and NE microinjected into the lateral ventricle (LV) of conscious rats leads to enhanced natriuresis. This response was associated with increased proximal and post-proximal sodium excretion accompanied by an unchanged rate of glomerular filtration. We showed that cholinergic-induced natriuresis in WR and SHR was attenuated by previous i.c.v. administration of atropine and was significantly lower in the hypertensive strain than in WR. In both groups the natriuretic effect of injection of noradrenaline into the LV was abolished by previous local injection of an α1-adrenoceptor antagonist (prazosin). Conversely, LV α2-adrenoceptor antagonist (yohimbine) administration potentiated the action of noradrenaline. The LV yohimbine pretreatment normalized urinary sodium excretion in SHR compared with age-matched WR. In conclusion, these are, as far as we are aware, the first results showing the importance of interaction of central cholinergic and/or noradrenergic receptors in the pathogenesis of spontaneous hypertension. These experiments also provide good evidence of the existence of a central adrenergic mechanism consisting of α1 and α2-adrenoceptors which works antagonistically on regulation of renal sodium excretion.

Bupleurum falcatum Prevents Depression and Anxiety-Like Behaviors in Rats Exposed to Repeated Restraint Stress

Previous studies have demonstrated that repeated restraint stress in rodents produces increases in depression and anxietylike behaviors and alters the expression of corticotrophinreleasing factor (CRF) in the hypothalamus. The current study focused on the impact of Bupleurum falcatum (BF) extract administration on repeated restraint stress-induced behavioral responses using the forced swimming test (FST) and elevated plus maze (EPM) test. Immunohistochemical examinations of tyrosine hydroxylase (TH) expression in rat brain were also conducted. Male rats received daily doses of 20, 50, or 100 mg/kg (i.p.) BF extract for 15 days, 30 min prior to restraint stress (4 h/day). Hypothalamicpituitary- adrenal axis activation in response to repeated restraint stress was confirmed base on serum corticosterone levels and CRF expression in the hypothalamus. Animals that were pre-treated with BF extract displayed significantly reduced immobility in the FST and increased open-arm exploration in the EPM test in comparison with controls. BF also blocked the increase in TH expression in the locus coeruleus of treated rats that experienced restraint stress. Together, these results demonstrate that BF extract administration prior to restraint stress significantly reduces depression and anxiety-like behaviors, possibly through central adrenergic mechanisms, and they suggest a role for BF extract in the treatment of depression and anxiety disorders.

Mechanisms of Regulation of Erythropoiesis during Experimental Neuroses

We studied the mechanisms of erythropoiesis regulation in a conflict situation and during paradoxical sleep deprivation. Plastic reconstruction of the erythroid hemopoietic stem during experimental neuroses is regulated by a complex multicomponent and multilevel system. This system consists of central adrenergic structures, sympathetic part of the autonomic nervous system, and alpha- and beta-adrenoceptors on erythroid precursors and cells of the hemopoietic microenvironment. Erythroid cells receive instructive information from the central nervous system via adrenoceptors on cells of the hemopoiesis-inducing microenvironment and erythroid precursors. Hyperplasia (conflict situation) and suppression of erythropoiesis (paradoxical sleep deprivation) are associated with specificity of central adrenergic regulatory mechanisms.

Responses of erythroid cells to different neurotic influences

Cells of the erythrocytic series develop hyperplasia in mice exposed to immobilization stress, conflict situation, or conflict situation while being deprived of REM sleep. These mice contain increased numbers of morphologically recognizable erythroid cells and erythroid cell precursors in the bone marrow, and culture media conditioned by their nonadherent or adherent karyocytes shows elevated erythropoietic activity. In contrast, bone marrow erythropoiesis is depressed for a long time in mice deprived of REM sleep and mice with and without experiencing a conflict situation. Probably, enhancement of erythropoiesis is due to activation of adrenergic mechanisms regulating hematopoiesis, while its depression is due to impaired operation of the central adrenergic mechanisms.

Heart rate effect of angiotensin II involves the area postrema and central alpha-1 adrenergic mechanisms

Heart rate effect of angiotensin II involves the area postrema and central alpha-1 adrenergic mechanisms

Propranolol Impairs the Hyperventilatory Response to Acute Hypercapnia in Rainbow Trout

ABSTRACT This study investigated the possible role of catecholamines in the ventilatory response of rainbow trout (Oncorhynchus mykiss) to acute external hypercapnia. The ventilatory response to hypercapnia [partial pressure of CO2 in water of fish pre-treated with the selective β-adrenoceptor antagonist, D,L-propranolol, was compared with that of D-propranolol (an isomer with minimal β-antagonistic activity) and saline pre-treated fish (sham). A sustained 3.6-fold increase in gill ventilation volume was observed in the sham and D-propranolol-treated groups during the 30min interval of hypercapnia. Fish pre-treated with D,L-propranolol displayed a blunted hyperventilatory response to hypercapnia (1.9-fold increase at 30min). These results indicate that the β-component of an adrenergic response is involved in the usual hyperventilatory response to external hypercapnia. It is suggested that the impaired hyperventilatory response of the D,L-propranolol-treated group reflects an inhibition of central adrenergic mechanism(s) involved in the hyperventilatory reflex to respiratory acidosis.

Selective stimulation of colonic motor response to a meal by σ ligands in dogs

The influence of central vs. peripheral administration of σ ligands (dl- and 1-N-allylnormetazocine, 1–3-di-o-tolylguanidine, (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene and phencyclidine on colonic motility was investigated in fasted and fed dogs equipped with strain-gauge transducers implanted on proximal and transverse colon. When injected intravenously at a dose of 0.25 mg/kg just before feeding, dl- or d-N-allylnormetazocine, 1–3-di-otolylguanidine, and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (but not phencyclidine) enhanced the colonic motor response to a meal by increasing the 0–4-hour motility indexes from 64.1%–159.3% in both the proximal and transverse colon but had no effect on colonic motility in fasted animals or animals injected intracerebroventricularly. The motor-stimulatory effects of d-N-allylnormetazocine (1 mg/kg), 1–3-di-o-tolylguanidine (0.25 mg/kg), and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene (1 mg/kg) were abolished after previous treatment with haloperidol (0.5 mg/kg, intravenous) but not after sulpiride (0.1 mg/kg) or (+) R-(+)-8-chloro2,3,4, 5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzozepine-OH. Prazosin (0.1 mg/kg, intravenous) and 1-methyl-3-(2-indolyl) amino-5-phenyl-3H-1, 4-benzodiazepin-2-one (0.01 mg/kg) also suppressed the enhancement of the colonic motor response to eating induced by d-N-allylnormetazocine, 1–3-di-o-tolylguanidine, and (+) cinnamyl-1-phenyl-1-N-methyl-N-cyclopropylene whereas naltrexone did not affect their effects. It is concluded that d-N-allylnormetazocine, 1–3-di-o-tolylguanidine, and (+) cinnamyl-1phenyl-1-N-methyl-N-cyclopropylene stimulate the postprandial colonic motility in dogs by acting selectively on σ receptors located peripherally and probably by affecting the release of cholecystokinin octapeptide through a central adrenergic mechanism.

Influence of long-term treatment with the Ca 2+-antagonists nifedipine, verapamil, flunarizine and with the calmodulin antagonist trifluoperazine on β-adrenoceptors in rat cerebral cortex

1. 1. The binding of [ 3H]dihydroalprenolol ([ 3H]DHA) to β-adrenoceptors in cerebral cortex membranes (fraction P 2) was studied after 13-day oral treatment of male Wistar rats with the Ca 2+-antagonists nifedipine (20 mg/kg), verapamil (50 mg/kg), flunarizine (10 mg/kg) and with the calmodulin (CaM)-antagonist trifluoperazine (TFP) (3 mg/kg). 2. 2. A significant reduction in the number ( B max) of binding sites for [ 3H]DHA was established after the 3 Ca 2+-antagonists as well as after TFP. 3. 3. No changes in the affinity values ( K d ) [ 3H]DHA binding were found in all treated groups. 4. 4. The fluidity characteristics of the cerebral cortex membranes in nifedipine- and flunarizine-treated rats did not differ from those in controls. 5. 5. Based on these results, we concluded that long-term treatment with Ca 2+-and calmodulin-antagonists might induce changes in the central adrenergic mechanisms.

Dexmedetomidine, Acting Through Central Alpha-2 Adrenoceptors, Prevents Opiate-Induced Muscle Rigidity in the Rat

The highly-selective alpha-2 adrenergic agonist dexmedetomidine (D-MED) is capable of inducing muscle flaccidity and anesthesia in rats and dogs. Intense generalized muscle rigidity is an undesirable side effect of potent opiate agonists. Although the neurochemistry of opiate-induced rigidity has yet to be fully elucidated, recent work suggests a role for a central adrenergic mechanism. In the present study, the authors determined if treatment with D-MED prevents the muscle rigidity caused by high-dose alfentanil anesthesia in the rat. Animals (n = 42) were treated intraperitoneally with one of the following six regimens: 1) L-MED (the inactive L-isomer of medetomidine), 30 micrograms/kg; 2) D-MED, 10 micrograms/kg; 3) D-MED, 30 micrograms/kg; 4) D-MED [30 micrograms/kg] and the central-acting alpha-2 antagonist, idazoxan [10 mg/kg]; 5) D-MED [30 micrograms/kg] and the peripheral-acting alpha-2 antagonist DG-5128 [10 mg/kg], or; 6) saline. Baseline electromyographic activity was recorded from the gastrocnemius muscle before and after drug treatment. Each rat was then injected with alfentanil (ALF, 0.5 mg/kg sc). ALF injection resulted in a marked increase in hindlimb EMG activity in the L-MED treatment group which was indistinguishable from that seen in animals treated with saline. In contrast, D-MED prevented alfentanil-induced muscle rigidity in a dose-dependent fashion. The small EMG values obtained in the high-dose D-MED group were comparable with those recorded in earlier studies from control animals not given any opiate. The high-dose D-MED animals were flaccid, akinetic, and lacked a startle response during the entire experimental period.(ABSTRACT TRUNCATED AT 250 WORDS)

Disturbances of sleep and wakefulness associated with the use of antihypertensive agents

Sleep disturbances are frequently associated with the use of antihypertensive drugs. They are observed mainly during the administration of drugs that affect central adrenergic mechanisms. β-adrenoceptor antagon its which readily penetrate into the brain (propranol o l, pindolol) increase wakefulness and/or decrease REM sleep. α 2-adrenoceptor agonists (clonidine, guanfacine) markedly reduce the duration of REM sleep. The catecholamine depleting agent reserpine increases REM sleep during single or repeated-dose administration, while the MAOI phenelzine shows opposite effects. The 5-HT2 antagonist ritanserin, which is chemically related to the antihypertensive agent ketanserin, increases slow wave sleep while REM sleep is decreased. Sleep disturbances have not been reported during the administration of calcium entry antagonists. However, they seem to modify the effects of hypnotics and CNS stimulants. There are no formal studies on the effects of angiotensin converting enzyme inhibitors and vasodilators on sleep in man.

Central adrenergic mechanisms in hemorrhage-induced vasopressin secretion.

The effect of central administration of specific adrenergic agonists and antagonists on hemorrhage-induced vasopressin secretion was studied in conscious rats. The intracerebroventricular (icv) injection of the alpha 2-antagonist yohimbine, the alpha 1-antagonist corynanthine, or the beta-agonist isoproterenol failed to alter the vasopressin or blood pressure responses to two sequential 10% reductions in blood volume. Administration of the beta-antagonist propranolol, however, resulted in a significant attenuation of the vasopressin response to hemorrhage, with little effect on the blood pressure response. The alpha 2-agonist, butylated hydroxytoluene (BHT) 933, caused an enhanced vasopressin response to hemorrhage, with a resulting improved maintenance in blood pressure. The results indicate that both alpha 2- and beta-adrenoreceptors may be involved in the pressure-volume control of vasopressin secretion.

Central adrenergic mechanisms of blood pressure regulation in spontaneously hypertensive rats

Central adrenergic mechanisms of blood pressure regulation in spontaneously hypertensive rats

Involvement of Vasopressin in the Cardiovascular Effects of Intracerebroventricularly Administered ??1-Adrenoceptor Agonists in the Conscious Rat

To determine the interaction between central adrenergic and vasopressinergic mechanisms in the regulation of cardiovascular function, the effects of intracerebroventricular (i.c.v.) administration of the alpha 1-agonists, methoxamine and phenylephrine, in conscious Long-Evans (LE) rats were compared with those in Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI). In LE rats, both i.c.v. methoxamine and phenylephrine increased mean arterial pressure (MAP) and decreased heart rate (HR) in a dose-related manner, while they had no effect on MAP and HR in DI rats within the dose range of 3-30 micrograms/kg. Both i.c.v. methoxamine (10 micrograms/kg) and phenylephrine (30 micrograms/kg) also increased plasma levels of arginine vasopressin (AVP) in LE rats from 2.6 +/- 0.4 (n = 9) to 22.4 +/- 3.5 (n = 6, P less than 0.01) and 37.0 +/- 4.0 pg/ml (n = 6, P less than 0.01), respectively, without affecting plasma renin activity (PRA) and plasma angiotensin II (ANG II) levels. Central alpha 1-adrenoceptor stimulation increases vasopressin release from the posterior pituitary, which in part is responsible for the hypertensive and bradycardic responses. However, central vasopressinergic pathways have also been shown to be involved in these cardiovascular effects. Neither i.c.v. nor intravenous (i.v.) infusion of AVP restored the cardiovascular response to i.c.v. alpha 1-agonists in DI rats. In LE rats, however, i.v. pretreatment with the specific vascular antagonist to the pressor effect of AVP, d(CH2)5Tyr(Me)AVP (VP-ANT; 10 micrograms/kg), significantly attenuated, but did not completely block the hypertensive and bradycardic effects of i.c.v. methoxamine and phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood pressure following microinjection of somatostatin related peptides into the rat nucleus tractus solitarii

The possible role of medullary somatostatin as a neurotransmitter involved in blood pressure regulation was examined. Blood pressure and heart rate were measured in pentobarbital anesthetized rats while pmol quantities of somatostatin-28 (SS28), SS28-(15–28) (somatostatin-14), SS28-(1–12) or SS28-1(1–10) were injected into the caudal nucleus tractus solitarii (NTS). Injection of artificial cerebrospinal fluid (ACSF; 500 nl/10 s) alone was followed by a small (2 mmHg) statistically insignificant decrease in blood pressure. SS28, SS28-(15–28) or SS28-(1–12) induced an immediate and statistically significant decrease in blood pressure as compared to vehicle alone. SS28-(1–10) had no significant effect. SS28 was tested at three doses. The lowest dose of SS28 (2.5 pmol) induced an 8 mmHg drop in blood pressure, the medium dose (25 pmol), an 11 mmHg drop and the highest dose (250 pmol) a 16 mmHg drop. The other peptide fragments were tested only at the higher 250 pmol dose. SS28-(1–12) induced a significantly (P < 0.01) less drop in blood pressure (10 mmHg) when compared to either SS28 or SS28-(15–28) (18–19 mmHg). The hypotensive and bradycardiac effects of SS28 were prevented by pretreatment with methylscopolamine (5 mg/kg i.p.) 10 min prior to SS28. The cardiovascular effects of intramedullary injected SS28 were also blocked with an ipsilateral NTS injection of yohimbine or tolazoline 10 min prior to SS28. These data indicate that the hypotension and bradycardia following the intramedullary injection of SS28 is mediated through the parasympathetic nervous system and that the C-terminal portion of SS28 and SS28-(15–28) is important for potency, but not obligatory, for efficacy. In addition, because two different adrenergic blocking agents can prevent the cardiovascular effects of somatostatin, central adrenergic mechanisms may be involved.

Chronic salt loading and central adrenergic mechanisms in the spontaneously hypertensive rat.

The effects of chronic salt loading on central adrenergic mechanisms were evaluated in spontaneously hypertensive rats maintained on tap water or 1.2% sodium chloride drinking water for 4 weeks. Basal blood pressure was increased by 10% in the high salt group. Central catecholamines were measured spectrofluorimetrically after cation exchange chromatography. Endogenous levels of noradrenaline (NA) were not influenced by salt loading but the NA turnover (disappearance of NA following synthesis inhibition by alpha-methyltyrosine) was increased in the hemisperes. Central alpha 2-adrenoceptor sensitivity was assessed as the clonidine-induced reduction in blood pressure and as the clonidine-induced deceleration of NA turnover and locus coeruleus (LC) NA cell firing rate (single unit recording). The results were slightly disparate but the unchanged sensitivity of clonidine to reduce LC NA cell firing suggests that there were no alterations in central alpha 2-adrenoceptor sensitivity following a salt load. There were also no changes in alpha 1-adrenoceptor function, which was assessed semiquantitatively as the clonidine-induced increase in flexor reflex activity in spinalized rats. In salt loaded rats there was an enhanced blood pressure and heart rate reduction following ganglionic blockade which may be interpreted as an increased basal sympathetic tone. In the periphery the pressor responses to phenylephrine were increased whereas the chronotropic response to isoprenaline was unchanged. In conclusion, in the spontaneously hypertensive rat on a high salt intake the aggravated development of hypertension was not associated with major changes in central alpha 1 and alpha 2-adrenoceptor mediated functions or in neuronal activity of brain stem NA neurons. There were indications of an increased basal sympathetic tone and increased blood pressure response to pressor substances.

Hypothalamic pressor responses and salt-induced hypertension in Dahl rats.

Hypothalamic pressor responses and salt-induced hypertension in Dahl rats.

Selective blockade of the responses of reticulo-ruminal muscle to 5-HT in sheep.

The effects of intravenous administration of 5-HT on the patterns of reticulo-rumen contractions were studied in conscious sheep. Contractions were measured by strain gauges applied to the external wall of the reticulum and the ventral and/or dorsal sac of the rumen. The responses to 5-HT comprised (i) a short-lived contraction followed by (ii) a sustained increase in muscle tone and (iii) a concomitant inhibition of the extrinsic reticulo-rumen contractions. The corresponding blockades produced by (i) atropine, (ii) 5-HT antagonists and (iii) chemical sympathectomy suggest involvement of a peripheral cholinergic mechanism in the initial contractile response and a central adrenergic mechanism in the reflex inhibition of extrinsic reticulo-rumen contractions.

The effect of diethyldithiocarbamate on brain uptake of cadmium

A previous study in mice has shown that the chelating agent diethyldithiocarbamate (DDC), when used to treat intoxication with cadmium, increased the concentration of the metal in brain. Studies were undertaken to confirm these findings in rats and to determine the mechanism of the observed effect. DDC (10 mg/kg, ip) given to male Sprague-Dawley rats 30 min prior to intracarotid Cd administration resulted in a 10-fold increase in the single pass cerebral extraction of cadmium. Two possible mechanisms were studied to explain this observation. First, DDC via a central adrenergic mechanism may cause a generalized increase in cerebral capillary permeability ( CCP) to a diffusion-limited substance or may reduce cerebral blood flow ( CBF) thereby prolonging cerebral circulatory transit time. Second, DDC ma6 chelate Cd to form a complex more permeable to the blood:brain barrier (BBB). CBF was determined from the ratio of [ 14C]butanol taken up by the brain to the [ 14C]butanol in an arterial blood sample withdrawn at a constant rate following iv injection of the tracer. CCP was determined as E w (extraction fraction of water) by the double-diffusion tracer technique. DDC did not alter either parameter, suggesting that the mechanism of the DDC-Cd interaction may involve the formation of a complex more permeable to the BBB. This conclusion is supported by the finding that the addition of DDC to a CdCl 2 solution increased the octanol-water partition coefficient of Cd (as DDC-Cd complex) by 375-fold.

Clonidine mydriasis in the rat

Pupillary responses to clonidine (3–100 μg/kg, i.v.) and epinephrine (1–30 μg/kg, i.v.) were observed in anesthetized rats. Clonidine caused a dose-dependent mydriasis which was effectively antagonized by pretreatment with yohimbine (1.5 mg/kg, i.v.). Pretreatment with phentolamine (5 mg/kg, i.v.) was less effective in antagonizing this clonidine-induced mydriasis. Phenoxybenzamine (2 mg/kg, i.v.) was almost without effect. In contrast, both phentolamine and phenoxybenzamine blocked the pupillary dilatin produced by epinephrine while yohimbine pretreatment resulted in no antagonism of epinephrine-induced mydriasis. These results suggest that clonidine-induced mydriasis in the rat is mediated by a central adrenergic inhibitory mechanism.

Clonidine mydriasis in the cat. Further evidence for a CNS postsynaptic action.

Both clonidine (1–100 μg/kg, i.v.) and d-amphetamine (500 μg, i.c.v.) produced mydriasis associated with depression of tonic ciliary nerve activity in the anaesthetized cat. Clonidine administration in preparations depleted of noradrenaline, dopamine and serotonin by pretreatment with reserpine (5 mg/kg, i.p.) and α-methyl-p-tyrosine (2×300 mg/kg, i.p.) resulted in a quantitatively similar mydriasis and inhibition of nerve activity. Thus it is concluded that both drugs cause pupillary dilation by inhibition of parasympathetic tone to the iris and that clonidine's action on this particular system is probably postsynaptic. In contrast, amine depletion totally prevented amphetamine-induced mydriasis and parasympathetic nerve depression, supporting the contention that centrally administered amphetamine acts in this system by means of releasing endogenous stores of monoamines. Pretreatment with yohimbine (0.5 mg/kg, i.v.) totally blocked the effects of i.c.v. amphetamine as it does with clonidine. These studies suggest that the pupillary dilation by i.v. clonidine and i.c.v. amphetamine is primarily the result of central inhibition of parasympathetic tone to the iris. It would appear that clonidine produces this effect by acting on postsynaptic mechanisms and that amphetamine acts indirectly through release of an endogenous inhibitory neurotransmitter. The observation that the effects of both of these compounds are blocked by yohimbine supports the suggestion that a central adrenergic inhibitory mechanism is involved.