肾上腺皮质球状带细胞的电兴奋性与醛固酮分泌:离子通道的作用

醛固酮是肾上腺皮质球状带(ZG)细胞产生的类固醇类激素,对体液电解质平衡和血压稳定起着关键调控作用。醛固酮生成是一个钙离子依赖性的过程,离子通道在这一过程中扮演着关键角色。临床上发现的原发性醛固酮增多症大多与离子通道的突变有关。最近ZG细胞独特的rosette结构与其电兴奋性的关系引起了更多研究兴趣。阐明rosette与ZG细胞电兴奋性以及醛固酮分泌之间的关系,有助于更深入地了解调节醛固酮分泌的机制,为原发性醛固酮增多症的发病机制提供新见解。

BENZODIAZEPINE RECEPTORS IN ISOLATED ADRENAL GLOMERULOSA CELLS

In our experiments the isolated rat adrenal glomerulosa cells displayed perlpheral-type benzodiazepine receptors, which could bind to [3H] PKl1195 with an apparent equilibrium dissociation constant （KD） of 9.4±2.8 nmol/L and a maximal binding capacity (Bmax) of 5.6q-1.8 pmol/106 cells. The effects of five ligands: PKl1195, Ro5--4846, flunitrazepam, diazepam and clonazepam on aldosterone secretion responses of isolated glomerulosa cells to anglotensin Ⅱ or extracellular potassium ions were observed. The logarithm of EO50 for these ligands as stimulators was well correlated with the logarithm of their Ki value for [3H] PK11195 binding, suggesting that the stimulative effects might be mediated by the benzodiazepine receptor in isolated glomerulosa cells.

Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II(Ang II). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure(HF), is induced by Ang II type 1 receptors(AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1(βarr1) or-2(βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 proteinindependent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers(ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes(G protein-, and βarr1-dependent) at the Ang IIactivated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by Ang II and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-"biased" blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan(and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

慢性低氧大鼠肾上腺皮质球状带的变化

将Ｗｉｓｔａｒ大鼠喂养在逐渐降低的常压低氧条件下，用氮气和空气的混合气体调节氧含量。氧浓度由正常含量逐步降低为１５％、１２％、１０％、８％，最后降至７％，实验共进行１１２ｄ。结果显示低氧动物体重下降，肾上腺重量减少，肾上腺皮质球状带萎缩，脂质丢失，球状带细胞线粒体肿胀和空泡变性，溶酶体增多。表明在慢性常压低氧中，当吸入气氧含量降至７％时，可导致肾上腺皮质球状带细胞超微结构改变，从而影响醛固酮的合成与分泌。

Nicotine-induced adrenal beta-arrestin1 upregulation mediates tobacco-related hyperaldosteronism leading to cardiac dysfunction

BACKGROUND Tobacco-related products,containing the highly addictive nicotine together with numerous other harmful toxicants and carcinogens,have been clearly associated with coronary artery disease,heart failure,stroke,and other heart diseases.Among the mechanisms by which nicotine contributes to heart disease is elevation of the renin-angiotensin-aldosterone system(RAAS)activity.Nicotine,and its major metabolite in humans cotinine,have been reported to induce RAAS activation,resulting in aldosterone elevation in smokers.Aldosterone has various direct and indirect adverse cardiac effects.It is produced by the adrenal cortex in response to angiotensin II(AngII)activating AngII type 1 receptors.RAAS activity increases in chronic smokers,causing raised aldosterone levels(nicotine exposure causes the same in rats).AngII receptors exert their cellular effects via either G proteins or the twoβarrestins(βarrestin1 and-2).AIM Since adrenal?arrestin1 is essential for adrenal aldosterone production and nicotine/cotinine elevate circulating aldosterone levels in humans,we hypothesized that nicotine activates adrenal?arrestin1,which contributes to RAAS activation and heart disease development.METHODS We studied human adrenocortical zona glomerulosa H295R cells and found that nicotine and cotinine upregulateβarrestin1 mRNA and protein levels,thereby enhancing AngII-dependent aldosterone synthesis and secretion.RESULTS In contrast,siRNA-mediatedβarrestin1 knockdown reversed the effects of nicotine on AngII-induced aldosterone production in H295 R cells.Importantly,nicotine promotes hyperaldosteronism via adrenalβarrestin1,thereby precipitating cardiac dysfunction,also in vivo,since nicotine-exposed experimental rats with adrenal-specificβarrestin1 knockdown display lower circulating aldosterone levels and better cardiac function than nicotine-exposed control animals with normal adrenalβarrestin1 expression.CONCLUSION Adrenalβarrestin1 upregulation is one of the mechanisms by which tobacco compounds,like nicotine,promote cardio-toxic hyperaldosteronism in vitro and in vivo.Thus,adrenalβarrestin1 represents a novel therapeutic target for tobaccorelated heart disease prevention or mitigation.

斑马肾上腺的组织学研究(英文)

探明斑马肾上腺的组织学结构,为深入研究斑马的生理学、病理学和保护濒危物种的生物多样性提供形态学依据。采用石蜡切片,HE染色和Masson染色技术,显微摄影,以及图像分析技术,与家畜的肾上腺进行比较,研究了斑马肾上腺的组织结构特点。结果显示斑马肾上腺具有以下特点:表面结缔组织被膜较厚,平均厚度大约230μm。被膜内有大量神经和血管分布。皮质约为髓质面积的5倍。皮质球状带厚度大约300μm,比较薄,细胞排列成柱状、团块状;束状带厚度1750μm左右,约为球状带的6倍,细胞排列成条索状;网状带厚度250μm左右,网状带细胞与髓质紧密相邻并与之形成参差不齐的锯齿状界限;网状带中含有神经元。斑马髓质染色比较深,面积大约4mm2,髓质细胞比较大,胞质嗜碱性。髓质中未见到交感神经节细胞;髓质中央静脉内壁局部发现有结缔组织,且其中含有神经元。该研究结果为深入研究斑马的形态学、生理学和病理学提供可靠的形态学依据。

苯二氮受体调控醛固酮分泌机制中Ca^(2+)和cAMP的作用

外周型苯二氮受体的配体PK11195增强大鼠肾上腺皮质球状带细胞醛固酮分泌的效应可被主要作用于胞浆膜Ca^(2+)通道的阻断剂硝苯啶所取消,而不被选择性作用于线粒体Ca^(2+)通道的阻断剂硝苯啶呋海因(Da—ntrolene)所取消。PK11195在其增强醛固酮分泌的最大效应条件下并不影响球状带细胞内cAMP水平。本文的结果表明苯二氮(?)受体调控醛固酮分泌的机制中,细胞内信使物质不是cAMP,也不是来自线粒体的Ca^(2+),而是来自胞浆膜外的Ca^(2+)。

The Role of Ca^(2+) and Cyclic AMP in the Modulation of BenzodiazepineReceptor on Aldosterone Secretion

PK11195, a ligand of peripheral-type benzodiazepine receptor can stimulate thealdosterone secretion of isolated adrenal glomerulosa cell: this effect could be abolished by nifedipinewhich mainly blocks the calcium channel in plasma membrane, but could not be abolished bydantrolene, a selective blocker of mitochondria calcium channel. Even under the condition of themaximum stimulative effects on aldosterone secretion, PK11195 could not change the cyclic AMP（cAMP） content in isolated glomerulosa cells. These results indicated that in the modulatory mecha-nism of benzodiazepine receptor on aldosterone secretion, the intracellular messenger might be theCa2+ from extracellular Ca2+ pool, but not the Ca2+ from mitochondria Ca2+ pool or cAMP.