Isoamericanoic Acid B from Acer tegmentosum as a Potential Phytoestrogen.

Phytoestrogens derived from plants have attracted the attention of the general public and the medical community due to their potentially beneficial role in relieving menopausal symptoms. The deciduous tree Acer tegmentosum Maxim (Aceraceae) has long been utilized in Korean folk medicine to alleviate many physiological disorders, including abscesses, surgical bleeding, and liver diseases. In order to explore structurally and/or biologically new constituents from Korean medicinal plants, a comprehensive phytochemical study was carried out on the bark of A. tegmentosum. One new phenolic compound with a 1,4-benzodioxane scaffold, isoamericanoic acid B (1), as well as with nine known phenolic compounds (2⁻10), were successfully isolated from the aqueous extracts of the bark of A. tegmentosum. A detailed analysis using 1D and 2D NMR spectroscopy, electronic circular dichroism (ECD) spectral data, and LC/MS afforded the unambiguous structural determination of all isolated compounds, including the new compound 1. In addition, compounds 2, 4, 5, and 9 were isolated and identified from the bark of A. tegmentosum for the first time. All isolated compounds were tested for their estrogenic activities using an MCF-7 BUS cell proliferation assay, which revealed that compounds 1, 2, and 10 showed moderate estrogenic activity. To study the mechanism of this estrogenic effect, a docking simulation of compound 1, which showed the best estrogenic activity, was conducted with estrogen receptor (ER) -α and ER-ß, which revealed that it interacts with the key residues of ER-α and ER-ß. In addition, compound 1 had slightly higher affinity for ER-ß than ER-α in the calculated Gibbs free energy for 1:ER-α and 1:ER-ß. Thus, the present experimental evidence demonstrated that active compound 1 from A. tegmentosum could be a promising phytoestrogen for the development of natural estrogen supplements.

Antimicrobial Metabolites from a Marine-Derived Actinomycete in Vietnam's East Sea.

Two new compounds, a quinoline alkaloid (1) and a 1,4-dioxane derivative (2), were isolated from culture broth of the marine-derived actinomycete Micromonospora sp. (strain G019) by bioassay-guided fractionation. This actinomycete strain was isolated from sediment, collected at Cát Bà Peninsula, Vietnam. The taxonomic identification was achieved by analysis of 16S rRNA gene sequences. On the basis of morphological and phylogenetic evidence, strain G019 was assigned to the genus Micromonospora. The structures of 1 and 2 were established by spectroscopic data analysis, including one- and two-dimensional NMR, and MS. Compound 1 was found to have antibacterial activity against Escherichia coli (MIC: 48 µg/mL), Salmonella enterica (MIC: 96 µg/mL) and Enterococcus faecalis (MIC: 128 µg/mL), while compound 2 showed inhibitory activity against Enterococcusfaecalis (MIC: 32 µg/mL) and Candida albicans (MIC: 64 µg/mL).

6-(4-Benzylpiperazin-1-yl)benzodioxanes as selective ligands at cloned primate dopamine D(4) receptors.

A series of novel 6-(4-benzylpiperazin-1-yl)benzodioxanes were prepared and screened at selected dopamine receptor subtypes. 6-(4-[4-Chlorobenzyl]piperazin-1-yl)benzodioxane (2d) had high affinity and selectivity for the D(4) dopamine receptor subtype and was identified as a D(4) antagonist via its attenuation of dopamine-induced GTPgamma(35)S binding at the D(4) receptor.

N-Substituted (2,3-dihydro-1,4-benzodioxin-2-yl)methylamine derivatives as D(2) antagonists/5-HT(1A) partial agonists with potential as atypical antipsychotic agents.

A series of N-substituted 1-(2,3-dihydro-1, 4-benzodioxin-2-yl)methylamine derivatives with D(2) antagonist/5-HT(1A) partial agonist activity has been prepared as potential atypical antipsychotic agents. Optimization of in vitro receptor binding activity and in vivo activity in rodent models of psychosis has led to compound 24, which showed good affinities for human D(2), D(3), and 5-HT(1A) receptors but significantly less affinity for human alpha(1) adrenoceptors and rat H(1) and muscarinic receptors. In rodents, 24 showed functional D(2)-like antagonism and 5-HT(1A) partial agonism. After oral dosing, 24 showed good activity in rodent antipsychotic tests and very little potential to cause extrapyramidal side effects (EPS), as measured by its ability to induce catalepsy in rats only at very high doses. In the light of this promising profile of activity, 24 has been selected for clinical investigation as a novel antipsychotic agent with a predicted low propensity to cause EPS.

A thermodynamic analysis of estrogen regulation of alpha 2-adrenoceptor binding.

We previously demonstrated that in vivo estradiol treatment markedly attenuates alpha 2-adrenoceptor function and coupling to G-proteins in the hypothalamus of female rats. Ligand binding studies indicated that 48 h exposure to estradiol decreases the number of alpha 2-adrenergic receptors in the agonist high affinity state. In the present studies, when [3H]RX821002 was used to label brain alpha 2-adrenoceptors, the density of binding sites significantly increased in the hypothalamus and preoptic area 48 h after estrogen treatment. Moreover, the thermodynamics of ligand binding to alpha 2-adrenergic receptors in membranes of female rat hypothalamus were modified by the same estradiol treatments that reduce alpha 2-adrenoceptor function. In hypothalamic membranes from ovariectomized control rats, antagonist (RX821002)-receptor binding was primarily entropy-driven while agonist (oxymetazoline) binding had a higher enthalpy component. In membranes from estradiol-exposed animals, the entropic contribution to both agonist and antagonist bindings was markedly increased, and the enthalpy component was reduced. Since the thermodynamic characteristics of ligand-receptor binding are strongly correlated with efficacy in activating signal transduction [36], these data raise the intriguing possibility that steroids regulate transmembrane signaling by stabilization of a receptor conformation with reduced intrinsic efficacy.

Estradiol reduction of the agonist high affinity form of the alpha 2-adrenoceptor in the hypothalamus of female rats: identification as the alpha 2D subtype.

These studies examined which alpha 2-adrenoceptor subtype is expressed in the hypothalamus and preoptic area and the influence of estradiol administration on alpha 2-adrenoceptors in the hypothalamus of female rats. The alpha 2-adrenoceptor antagonist [3H] RX821002 bound to a single site in hypothalamus, preoptic area, and cortex membranes, with high affinity and low nonspecific binding, as determined by Scatchard and kinetic binding analyses. Competition for [3H]RX821002 binding in the hypothalamus and preoptic area by various noradrenergic agonists and antagonists revealed a unique pharmacological specificity with a high degree of similarity to that of the alpha 2D-adrenoceptor. Norepinephrine displacement of [3H]RX821002 binding in hypothalamic membranes from ovariectomized animals was monophasic and characterized by high affinity. In contrast, norepinephrine competition for [3H]RX821002 binding sites in the hypothalamus from rats exposed to estradiol for 48 hr was biphasic, and norepinephrine bound to both a high (18%) and a low (82%) affinity site in these membranes. Thus, the formation of agonist high affinity alpha 2D-adrenoceptor complexes was inhibited by prior exposure to estrogen. In both control and estradiol-exposed hypothalamic membranes, 100 microM 5'-guanylylimidodiphosphate [Gpp(NH)p] converted the norepinephrine competition curves to ones characterized by monophasic, low affinity binding. In addition, binding of the full alpha 2-adrenoceptor agonist [3H]UK-14,304 in the hypothalamus and preoptic area of female rats was concentration-dependently diminished by Gpp(NH)p treatment. Complete loss of [3H]UK-14,304 binding was effected by 100 microM Gpp(NH)p. This suggests that [3H]UK-14,304 may be useful in labeling the agonist high affinity state of alpha 2-adrenoceptors. Decreasing the incubation temperature in saturation studies from 25 degrees to 0 degrees increased [3H]UK-14,304 binding in hypothalamic membranes of control rats but not in membranes from estradiol-treated rats. Estradiol treatment for 48 hr decreased [3H]UK-14,304 binding in hypothalamic membranes by 34% (0 degrees) to 60% (25 degrees), without changing the Kd. These results suggest that the alpha 2D-adrenoceptor is the predominant subtype in the hypothalamus and preoptic area of female rats and that estradiol treatment markedly reduces the number of alpha 2D-adrenoceptors in the agonist high affinity state.

Heterogeneity of the specific imidazoline binding of [3H]idazoxan in the human cerebral cortex.

The aim of the present study was to verify whether [3H]idazoxan can be considered as a highly selective ligand for imidazoline preferring receptors (IPR). In human frontal cortex membrane preparations [3H]idazoxan at a low concentration (2 nM) only labelled imidazoline sensitive, catecholamine insensitive sites. Binding was of high affinity, saturable and stereospecific. The rank order of potency of different compounds able to inhibit this binding was cirazoline > (+/-)-idazoxan > guanoxan > (-)-idazoxan > tolazoline > UK-14304 > clonidine. Amiloride, imidazol-4-acetic acid and histamine had no significant affinity for IPR labelled by [3H]idazoxan. [3H]idazoxan bound to 2 different sites (KD1 = 1 nM and KD2 = 16.4 nM). Clonidine behaved as a non competitive, non allosteric inhibitor of [3H]idazoxan binding. Both [3H]idazoxan binding sites were equally affected by clonidine. In membrane preparations obtained from the Nucleus Reticularis Lateralis region (NRL) of the brainstem, [3H]idazoxan binding was similar to that in cortical membranes, particularly with regard to specificity and kinetics. However, in the NRL region binding sites were 4-5 times more numerous than in the frontal cortex. Non linear analyses of saturation data obtained with NRL membrane preparations were compatible with both a one site and a two sites model. No significant effects of 1 mM MgCl2 alone or with 100 microM Gpp(NH)p were observed on either [3H]idazoxan binding or the competition with clonidine or rilmenidine. As in the cortical membrane, clonidine was a non competitive inhibitor of [3H]idazoxan binding to membranes from the NRL region. In conclusion, we show that when a low concentration is used, [3H]idazoxan binding to human brain involves sites almost completely insensitive to catecholamines and specific for imidazolines or related compounds. This binding involves two distinct sites. We also report that [3H]idazoxan imidazoline binding sites are not coupled with a G protein. Because of the non competitive interaction between clonidine and [3H]idazoxan for the binding sites of the latter, we are unable to conclude that the binding sites of the two drugs are identical. However, the non competitive, non allosteric interaction suggests a complex model of multiple binding sites.

Long-term treatment with different calcium- and calmodulin-antagonists induces changes in rat brain alpha-adrenoceptors.

1. The binding characteristics (Bmax and Kd) of the alpha-adrenoceptor radioligand [3H] WB4101 in crude membrane fraction (fraction P2) from cerebral cortex were 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-antagonist trifluoperazine (TFP) (3 mg/kg). 2. A significant reduction of the binding sites (Bmax) for [3H] WB4101 was established after the three Ca(2+)-antagonists as well as after TFP treatment. 3. Different changes in the affinity constant (Kd) of brain adrenoceptors were observed depending on the type of the Ca2+ or CaM-antagonist used: nifedipine did not change the Kd value, verapamil and TFP decreased whereas flunarizine increased the Kd value. 4. Relationships between Ca ions and alpha-adrenoceptor functions are suggested.

Repeated idazoxan increases brain imidazoline receptors in normotensive (WKY) but not in hypertensive (SHR) rats.

The specific binding of [3H]idazoxan in the presence of 10(-6) M (-)-adrenaline was used to evaluate the density of imidazoline receptors in the brain of spontaneously hypertensive (SHR) rats and sex- and age-matched normotensive Wistar-Kyoto (WKY) rats. In SHR rats the density of imidazoline receptors (cerebral cortex, hypothalamus, and medulla oblongata) was not different from that in normotensive (WKY) rats. However, repeated treatment with idazoxan consistently increased (23-80%) the density of imidazoline receptors in the various brain regions of WKY rats but not in SHR rats. In normotensive Sprague-Dawley rats, repeated treatment with the imidazoline drugs idazoxan and cirazoline also increased (33-37%) the density of imidazoline receptors in the cerebral cortex. The lack of regulation by idazoxan of the density of imidazoline receptors in the brain of SHR rats might reflect the existence of a relevant abnormality of these receptors in this genetic model of hypertension.

Impairment of glucostatic, adrenergic and serotoninergic feeding parallels the lack of glucoprivic signals in the golden hamster.

The administration of 2-deoxyglucose (2-DG) to several animal species, including humans, results in reduction of cellular glucose availability which evokes sympathoadrenal activation, hyperglycemia and stimulation of food intake. We have investigated the effects in the hamster of several drugs which are known to stimulate food intake and induce hyperglycemic response in other species. Golden hamsters pretreated with either 2-DG (0.5 g/kg IP), the alpha-2 adrenoceptor agonist UK-14304 (0.3 mg/kg IP) or the 5-HT1A selective agonist 8-OH-DPAT (0.03 mg/kg IP), have a significant hyperglycemic response, which is similar to the response in mice or rats. However, neither 2-DG, UK-14304 nor 8-OH-DPAT were capable of stimulating food intake in these hamsters. Previous studies in rats and mice demonstrated that hyperglycemic conditions result in activation of a hypothalamic anorectic recognition site, labeled with [3H]mazindol, as well as alpha-2 adrenoceptors, labeled with [3H]idazoxan. No such activation of [3H]mazindol nor [3H]idazoxan binding was observed in the hypothalamus of hamsters treated with 2-DG, despite a normal glycemic response. Thus, in this species an uncoupling between feeding responses and glucoprivic signals may represent a lack of ischymetric regulation of feeding.

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on food and water intake in the rat.

1. Idazoxan (1, 3, 10 mg kg-1, i.p.) produced a significant increase in food and water intake in freely feeding rats during the daylight phase. 2. The more selective and specific alpha 2-adrenoceptor antagonists, RX811059 (0.3, 1, 3 mg kg-1, i.p.) and RX821002 (0.3, 1, 3 mg kg-1, i.p.), did not produce hyperphagia in rats, however, the highest dose produced a significant increase in water intake. 3. The peripherally acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1, i.p.), did not affect food intake in the 4 h following injection, but the highest dose (10 mg kg-1), produced a large increase in water intake. 4. These results indicate that alpha 2-adrenoceptor antagonists may increase water intake by a peripherally mediated mechanism. 5. The lack of effect RX811059 and RX821002 on food intake contrasts with the large dose-related increases induced by idazoxan and suggests that the hyperphagic effects of idazoxan are not due to alpha 2-adrenoceptor blockade but may instead reflect its affinity for a non-adrenoceptor site, a property not shared by the other alpha 2-antagonists.

Coupling between hypothalamic alpha 2-adrenoceptors and [3H]mazindol binding site in response to several hyperglycaemic stimuli in mice.

The hypothalamic response to circulating glucose and insulin levels was studied in the mouse by differentially attenuating glucose-homeostasis. The administration of glucose, 2-deoxyglucose or the alpha 2-adrenoceptor agonist UK 14.304 was accompanied by a persistent hyperglycaemia; however, an increase in insulin levels was obtained with glucose and a decrease with the other two manipulations. Both alpha 2-adrenoceptors (labeled with [3H]idazoxan) and the anorectic recognition site (labeled with [3H]mazindol) were upregulated by the three treatments. A good correlation was obtained between circulating glucose levels and either hypothalamic [3H]mazindol binding (r = 0.70, P less than 0.001) or [3H]idazoxan binding (r = 0.63, P less than 0.001), as well as between the two binding sites (r = 0.88, P less than 0.001). No correlation was obtained between circulating insulin levels and these binding sites (r = 0.18, r = 0.26, P = n.s. for [3H]mazindol and [3H]idazoxan binding, respectively). It is suggested the alpha 2-adrenoceptors and the anorectic binding sites are associated in their response to glucose as part of a hypothalamic center involved in the regulation of feeding mechanisms.

Alpha 2-adrenoceptor blocking properties of idazoxan stereoisomers: stereoselectivity for presynaptic alpha 2-adrenoceptors.

The alpha 2-adrenoceptor blocking properties of idazoxan enantiomers were evaluated at pre- and postsynaptic level. The antagonism of the two idazoxan stereoisomers was assessed, at presynaptic level, by their ability to antagonize clonidine at the alpha 2-adrenoceptors regulating noradrenaline release. The antagonist (+)-idazoxan showed an affinity towards the alpha 2-autoreceptors 40 times higher than that showed by (-)-idazoxan. Binding studies revealed (+)-idazoxan to be 7-8 times more potent than (-)-idazoxan in inhibiting the p-[3H]aminoclonidine binding. These results indicate a different affinity of alpha 2-adrenoceptors for the two idazoxan stereoisomers, thus suggesting that the alpha 2-adrenoceptors located pre- and postsynaptically may be of two stereochemically different subtypes.

Impact of food deprivation on alpha 1- and alpha 2-noradrenergic receptors in the paraventricular nucleus and other hypothalamic areas.

Hypothalamic norepinephrine may modulate normal eating behavior through activation of alpha 2-noradrenergic receptors, localized in the paraventricular nucleus (PVN). We investigated whether these receptors, which stimulate food ingestion, may in turn be altered by the nutritional state of the organism. Thus the impact of food deprivation, on the specific binding of [3H]-p-aminoclonidine ([3H]PAC) to alpha 2-noradrenergic receptors in discrete hypothalamic areas, was examined in rats. The results of our first experiment revealed that 48 hr food deprivation reduced (by 50%) the maximum number of binding sites (Bmax) of the high affinity component of [3H]PAC binding to alpha 2 receptors. This effect occurred exclusively in the medial hypothalamus (which includes the PVN), without any change in the affinity (Kd) of these receptors. A smaller decline was seen in the low affinity binding sites of the medial hypothalamus, whereas no changes were observed in the density or affinity of the high and low affinity alpha 2 receptor sites in the lateral hypothalamus or frontal cortex. The alpha 1-noradrenergic receptor sites, as defined by [3H]prazosin and [3H]WB-4101 binding, were also unaffected in the different brain areas by 48 hr food deprivation. An additional analysis of alpha 2 receptors in discrete hypothalamic nuclei demonstrated that the deprivation-induced decline in alpha 2-receptor binding: occurred specifically in the PVN; was apparent after as little as 3 hr food deprivation; and occurred only when this brief deprivation fell at the onset of the dark cycle, as opposed to at the end of the dark cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Stimulation by noradrenaline of inositol phospholipid breakdown in the rat hippocampus: effect of the ambient potassium concentration.

The stimulation by noradrenaline (NA) of inositol phospholipid (PI) breakdown has been studied using rat hippocampal miniprisms. Pretreatment with the monoamine oxidase inhibitor, pargyline, potentiated the stimulation produced by NA. On the other hand, pargyline pretreatment did not affect the stimulation of PI breakdown by the alpha 1-adrenoceptor agonist phenylephrine. NA- and phenylephrine-stimulated PI breakdown were enhanced by increasing the ambient potassium concentration in the assay from 5.88 to 18.2 mM. This enhancement did not, in the case of NA, change either the EC50 value for this agonist (2-3 microM) or the pA2 value for the competitive antagonism of the stimulation by the alpha 1-antagonist prazosin (pA2 value 9.2). Time-courses of the NA-stimulated PI turnover in different brain regions indicated that the rate of stimulation was in the order frontal cortex greater than hypothalamus greater than or equal to hippocampus much greater than cerebellum.

The alpha-adrenergic receptor: radiohistochemical analysis of functional characteristics and biochemical differences.

The partial agonist [3H]para-aminoclonidine was used to label alpha 2-adrenergic binding sites in intact sections of the rat central nervous system using in vitro labeling receptor autoradiographic techniques. The distribution of alpha 2-agonist binding sites closely parallels the reported distribution of noradrenergic and adrenergic cell groups and their terminal fields, particularly the projections of the medullary catecholamine neurons. This distribution of alpha 2 binding sites confirms physiological studies which indicate that the anti-hypertensive actions of alpha 2-agonist compounds are mediated centrally in medullary and spinal centers involved in the control of parasympathetic and sympathetic outflow. Further, the high concentrations of alpha 2 binding sites in pontine and limbic areas such as the locus coeruleus, parabrachial nucleus, dorsal raphe, hypothalamus, amygdala, bed nucleus of the stria terminalis, septum and entorhinal cortex offer an anatomical basis for understanding the anxiolytic and antidepressant actions of drugs like clonidine. The antagonists [3H]prazosin and [3H]WB4101 were used to study the distribution of alpha 1-adrenergic binding sites in the rat forebrain and biochemical studies were performed to analyze the marked differences that were initially seen in the distribution of [3H]prazosin and [3H]WB4101 binding sites. Several pieces of evidence derived from both biochemical and autoradiographic studies suggest that [3H]prazosin and [3H]WB4101 act at distinctly different binding sites. However, both sites may represent components of an alpha 1-adrenergic receptor-effector complex since a high degree of overlap was seen in the binding site distribution of these two ligands and since kinetic interactions could be demonstrated in at least one region of the brain, the hippocampus. Differences noted in the relative displacements of [3H]prazosin and [3H]WB4101 binding in various forebrain regions could reflect differences in the coupling efficiency of the [3H]prazosin and [3H]WB4101 component of the hypothesized complex. Further, in some regions, [3H]WB4101 labeled a binding site that is different from the alpha 1-receptor. Thus, [3H]prazosin and [3H]WB4101 binding sites seen in forebrain regions such as lamina V of the cortex, thalamic nuclei and dorsal raphe probably represent alpha 1-adrenergic receptors and confirm electrophysiological and biochemical studies which demonstrate that adrenergic transmission in these regions can be mediated through an alpha 1-receptor.

Long-term treatment with clonidine and alpha-receptors in the brain of normotensive rats.

The aim of the present study was to investigate whether or not changes in rat brain alpha-adrenoceptors take place during chronic treatment with a low dose of clonidine. Male Wistar normotensive rats were treated with clonidine (0.1 mg/kg)i.p. twice daily for 12 days. This treatment caused a significant increase in [3H]clonidine and in [3H]WB4101 binding, respectively, to alpha 2- and to alpha 1-adrenoceptors of the frontal cortex; the levels were 30% for [3H]clonidine and 20% for [3H]WB4101. The Scatchard analysis of data obtained in binding studies indicated that the enhanced binding of two ligands to membranes prepared from chronically clonidine-treated animals, was due to an apparent increase in the number of binding sites. These changes were seen 4 h after administration of the last treatment, before the appearance of the withdrawal syndrome. However, noradrenergic alpha 2-autoreceptors of synaptosomes, from the frontal cortex and hypothalamus of treated animals, were sensitive to the regulatory action of clonidine or of noradrenaline on the [3H]noradrenaline overflow elicited by high K+ as well as on the control animals. On the contrary, the alpha 2-receptors on the serotoninergic nerve terminals from the frontal cortex of treated animals were more sensitive than those of control animals to the action of clonidine or of noradrenaline in counteracting the [3H]5-hydroxytryptamine overflow elicited by high K+. These results suggest that during treatment with clonidine no autoreceptor hyposensitivity to the regulatory action of clonidine or noradrenaline on [3H]noradrenaline overflow elicited by high K+ takes place, but, as a consequence of the diminished noradrenaline availability at the synaptic cleft, the binding of [3H]WBA101 to alpha 1-receptors and of [3H]clonidine to pre- and postsynaptic alpha 2-receptors were significantly elevated in the frontal cortex, a brain areas where the alpha-2-receptors are mainly postsynaptic. Thus, the neurotransmitter concentration in the synaptic cleft may be responsible for the trans-synaptic modulation of the alpha 2-adrenoceptor postsynaptic population. In fact, the alpha 2-adrenoceptors which are presynaptically located on the serotoninergic terminals, but are postsynaptic in relation to the noradrenergic neurons, also show increased sensitivity after chronic clonidine treatment.

Alpha 1- and alpha 2-adrenoceptor binding in the Dahl rat model of hypertension.

Dahl sensitive rats on a high salt diet (DSH group) developed significant elevations in blood pressure (BP). Sensitive rats maintained on a low salt diet (DSL group) and Dahl resistant rats on a high or low salt diet (DRH and DRL groups, respectively) remained normotensive. The DSH and DRH groups displayed a lower density of alpha 2-adrenoceptors (as measured with [3H]-clonidine) in the cerebral cortex than normotensive DSL and DRL groups. In contrast, the density of alpha 2-adrenoceptors in the medulla was significantly lower in the DSH group than the DSL group, but significantly higher in the DRH group compared to the DRL group. The density of alpha 1-adrenoceptors (as measured with [3H]-WB4101) in the hypothalamus was lower in the DSH group than the DSL group but greater in the DRH group than the DRL group. The results suggest that the sensitive and resistant lines can be distinguished by the density of alpha 1- adrenoceptors in the hypothalamus and medulla, respectively. The interactive effects of dietary NaCl and susceptibility to hypertension on adrenoceptors lend further support to the hypothesis that the genetic predisposition to hypertension is associated with a disruption in central adrenergic activity.

Adrenoceptor changes in spontaneous hypertensive rats: a circadian approach.

Circadian adrenoceptor rhythms were measured in the cortex, hypothalamus, cerebellum and pons-medulla of WKY and SHR rats. The 24-h mean binding to alpha 1-, and beta-adrenoceptors was higher in SHR than WKY in all regions:greatest differences were found at the end of the dark phase. The most consistent and large amplitude circadian rhythms in adrenoceptor binding occurred in the hypothalamus; strain differences in wave form of the rhythm were the most noticeable phenomenon. In the pons-medulla SHR rats showed decreased rhythm amplitudes. In the cerebellum, beta-adrenoceptor binding was higher in SHR rats at all time points, with an identical rhythm to that in WKY rats. Thus regional differences between SHR and WKY rats were expressed in changes in many circadian rhythm parameters. There were no differences between SHR and WKY in the ratios of pre-synaptic: post-synaptic receptors. High affinity binding to alpha-adrenoceptors showed similar circadian rhythms to total specific binding, indicating that the short-term fluctuations cannot be attributed to change in affinity state. Whether these modifications in circadian rhythm characteristics are related to the development or maintenance of hypertension in the SHR strain remains to be investigated.