Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Myopathy and hypertrophic cardiomyopathy with selective lysis of thick filaments

We present a undescribed condition in a girl who died at 8 years of hypertrophic cardiomyopathy. Muscle and endomyocardial biopsies disclosed a selective loss of thick filaments ultrastructurally. In muscle biopsy histochemical abnormalities of myofibrillar AT-Pase were confined to type 1 fibres. Gel electrophoresis of muscle homogenate showed no qualitative abnormalities of slow and fast myosin heavy chains (MHC) and light chains, and the amount of the different myosin isozymes was in agreement with histochemical myofibrillar ATPase findings. The pathogenetic mechanisms have not been elucidated in this case but we suspect an abnormality of the-cardiac MHC gene, the only gene expressed in the heart and in type 1 skeletal muscle fibres.     

Gaba and endorphln mechanisms in relation to the effects of benzodiazepines on feeding and drinking

1. 1. Behavioural actions of benzodiazepines have a number of significant characteristics. Anxiolytic effects are demonstrable both clinically and experimentally; in addition, there is excellent evidence for a reinforcing effect of these compounds, and a direct involvement in ingestional responses. This review focusses on the effects of benzodiazepines on the latter feeding and drinking responses.

2. 2. A necessary mediator of benzodiazepine action in the central nervous system appears to be the facilitation of inhibitory GABAergic neurotransmission. It follows, therefore, that behavioural consequences of benzodiazepine action may depend crucially on enhanced GABAergic activity in the brain. Evidence for some involvement of GABAergic mechanisms in the control of feeding and drinking responses is reviewed. Only a few data are so far available to link benzodiazepines effects on ingestional behaviour directly to GABAergic transmission.

3. 3. A major current theme in the psychopharmacology of feeding and drinking behaviour is the possible involvement of endogenous opioid peptides. There is a strong suggestion in the experimental data that there are links between benzodiazepine and endorphinergic mechanisms in relation to ingestional responses. A promising future line of approach appears to be a delineation of benzodiazepine-GABA-endorphin interrelations in the control of food and water consumption.

Enhancement of imipramine-induced rat brain β-adrenoreceptor desensitization by subacute co-administration of trazodone,zimelidine, quipazine or 5-hydroxytryptophan

The present work was undertaken to characterize the role of serotonin in the regulation of -adrenoceptors utilizing isoprenaline-induced water drinking in the rat. For this purpose, a serotonin precursor, 5-hydroxytryptophan (24.3 mg/kg/day, PO), the serotonin neuronal uptake blockers, trazodone (18.5 mg/kg/day, PO), or zimelidine (14.6 mg/kg/day, PO) or a serotonin agonist, quipazine (12.6 mg/kg/day, PO) were administered either alone or in combination with imipramine for a period of 4 days. While none of these drugs alone showed any significant effect in attenuating the effects of isoprenaline-induced water drinking, their co- administration with imipramine did produce a significant reduction in isoprenaline-induced drinking. Simultaneous injection of the serotonin synthesis inhibitor,p-chlorophenylalanine (200 mg/kg/day, IP), has resulted in blockade of this acceleration of desensitization of -adrenoceptors produced by the subacute co-administration of trazodone or quipazine with imipramine. The selective 5HT₂ receptor antagonist ketanserin (4 mg/kg/day/ IP) significantly inhibited the attenuation of the isoprenaline-induced drinking attained by the co-administration of quipazine with imipramine, while methysergide (2 mg/kg/day, IP) which blocks both 5HT₁ and 5HT₂ receptors failed to produce a significant effect on this response. These results indicate that the inhibition of the synaptosomal uptake of serotonin by quipazine seems to be more pertinent than its serotoninergic agonistic effect in the desensitization of central -adrenoceptors in the rat. Thus, it can be concluded that noradrenaline and serotonin are both required for the process of the desensitization of central -adrenoceptor systems by antidepressants.Part of this paper was presented at the International Symposium of Serotonin from Cell Biology to Pharmacology and Therapeutics, Florence (Italy), March 29–April 1989     

The measurement of harmful outcomes following drinking on licensed premises

The relationships between five potential indicators of alcohol-related harm following drinking on licensed premises in Perth were explored. These were annual purchases made by individual licensees of 'high' (>=3.8%) and 'low' (<3.8%) alcohol content drinks, the number of times a particular licensed establishment is cited by drivers as the last place of drinking prior to failing a roadside breath-test (including after accidents) and the annual number of assaults occurring either on or in the vicinity of particular licensed premises. The study area selected was a central part of the Perth metropolitan area with 367 licensed premises serving a residential population of 400 000. Highly significant correlations were found between each of the five variables. The correlations involving purchases of low alcohol drinks, however, were small. When purchases of alcohol were controlled, significant, though lower, correlations, were still evident between the other three variables. This suggests that there are risk factors other than extent of alcohol sales which further research will need to identify, and that these indicators of harm can be of value in monitoring the impact of future intervention strategies.     

Alcohol and recreational drug use by HIV-seropositive homosexual men

The objectives of this study were to describe the patterns of alcohol and recreational drug use of HIV-seropositive homosexual men and to determine the effect of alcohol use on HIV risk-taking behaviour. Of particular interest was the effect of knowledge of HIV status on these behaviours. Information on alcohol and drug use was obtained from 485 HIV-seropositive homosexual and bisexual men presenting to a HIV-antibody testing and medical management clinic. Heavy alcohol use was common, with 46.2% reporting consumption of six or more standard drinks on one day recently. Men who knew that they were HIV infected drank significantly more than those men who had yet to learn of their HIV status at the time of interview. There was clear evidence in this study for a role of alcohol use in HIV risk-taking behaviour. Almost one-third (27%) of the HIV-seropositive men reported unprotected anal intercourse during the previous 3 months with approximately one-third of these (27/76, 35·5%) nominating alcohol as contributing to their high HIV-risk behaviour.     

Cerebral metabolic and vasopressin and oxytocin responses during osmotic stimulation in conscious rats

Intravenous infusion of hypertonic saline increased plasma [Na (+) ] and osmolality and induced a short-latency drinking response. These changes were associated with increased glucose utilization in the supraoptic and paraventricular nuclei and neural lobe, and decreases in the medial septum and nucleus ambiguus. The increases in glucose utilization were more accentuated in the supraoptic nuclei than in paraventricular nuclei, indicating that they are more sensitive to osmotic stimulation than the paraventricular nuclei. In association with enhanced activity in the hypothalamo-neurohypophysial system, plasma vasopressin and oxytocin concentrations increased, with a preferential increase of oxytocin over vasopressin. The hormonal contents in the neural lobe were not depleted by the osmotic stimulus despite the large increases of their concentrations in the plasma.     

谷胱甘肽治疗急性酒精中毒

目的 :探讨谷胱甘肽注射液治疗急性酒精中毒的疗效及安全性。方法 :5 0例急性酒精中毒昏睡期病人随机分为 2组 :谷胱甘肽组 2 8例 [男性 2 3例 ,女性 5例 ,年龄 (33±s 11)a],给予谷胱甘肽注射液 1.8g加入 5 %葡萄糖注射液 2 5 0mL中静脉滴注。促进乙醇氧化组 2 2例 [男性 18例 ,女性 4例 ,年龄 (35± 9)a],给予 5 %葡萄糖注射液 2 5 0mL +2 0U正规胰岛素注射液静脉滴注 ,同时给予维生素C、维生素B6 静脉注射。 2组病人均给予温水洗胃 ,并给予静脉注射呋塞米、西咪替丁及补液治疗。结果 :在清醒时间及给药后 3h清醒例数方面 ,治疗组明显优于对照组 ,治疗组病人苏醒时间为 (76± 4 4 )min ;对照组为 (133± 5 9)min(P <0 .0 1)。给药后 3h治疗组清醒 2 5例 (89% ) ,对照组清醒 7例(32 % ) (P <0 .0 1)。结论 :谷胱甘肽注射液治疗急性酒精中毒昏睡期病人的苏醒时间明显短于传统的促进乙醇氧化疗法 ,对急性酒精中毒具有可靠的治疗效果     

Influence of Hypertension, Lipometabolism Disorders, Obesity and Other Lifestyles on Spontaneous Intracerebral Hemorrhage

Objective To investigate whether hypertension, abnormal lipometabolism, obesity, cigarette smoking and alcohol drinking affect the intracerebral hemorrhagic volumes (IHV) in patients with spontaneous intracerebral hemorrhage (SIHP), and to explore the roles of these factors in spontaneous intracerebral hemorrhage (SIH). Methods Five hundred patients with acute SIH and 200 healthy adult volunteers (HAV) were enrolled in a study of independently randomized controlled design, in which the levels of systolic pressure (SP) and diastolic pressure (DP), and total cholesterol (TCH), triacylglycerols (triglycerides, TG), high density lipoprotein cholesterol (HDL-CH), low density lipoprotein cholesterol (LDL-CH) in serum as well as the level of erythrocytic membrane cholesterol (EM-CH) were measured, and the body mass index (BMI), daily cigarette smoking consumption (DCSC) and daily pure alcohol consumption (DPAC) were calculated. Results Compared with the average parameters in the HAV group, those of SP, DP, TG,     

胸苷酸合成酶基因多态性及烟酒茶嗜好与贲门癌易感性的关系

目的 :研究胸苷酸合成酶TS3′ UTR多态性及其和烟酒茶嗜好相互作用与贲门癌易感性的关系。方法 :在上消化道癌高发区淮安市进行了一个病例对照研究 (贲门癌 89例 ,人群对照 2 2 3例 ) ,调查研究对象的生活习惯 ,采用PCR RFLP技术检测研究对象的TS 3′ UTR基因型。结果 :贲门癌组TS 6/ 6bp、 6/-6bp和 -6/-6bp基因型频率分别为7 9%、43 8%和 48 3 % ,与对照组( 8 1%、5 4 3 %和 3 7 7% )相比差异无统计学意义。与携带TS 6bp等位基因且不吸烟、每周饮酒 <2次和饮茶者相比 ,在吸烟、每周饮酒≥ 2次和不饮茶者中 ,携带TS -6/-6bp基因型者发生贲门癌的危险性显著上升 ,调整后的OR分别为 3 99( 95 %CI:1 5 1～ 10 5 0 )、3 2 2 ( 95 %CI :1 2 1～8 5 5 )和 6 14 ( 95 %CI:2 3 9～ 15 77)。结论 :TS 3′ UTR基因多态性影响吸烟、饮酒和饮茶与贲门癌之间的关系