Influence of propranolol coadministration or cigarette smoking on the kinetics of desmethyldiazepam following intravenous clorazepate

Summary The influence of propranolol coadministration or of cigarette smoking on the kinetics of desmethyldiazepam following a single 20-mg intravenous dose of clorazepate dipotassium was evaluated in healthy volunteers. In Study One, intravenous clorazepate was given once in the control condition, and again during coadministration of propranolol, 80 mg twice daily. Compliance with the prescribed propranolol regimen was verified by measurement of serum propranolol concentrations (mean, 37 ng/ml). In control vs propranolol treatment conditions, there was no significant difference in desmethyldiazepam volume of distribution (1.27 vs 1.23 liters/kg) or in free fraction in serum (1.83 vs 1.80% unbound). There was a small although statistically significant prolongation of desmethyldiazepam half-life (55 vs 61 h,P<0.05) and reduction in clearance (0.281 vs 0.247 ml/min/kg,P<0.02) attributable to propranolol. In Study Two, desmethyldiazepam kinetics were compared in eight cigarette smokers (mean, 19 cigarettes/day) and in 11 nonsmoking controls matched for age, sex, and body weight. There was no significant difference between controls and cigarette smokers in desmethyldiazepam volume of distribution (1.29 vs 1.34 liters/kg), elimination half-life (55 vs 59 h), clearance (0.284 vs 0.276 ml/min/kg), or free fraction in serum (1.96 vs 1.92% unbound). Thus, propranolol slightly although significantly impairs the clearance of desmethyldiazepam and prolongs its halflife. Cigarette smoking has no apparent influence on desmethyldiazepam kinetics.Supported in part by grants Oc 10/6–4 from the Deutsche Forschungsgemeinschaft and grants MH-34223 and AG-00106 from the United States Public Health ServicePart of doctoral thesis J. Weinbrenner, Bonn 1986     

Adrenergic regulation of [H]ketanserin binding sites during immobilization stress in the rat frontal cortex

Acute immobilization stress increased serotonin and 5-hydroxyindoleacetic acid levels, the 5-hydroxyindoleacetic/serotonin ratio, and the number of [³H]ketanserin binding sites, representing serotonin-2 type receptors, in the rat frontal cortex. Peripheral administration of propranolol or central administration of 6-hydroxydopamine abolished the stress induced elevation of [³H]ketanserin binding sites. Treatment with 6-hydroxydopamine did not affect the increase in serotonin and 5-hydroxyindoleacetic acid levels, and enhanced the increase in the 5-hydroxyindoleacetic acid/serotonin ratio produced by stress. Conversely, chemical serotoninergic denervation with 5,7-dihydroxytryptamine had no influence on the stress-induced elevation of [³H]ketanserin binding sites, but abolished the serotonin and 5-hydroxyindoleacetic acid increase produced by stress. These results suggest that an intact serotoninergic system is not essential for serotonin-2 type receptor regulation during stress. Instead, the noradrenergic system, most probably through stimulation of β-adrenoreceptors, may control the regulation of [³H]ketanserin binding sites in the rat frontal cortex during acute stress.     

Neither adrenergic nor cholinergic antagonists in the central nervous system affect 2-deoxy-d-glucose(2-DG)-induced hyperglycemia

To investigate whether the brain adrenergic and cholinergic neurotransmitter systems are involved in the regulation of 2-deoxy-d-glucose (2-DG)-induced hyperglycemia, we studied the effects of adrenergic and cholinergic antagonists on 2-DG-induced secretion of epinephrine and glucagon, and hyperglycemia, in anesthetized fed rats. When 2-DG (10 mg/10 μl) was injected into the third cerebral ventricle, hepatic venous plasma glucose, glucagon, and epinephrine concentrations were significantly increased. Co-administration of phentolamine, propranolol, atropine and hexamethonium (1 × 10⁻⁷ mol) with 2-DG did not modify the hyperglycemia responses normally observed after the administration of 2-DG alone. From this evidence we concluded that neither brain adrenoceptive nor cholinoceptive neurons are involved in the regulation of 2-DG-induced hyperglycemia.     

Pulmonary valve stenosis associated with hypertrophic cardiomyopathy

Summary The association of pulmonic stenosis with hypertrophic cardiomyopathy is rare in infancy. Presented here is an infant with atypical picture of pulmonic stenosis and echocardiographic evidence of hypertrophic cardiomyopathy. At eight months of age, she had a successful percutaneous balloon valvuloplasty and has subsequently been managed with propranolol.     

雌二醇对大鼠离体胃平滑肌收缩活动的影响

目的 观察雌二醇对大鼠离体胃平滑肌收缩活动的影响，并探讨其可能的作用机制。方法 取大鼠离体平滑肌条，将其置于灌流肌槽中，经张力换能器将信号输入生理记录仪，记录股条的等长收缩活动。结果 雌二醇显著地降低胃底纵行肌及胃体纵行肌和环行肌张力，减少胃体、胃窦纵行肌和环行肌收缩波平均振幅及幽门环行肌运动指数，其作用不被六烃季胺、消炎痛、心得安、酚妥拉明及L-NNA所阻断。结论 雌二醇可抑制大鼠离体胃平滑肌收缩活动，可能是直接作用于胃平滑肌细胞或通过其他受体起作用。     

Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through β-adrenoceptors blockade and COX2 inhibition

Liver metastases are a major cause of colorectal cancer death, and the perioperative period is believed to critically affect the metastatic process. Here we tested whether blocking excess release of catecholamines and prostaglandins during surgical procedures of different extent can reduce experimental liver metastasis of the syngeneic CT26 colon cancer in female and male BALB/c mice. Animals were either treated with the beta-blocker, propranolol, the COX-2 inhibitor, etodolac, both drugs, or vehicle. The role of NK cells in controlling CT26 hepatic metastasis and in mediating the effect of the drugs was assessed by in vivo depletion or stimulation of NK cells, using anti-asialo GM1 or CpG-C, respectively. Surgical extent was manipulated by adding laparotomy to small incision, extending surgical duration, and enabling hypothermia. The results indicated that combined administration of propranolol and etodolac, but neither drug alone, significantly improved host resistance to metastasis. These beneficial effects occurred in both minor and extensive surgeries, in both sexes, and in two tumor inoculation approaches. NK cell-mediated anti-CT26 activity is involved in mediating the beneficial effects of the drugs. Specifically, CpG-C treatment, known to profoundly activate mice marginating-hepatic NK cytotoxicity, reduced CT26 hepatic metastases; and NK-depletion increased metastases and prevented the beneficial effects of the drugs. Overall, given prevalent perioperative psychological and physiological stress responses in patients, and ample prostaglandin release by colorectal tumors and injured tissue, propranolol and etodolac could be tested clinically in laparoscopic and open colorectal surgeries, attempting to reduce patients’ metastatic disease.     

The Role of the Beta-Adrenergic Receptor in the Secretion of Gastrin: Studies in Normal Subjects and in Patients with Duodenal Ulcers

Intravenous infusion of isoproterenol, a beta-adrenergic receptor stimulatory agent, increased serum gastrin concentration significantly more in patients with a duodenal ulcer than in healthy subjects. The rise in pulse rate, blood glucose concentration and in serum insulin was the same in both groups of subjects. Gastrin secretion was also increased significantly more in the patients than in the control subjects after a beef-meal. Basal serum gastrin concentrations were higher in the patients than in the control subjects and correlated to the rise in serum gastrin during both tests in the patients with a duodenal ulcer. Isoproterenol and meal stimulated gastrin secretion, expressed as percent of the basal value, were twice as high in the patients as in the control subjects. The combined administration of isoproterenol and the meal had an additive effect on the rise in serum gastrin. Isoproterenol stimulated gastrin secretion was completely suppressed by propranolol, a beta-adrenergic receptor blocking agent, which had no effect on meal stimulated gastrin secretion. It is concluded that the mechanism of the hypersecretion of gastrin in patients with a duodenal ulcer did not involve a specific abnormality of the beta-adrenergic receptor or the receptor which recognized proteins and their digested products. There is no established role of beta-adrenergic receptor activity in the hypersecretion of gastrin in patients with duodenal ulcers. It is suggested that the beta-adrenergic receptor may have some yet unknown function unrelated to the acute secretory response of gastrin.     

普萘洛尔在甲状腺功能亢进症孕产妇中的应用

甲状腺功能亢进症(甲亢)和妊娠同时存在的病例临床并不少见,这类孕妇的药物治疗中,普萘洛尔的适应证和禁忌证大多教科书常常没有提及,因此值得讨论.少数文献报道该药可增加自然流产几率,并可致胎儿宫内发育迟缓、心动过缓、出生后呼吸窘迫等异常.相关动物试验显示,普萘洛尔可减缓心率,且对胎肺β受体的阻滞可能导致胎儿出生后呼吸窘迫.大部分学者认为,在常规剂量下,该药没有临床致畸性,应用于妊娠期是相对安全的.也有专家认为,普萘洛尔应尽量短期使用以减少其可能的副作用,如在抗甲状腺药物起效之前的数周以及甲状腺危象时应用.胎儿在出生以后因药物在体内重新分布导致血浆药物浓度升高,建议产前减少药物用量.而在哺乳期,婴儿经乳汁摄取的药物极少,治疗剂量的产妇哺乳是安全的.另外,普萘洛尔还可安全地用于保守治疗难以控制的妊娠剧吐.     

去甲肾上腺素对胶质母细胞瘤侵袭迁移能力的影响及机制研究

目的   研究应激激素去甲肾上腺素(NE)对胶质母细胞瘤侵袭迁移能力的影响及机制,并探讨β受体阻断剂普萘洛尔(propranolol)抗应激所致肿瘤侵袭转移的可行性。方法   培养胶质母细胞瘤细胞系T98G、U251及U87,采用RT-PCR检测胶质瘤细胞系β肾上腺素能受体表达,Transwell评价NE对胶质瘤细胞侵袭迁移的影响,明胶酶谱法检测NE对胶质瘤细胞系MMP 2分泌水平影响。结果   随NE浓度增加(0.1~10μmol/L),胶质瘤细胞侵袭力逐渐增强(P>0.05),普萘洛尔(1nmol/L)可抑制此效应;随NE浓度增加(0.1~10μmol/L),胶质瘤细胞基质金属蛋白酶 2(MMP-2)分泌显著增多,普萘洛尔(1nmol/L)可抑制NE诱导的MMP 2分泌。结论   应激激素去甲肾上腺素可以促进胶质母细胞瘤MMP-2分泌酶活性从而增强其迁移能力,普萘洛尔可以抑制NE诱导的胶质瘤侵袭增强。