Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.     

侧脑室及下丘脑视前区微量注射孤啡肽对大鼠血压、心率的影响

孤啡肽（OrphaninFQ,OFQ）是1995年底发现的内阿片肽,一级结构与强啡肽A很相似,但生物学作用与其它内阿片肽有所不同。本工作采用侧脑室及核团微量注射的方法,观察了中枢OFQ对大鼠心血管活动的影响。结果表明：侧脑室注射1、10μgONQ可明显降低大鼠平均动脉压（MAP）及心率（HR）;侧脑室预先注射4μg纳洛酮不影响1μgOWQ的降压及减慢心率的效应。下丘脑视前区（POA）微量注射1μgOFQ也可降低血压、减慢心率。结果表明,中枢OFQ与其它内阿片肽相似,可抑制心血管活动,且其抑制作用不是通过μ、δ、κ阿片受体介导。POA为中枢OFQ抑制心血管活动的靶区之一。     

SMS 201-995, an octapeptide somatostatin analogue. Assignment of the 1H 500 MHZ n.m.r. spectra and conformational analysis of SMS 201-995 in dimethylsulfoxide

The possible conformations of SMS 201-995, an active analogue of somastostatin, have been studied in dimethylsulfoxide solution by 500 MHz proton n.m.r. spectroscopy. The assignments have been made by use of 2D-correlated methods to detect long-range coupling connectivities in aromatic residues and between the alpha protons of consecutive residues. NOESY experiments enabled us to correlate amide and alpha protons of neighbouring amino acid residues, which indicate a less flexible situation than in water. Measurements of temperature coefficients of the amide protons, of NH-C alpha H coupling constants and NOE effects are in favour of one predominant conformation with a beta turn, of type II', involving amino acids Phe3 to Thr6.     

Effect of chronic suppression of growth hormone secretion, by SMS 201-995 on lactation in mice

The effect of chronic suppression of growth hormone (GH) secretion by SMS 201-995 on lactation was studied in primiparous C3H/He mice. Mammary gland DNA content on day 12 of lactation was significantly lower in SMS 201-995 treated mice than in the control. There were little differences between groups in mammary gland RNA content and litter growth on day 12 of lactation. That was associated with a slightly higher RNA/DNA ratio and a significant increase in food intake during lactation. These results indicate that inhibited mammary gland growth by GH suppression has little effect on lactation. The smaller mammary gland can compensate by increasing its secretory activity.     

Food intake in rats is increased by intracerebroventricular infusion of the somatostatin analogue SMS 201-995 and is decreased by somatostatin antiserum

The chronic intracerebroventricular infusion of the somatostatin analogue SMS 201-995 resulted in a significant increase in daily food intake which was accompanied by an unexpected body weight loss. The neutralisation of central somatostatin using a specific somatostatin antiserum resulted in a significant decrease in daily food intake. These results suggest that endogenous somatostatin in the brain can drive feeding behavior and alter body weight.     

电刺激迷走神经对蟾蜍心率和心率变异的影响

目的:观察不同频率迷走神经刺激对蟾蜍离体心脏的心率及心率变异的影响。方法:将蟾蜍心脏和右侧迷走交感干离体后,以不同频率电刺激神经,记录心电图曲线并作心率变异性(HRV)分析。结果:交感神经阻断后,电刺激迷走交感干,心率(HR)显著下降(P0.01),全部正常心动周期的标准差(SDNN)和相邻正常心动周期差值的均方根(RMSSD)显著升高(P0.01),不同频率刺激组之间没有明显差异;与对照组相比,各指标变化较大;给药组0.2Hz时高频(HF)显著升高(P0.01),低频/高频比值(LF/HF)明显降低(P0.05),0.8Hz时HF和LF/HF接近刺激前水平。结论:一定范围内增加刺激频率,迷走神经降低心率的作用增强;没有交感神经调节条件下的迷走神经对心率和心率变异的调节可能存在不同的机制。     

电刺激家兔迷走神经中枢端诱导的黑-伯反射中的非联合型学习现象

本文旨在研究电刺激家兔迷走神经诱导的黑-伯（Hering-Breuer,HB）反射中的学习和记忆现象。选择性电刺激家兔迷走神经中枢端（频率10～100Hz,强度20～60μA,波宽0．3ms,持续60s）,观察对膈神经放电的影响。以不同频率电刺激家兔迷走神经可模拟HB反射的两种成分,即类似肺容积增大所致抑制吸气的肺扩张反射和类似肺容积缩小所致加强吸气的肺萎陷反射。（1）长时高频（≥40Hz,60s）电刺激迷走神经可模拟呼吸频率减慢,呼气时程延长的肺扩张反射。随着刺激时间的延长,膈神经放电抑制的程度逐渐衰减,表现为呼吸频率的减慢（主要由呼气时程延长所致）在刺激过程中逐渐减弱或消失,显示为适应性或“习惯化”的现象;刺激结束时呼吸运动呈现反跳性增强,表现为一过性的呼气时程缩短,呼吸频率加快,然后才逐渐恢复正常。长时低频（〈40Hz,60s）电刺激迷走神经可模拟呼吸频率加快、呼气时程缩短的肺萎陷反射。随着刺激时间的延长,膈神经放电增强的程度逐渐衰减,同样表现出“习惯化”现象;刺激结束后,膈神经放电不是突然降低,而是继续衰减,表现为呼气时程逐渐延长,呼吸频率逐渐减慢,直至恢复到前对照水平,表现了刺激后的短时增强效应。（2）HB反射的适应性或“习惯化”程度反向依赖于刺激强度和刺激频率,表现为随着刺激强度和频率的增加,膈神经放电越远离正常基线水平,即爿惯化程度减弱。结果表明,家兔HB反射具有“习惯化”这一非联合型学习现象,反映与其有关的呼吸神经元网络具有突触功能的可翅性,呼吸的中枢调控反射具有一定的适应性。     

解除模拟失重后清醒大鼠血压信号的谱分析

本文旨在观察模拟失重28 d大鼠解除尾部悬吊前、后(2 h内),清醒自由活动状态下动脉收缩压(systolic bloodpressure,SBP)、舒张压(diastolic blood pressure,DBP)和心率(heart rate,HR)的变化.采用自回归模型法对不同时间点的收缩压变异性(SBP variability,SBPV)和心率变异性(HR variability,HRV)进行自谱与互谱分析,并比较自回归法与周期图法的自谱分析结果:由传递函数分析得到反映压力感受器-心率反射敏感性(baroreceptor-heart rate reflex sensitivity,BRS)变化的有关数据.结果显示,用自回归模型法对清醒大鼠血压信号进行短时程谱分析可得到较为平滑、谱峰清楚的谱估计曲线.28 d模拟失重大鼠解除尾部悬吊前、后,SBP、DBP和HR及其主要谱指标,以及高、低频段传递函数的平均增益均无显著性变化,不同时间点的谱指标也无显著差别;但模拟失重组的SBP、DBP和HR却显著高于对照组.上述结果提示,中期模拟失重大鼠恢复正常体位后,其清醒状态的BPV与HR均处于升高状态,但其短时程BPV与HRV谱及BRS均无显著变化,与最近报道的航天员HRV与BRS无显著改变一致.     

Suppression of growth hormone and somatomedin C by long-acting somatostatin analog SMS 201-995 in type I diabetes mellitus

The effect of a new long-acting somatostatin analog SMS 201-995 (SMS) on hormonal mechanisms controlling the glucose metabolism was tested in 8 type I diabetics over a 3-day period. In addition to dietary measures and conventional insulin therapy, the patients received a subcutaneous dose of 50 micrograms SMS three times daily for 3 days. Serum growth hormone (GH) was measured at various intervals throughout the investigational period. Glucagon, somatomedin C (SM-C), triiodothyronine, thyroxine, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) were also determined before and at the end of the therapy with SMS. Basal GH and plasma SM-C had decreased significantly (p less than 0.05 and p less than 0.01, respectively) by the 3rd day. In all cases the insulin requirements could be reduced (mean 28%) without deterioration of the metabolic control. Moreover, blood glucose profiles showed a tendency to lower postprandial peaks after SMS treatment. Glucagon, triiodothyronine, thyroxine, LH, FSH and PRL showed no significant changes. No side effects or alterations in laboratory chemistries were recorded. Dampening of glucose oscillations and counterregulatory mechanisms, and reduction of insulin dosage by SMS may enable a better control of unstable diabetes. Its slow plasma clearance and long action compared to the native peptide will warrant the use of this analog as a additive to standard diabetes therapy in more prolonged trials.     

迷走背核微量注射P物质抑制大鼠胃肌电活动和胃运动

本工作观察到大鼠迷走背核微量注射Ｐ物质（Ｓｕｂｓｔａｎｃｅ Ｐ,ＳＰ）抑制胃肌电快波和胃运动。该效应可分别迷走背核注射ＳＰ抗血清,ＳＰ受体拮抗剂「Ａｒｇ＾６,Ｄ－Ｔｒｐ＾７,９,Ｎ－Ｍｅ－Ｐｈｅ＾８」－ＳＰ６－１１或切断迷走神经所消除。用利血平耗竭交感神经递质则不影响该效应。     

Body heating induced by sub-resonant (350 MHz) microwave irradiation: Cardiovascular and respiratory responses in anesthetized rats

These experiments were designed to investigate the effects of sub-resonant microwave (MW) exposure (350 MHz, E orientation, average power density 38 mW/cm², average whole-body specific absorption rate 13.2 W/kg) on selected physiological parameters. The increase in peripheral body temperature during 350 MHz exposure was greater than that in earlier experiments performed at 700 MHz (resonance). Heart rate and mean arterial blood pressure were significantly elevated during a 1 °C increase in colonic temperature due to 350 MHz exposure; respiratory rate showed no significant change. The results are consistent with other investigators' reports comparing sub-resonance exposures with those at resonance and above. Bioelectromagnetics 18:335–338, 1997. © 1997 Wiley-Liss, Inc.     

Cardiovascular responses to intrathecal administration of arginine vasopressin in rats

Arginine vasopressin (AVP) has been localized in numerous extrahypothalamic brain regions and in the spinal cord. The results of intracerebroventricular AVP injections and microinjection of AVP into the brain stem suggest that this peptide, acting centrally at higher levels, may influence cardiovascular function. No function for the AVP occurring at spinal levels has been reported. In this study we report that AVP, in picomole quantities, increased arterial blood pressure and integrated heart rate in a dose-dependent manner following intrathecal application to the thoracic region in the rat. This response was not blocked by intravenous administration of the AVP antagonist d(CH₂)₅-d-Tyr-VAVP. These results suggest that AVP, acting within the spinal cord, may alter neural outflow regulating blood pressure and heart rate.     

Endocrine and cardiovascular rhythms differentially adapt to chronic phase-delay shifts in rats

Disturbances in regular circadian oscillations can have negative effects on cardiovascular function, but epidemiological data are inconclusive and new data from animal experiments elucidating critical biological mechanisms are needed. To evaluate the consequences of chronic phase shifts of the light/dark (LD) cycle on hormonal and cardiovascular rhythms, two experiments were performed. In Experiment 1, male rats were exposed to either a regular 12:12 LD cycle (CONT) or rotating 8-h phase-delay shifts of LD every second day (SHIFT) for 10 weeks. During this period, blood pressure (BP) was monitored weekly, and daily rhythms of melatonin, corticosterone, leptin and testosterone were evaluated at the end of the experiment. In Experiment 2, female rats were exposed to the identical shifted LD schedule for 12 weeks, and daily rhythms of BP, heart rate (HR) and locomotor activity were recorded using telemetry. Preserved melatonin rhythms were found in the pineal gland, plasma, heart and kidney of SHIFT rats with damped amplitude in the plasma and heart, suggesting that the central oscillator can adapt to chronic phase-delay shifts. In contrast, daily rhythms of corticosterone, testosterone and leptin were eliminated in SHIFT rats. Exposure to phase shifts did not lead to increased body weight and elevated BP. However, a shifted LD schedule substantially decreased the amplitude and suppressed the circadian power of the daily rhythms of BP and HR, implying weakened circadian control of physiological and behavioural processes. The results demonstrate that endocrine and cardiovascular rhythms can differentially adapt to chronic phase-delay shifts, promoting internal desynchronization between central and peripheral oscillators, which in combination with other negative environmental stimuli may result in negative health effects.     

Ultra-wideband electromagnetic pulses: Lack of effects on heart rate and blood pressure during two-minute exposures of rats

Exposure to fast-rise-time ultra-wideband (UWB) electromagnetic pulses has been postulated to result in effects on biological tissue (including the cardiovascular system). In the current study, 10 anesthetized Sprague-Dawley rats were exposed to pulses produced by a Sandia UWB pulse generator (average values of exposures over three different pulse repetition rates: rise time, 174–218 ps; peak E field, 87–104 kV/m; pulse duration, 0.97–0.99 ns). Exposures to 50, 500 and 1000 pulses/s resulted in no significant changes in heart rate or mean arterial blood pressure measured every 30 s during 2 min of exposure and for 2 min after the exposure. The results suggest that acute UWB whole-body exposure under these conditions does not have an immediate detrimental effect on these cardiovascular system variables in anesthetized rats. Bioelectromagnetics 19:330–333, 1998. Published 1998 Wiley-Liss, Inc.     

Modification of Baroreceptor Cardiac Reflex Function by Biofeedback

Baroreceptor sensitivity (BRS) is considered a powerful prognostic factor in cardiovascular health. This study investigated the possibility of modifying the baroreflex cardiac function through biofeedback. Thirty-two psychology students underwent 3 biofeedback sessions, with four 5-min trials each, in which they had to increase and decrease baroreflex function. BRS was assessed by a system that analyzed baroreflex cardiac function on-line using a noninvasive spontaneous sequence method in the time domain. Baroreceptor parameters were differentiated in terms of blood pressure increases ("up" sequences) or blood pressure decreases ("down" sequences). BRS in the "up" sequences increased during the Increase Condition and decreased during the Decrease Condition. BRS in the "down" sequences decreased during the Decrease Condition but was unchanged during the Increase Condition. The increase in BRS during the Increase Condition was associated with a significant reduction in blood pressure and increase in heart period. The opposite cardiovascular changes were observed during the Decrease Condition. Suggestions for future research were discussed.     

Effect of a single administration of somatostatin analogue (SMS 201-995) on GH, TSH and insulin secretion in patients with acromegaly

The effect of a long-acting somatostatin analogue SMS 201-995 on GH secretion was investigated. Eleven acromegalic patients received a single dose of 50 micrograms SMS 201-995 administered subcutaneously, and plasma GH, IGF-I, GRF, TSH, IRI and blood glucose were determined at regular intervals. Nine of 11 patients had elevated basal plasma GH levels above 5 ng/ml. In all patients, plasma GH levels fell immediately from 39.5 +/- 17.3 ng/ml (mean +/- SEM) to 4.3 +/- 1.6 ng/ml (P less than 0.05) with a maximal inhibition of 82.9 +/- 3.3% of the basal levels and the suppression persisted for about 6 h of the observation period. IGF-I and GRF levels were not apparently altered. TSH and IRI levels also rapidly fell. Blood glucose levels fell slightly by 0.5 h. Ten of 11 patients had pain at injection sites. Except for this, no side effects were observed. Our results show that the new somatostatin analogue SMS 201-995 may inhibit GH hypersecretion in acromegalic patients for significant periods, suggesting that this agent can be a useful clinical tool for the treatment of acromegaly.     

Effects of postnatal treatment with naloxone on plasma gonadotropin,prolactin, testosterone and testicular functions in male rats

Opioid peptides are implicated in the control of gonadotropin and prolactin secretion. The role of opioid antagonist naloxone and its effects on plasma gonadotropin, prolactin, testosterone levels and testicular hyaluronidase, acid phosphatase, [³H]uridine and thymidine incorporation, RNA, DNA and protein concentrations were evaluated in rats after administration of naloxone beginning day 1 through 21 and autopsied on 45, 60 and 90 days of age. Plasma gonadotropin and testosterone levels were significantly elevated after naloxone treatment. Testicular hyaluronidase and acid phosphatase activity increased till 60 days post treatment and declined thereafter. Concentrations of RNA and protein did not change significantly but the concentration of DNA declined at 45 and 60 days of age. These results suggest that endogenous opioid peptides exert regulatory influence on gonadotropin secretion which in turn control the testicular function in the male rat.     

Effects of RF exposure of teenagers and adults by CDMA cellular phones

Many cellular phone provocation studies have been conducted since the question of increased health risk from extended usage of cellular phones became a social issue. Internationally, most studies have been conducted regarding the effects of GSM cellular phones on blood pressure and heart rate of adult volunteers. On the other hand, very few provocation studies have been conducted regarding the physiological effects of CDMA phones on teenagers. In this study, two volunteer groups consisting of 21 teenagers and 21 adults were exposed to 300 mW of radio frequency (RF) electromagnetic field emitted by a CDMA cellular phone for half an hour. Physiological parameters such as systolic and diastolic blood pressures, heart rate, respiration rate, and skin resistance were simultaneously measured. All the parameters for both groups were unaffected during the exposure except for decreased skin resistance of the teenager group (P < .0001). For the regrouped 23 male and 19 female subjects, all the parameters for both groups were unaffected during the exposure except for decreased skin resistance of the male subjects (P = .0026). Those resistances at 10 min after the terminated exposure returned to the resistances at rest regardless of the different groups of age and sex.     

Two amino acids, located in transmembrane domains VI and VII, determine the selectivity of the peptide agonist SMS 201-995 for the SSTR2 somatostatin receptor.

Human somatostatin receptor subtypes (SSTR1-5) bind their natural ligands SRIF-14 and SRIF-28 with high affinity. By contrast, short synthetic SRIF analogues such as SMS 201-995, a peptide agonist used for the treatment of various endocrine and malignant disorders, display sub-nanomolar affinity only for the receptor subtype SSTR2. To understand the molecular nature of selective peptide agonist binding to somatostatin receptors we have now, by site-directed mutagenesis, identified amino acids mediating SMS 201-995 specificity for SSTR2. Sequentially, amino acids in SSTR1, a receptor subtype exhibiting low affinity for SMS 201-995, were exchanged for the corresponding SSTR2 residues. After three consecutive steps, in which eight amino acids were exchanged, a SSTR1 mutant receptor with high affinity for SMS 201-995 was obtained. Receptor mutants with different combinations of these eight amino acids were then constructed. A single Ser305 to Phe mutation in TM VII increased the affinity of SSTR1 for SMS 201-995 nearly 100-fold. When this mutation was combined with an exchange of Gln291 to Asn in TM VI, almost full susceptibility to SMS 201-995 was obtained. Thus, it is concluded that the specificity of SMS 201-995 for SSTR2 is mainly defined by these two amino acids in transmembrane domains VI and VII. Using the conjugate gradient method we have, by analogy to the well established structure of bacteriorhodopsin, built a model for SRIF receptor-ligand interactions that explains the importance of Gln291 and Ser305 for the selectivity of agonists.     

Somatostatin analogue (SMS 201-995) decreases plasma levels of corticotropin (ACTH) and corticotropin-releasing hormone in a patient with ectopic ACTH-producing tumors

Effects of long-acting somatostain analogue (SMS 201-995) on plasma corticotropin (ACTH) and corticotropin-releasing hormone (CRH) levels were studied in a patient (63-year-old woman) with ectopic ACTH-producing tumors associated with type I multiple endocrine neoplasia (MEN-I). The patient had undergone bilateral adrenalectomy. Plasma CRH, as well as plasma ACTH, beta-endorphin and alpha-MSH, increased. The hormone levels were dramatically decreased by acute administration of SMS 201-995. Moderately higher doses of dexamethasone (0.05 or 0.1 mg/kg a day) did not decrease plasma CRH or ACTH. An extremely high dose of dexamethasone (0.2 mg/kg a day), however, decreased plasma ACTH, but failed to decrease plasma CRH. Acute administration of SMS 201-995 further lowered the level of plasma ACTH even in this condition. In addition to the decrease in ACTH, SMS 201-995 decreased plasma CRH. Chronic administration of SMS 201-995 continuously decreased plasma CRH, ACTH and beta-endorphin. The decrease in these hormone concentrations accompanied the disappearance of hyperpigmentation. These results suggested that SMS 201-995 inhibits hypersecretion not only of ACTH but also of CRH, and that the agent is therapeutically useful in normalizing the hypersecretion of these hormones.