The new biology of histamine receptors

The physiologic functions of histamine have been recognized for more than 100 years, yet new roles are still being uncovered. Most importantly, a newly discovered receptor of the amine has helped refine our understanding of histamine. This new receptor, the histamine H₄ receptor (H₄R), has a higher affinity for histamine compared with the histamine H₁ receptor and appears to be more selectively expressed, found mainly on hematopoietic cells. H₄R is involved in chemotaxis and inflammatory mediator release by eosinophils, mast cells, monocytes, dendritic cells, and T cells. Studies in animal models using selective antagonists or H₄R-deficient mice have shown a role for the receptor in inflammation in vivo. In particular, H₄R antagonists have shown promise in experimental models of asthma and pruritus, two conditions where currently marketed antihistamines targeting the histamine H₁ receptor are not optimally effective in humans. Thus, a new class of H₄R-specific antihistamines may be distinctively effective in treating allergic diseases associated with chronic pruritus and asthma.     

Thyroid cysts: a new extra-adrenal site of aldosterone synthase expression and increased aldosterone content

BACKGROUND: The rapid re-accumulation of fluid following aspiration of thyroid cystic lesions suggests that active transport of sodium and water may be involved in volume regulation of these lesions. In this study we address the possibility that aldosterone may take part in this process. SUBJECTS AND METHODS: Thirty-one patients (29 women and two men), with a mean age of 52.7 +/- 13.2 years (range: 27-77 years) underwent evaluation for thyroid nodules that had a sonographic cystic component. Cystic fluid obtained by FNA biopsy was sent for cytological examination and biochemical measurements. In 10 patients, material was collected for RNA extraction and determination of aldosterone synthase expression by RT-PCR amplification. RESULTS: All lesions were benign, cystic, colloid nodules. Cyst fluid aldosterone levels as measured by routine radioimmunoassay (RIA) were elevated above the normal plasma levels in all but five patients. Mean aldosterone levels were 27.1 +/- 22.9 ng/dl (SD) (range: 5.9-117.5 ng/dl). In contrast, cyst cortisol values were in the low, low normal serum range (6.2 +/- 2.9 microg/dl, range: 0.2-10.2 microg/dl). Sodium, chloride and potassium levels were 137 +/- 4.7 mEq/l, 98 +/- 5 mEq/l and 4.9 +/- 1.4 mEq/l, respectively. Plasma aldosterone levels were normal in all patients tested. To confirm these results, 12 samples were assayed after extraction and chromatography using a highly specific antibody. Cyst aldosterone levels in this group were elevated above the normal serum range in all but one patient (mean concentration: 24.5 +/- 14.6 ng/dl, range: 8.72-40.1 ng/dl). In this group, 18(OH)B levels were within the normal plasma range (12-55 ng/dl) in all but one patient (34.9 +/- 17 ng/dl). Furthermore, aldosterone synthase mRNA expression was found in aspirates of four of 10 patients. CONCLUSIONS: The increased aldosterone concentration and the presence of aldosterone synthase expression suggest that aldosterone may be locally produced and secreted in thyroid tissue. The pathophysiological implications of this finding remain to be established.     

Chlorbutol, a new inhibitor of aldosterone biosynthesis identified during examination of heparin effect on aldosterone production

This study was designed to examine the mechanism whereby routine heparin therapy inhibits adrenal aldosterone production. In bovine adrenal glomerulosa cell suspensions, pure heparin, in concentrations up to 500 U/ml, had no significant effect on basal or angiotensin II-stimulated aldosterone production. A therapeutic preparation of heparin for parenteral use containing the preservative chlorbutol (2.8 X 10(-2) M) inhibited aldosterone production [67 +/- 8.7% (+/- SE); P less than 0.005]. Chlorbutol alone, in a dose-dependent manner, inhibited basal aldosterone production from 1548 +/- 355 to 316 +/- 152 pg/ml (P less than 0.001) and inhibited angiotensin II-stimulated production from 4950 +/- 724 to 589 +/- 257 pg/ml (P less than 0.001). To elucidate the inhibitory mechanism of chlorbutol, we used trilostane, an inhibitor of the conversion of pregnenolone to progesterone, and aminoglutethimide, an inhibitor of the conversion of cholesterol to pregnenolone. Aldosterone production was completely suppressed by each inhibitor. Pregnenolone accumulation in trilostane-treated cells fell from 9.70 +/- 1.66 to 1.40 +/- 0.28 ng/ml (P less than 0.005) with the addition of chlorbutol. Aldosterone accumulation from corticosterone added to aminoglutethimide-treated cells fell from 715 +/- 96 to 348 +/- 59 pg/ml (P less than 0.02) in cells incubated with chlorbutol. Thus, chlorbutol is a potent inhibitor of aldosterone production, inhibiting both the early biosynthetic phase and, to a lesser extent, the late phase. Since chlorbutol is a widely used pharmaceutical preservative and has a slow metabolic clearance, these findings may be of toxicological significance and may account for the inhibition of aldosterone production previously attributed to heparin.     

The evolution of aldosterone antagonists

Since the isolation and purification of aldosterone from adrenal extracts 50 years ago (Experientia 9 (1953) 33), scientists have learned a great deal about how and where aldosterone acts, the factors that control its release, what is its role in the pathophysiology of cardiovascular disease, how to make and study aldosterone antagonists, and for what medical purposes these agents are useful. In this paper, we will discuss the evolution of aldosterone antagonists from the relatively nonselective spironolactone (Aldactone), to the highly selective eplerenone (Inspra). Eplerenone represents a molecule with improved steroid receptor selectivity and pharmacokinetic properties in man compared to spironolactone. Recent clinical results have demonstrated that these improvements translate into tolerability and efficacy in patients with cardiovascular disease.     

The use of selective aldosterone antagonists

Mineralocorticoid hormones, specifically aldosterone, have been shown to be increasingly important in the development and maintenance of cardiovascular disorders, particularly hypertension and congestive heart failure. The use of the mineralocorticoid receptor blocker, spironolactone, has been fraught with side effects, largely related to the poor specificity of this agent. Eplerenone, a new and more specific mineralocorticoid receptor blocker with little effect on sex-hormone receptors, has offered an alternative approach. Many studies in hypertension as well as a major and compelling study in congestive heart failure have documented the efficacy and specificity of eplerenone with a minimum of side effects. The major findings with this new agent are presented herein.     

肺癌分子生物学的临床应用进展

20世纪 8 0年代以来 ,肺癌的病因、诊断、预后及临床治疗均进行了大量的现代分子生物学研究 ,并已初步认识到肺癌的发生、发展、侵袭、转移以及多药耐药的形成 ,都与人体内细胞基因结构和功能异常有关 ,包括癌基因的突变和激活 ;抑癌基因的突变和失活 ;基因不稳定性 ;端粒酶相关的细胞永生性激活 ;自分泌和旁分泌生长因子的激活 ;肿瘤血管生长因子的激活 ;宿主抗肿瘤免疫基因的破坏 ;转移抑制相关基因异常等。目前在肺癌分子生物学研究领域 ,已初步形成肺癌“分子诊断”、“分子指征”、“分子预后”、“分子分期”和“分子治疗”等新理论和…     

The regulation of aldosterone synthase expression

Vitamin D 1alpha-hydroxylase (1alpha(OH)ase), which converts the circulating prohormone 25-hydroxyvitamin-D(3) (25(OH)D(3)) to the active 1alpha-25-dihydroxyvitamin-D(3) (1,25(OH)(2)D(3)), is present in normal prostatic epithelium. However, prostate cancer cells, both primary cultured cells and cell lines, have greatly decreased activity of 1alpha(OH)ase and are therefore resistant to the tumor suppressor activity of circulating 25(OH)D(3). We quantitated 1alpha(OH)ase mRNA and protein levels to investigate mechanism(s) responsible for decreased 1alpha(OH)ase enzymatic activity in prostate cancer. Prostate cancer cell lines had low 1alpha(OH)ase mRNA levels. Primary prostate cell cultures derived from normal and cancer tissues had equivalent levels of 1alpha(OH)ase RNA and protein. Equivalent 1alpha(OH)ase protein levels were observed in prostate tissue sections containing normal and malignant cells. The protein levels of hsc70, whose homolog intracellular Vitamin D binding protein (IDBP-1) facilitates delivery of 25(OH)D(3) to 1alpha(OH)ase in monkey cells, were equivalent in the normal and cancer cells. Equivalent activity in normal and cancer cells of Vitamin D 24-hydroxylase, a mitochondrial enzyme that also uses 25(OH)D(3) as a substrate, further ruled out lack of access to substrate as a basis for low activity of 1alpha(OH)ase in cancer cells. We conclude that diminished 1alpha(OH)ase activity in prostate cancer cell lines is through decreased gene expression, whereas decreased activity in primary cultures and tissues is post-translational.     

The effect of aldosterone on glucose metabolism

There is an association of glucose intolerance and diabetes with primary aldosteronism, but the frequency and mechanisms are not clear. This paper reviews the possible mechanisms of impaired glucose metabolism in primary aldosteronism. Patients with primary aldosteronism can have impaired pancreatic insulin release and reduction in insulin sensitivity. These effects may be due to hypokalemia, but the evidence suggests other factors such as a direct impact of excess aldosterone on insulin action in contributing to the metabolic dysfunction. In general adrenal surgery in cases of aldosterone-producing adenoma will correct the metabolic abnormalities, but it is less sure if treatment with spironolactone in cases of idiopathic hyperplasia will correct impaired glucose tolerance.