Studies on the autonomic nervous system in borderline hypertension

Summary Parameters of the autonomic nervous system were studied in normotensive subjects (NT; standing blood pressure (BP)125/85 mmHg) and in subjects with borderline hypertension (BHT; 140/90standing BP<60/100 mmHg). No differences in plasma noradrenaline and adrenaline levels were found between NT and BHT subjects, neither at rest nor during exercise at 75% of maximum work capacity. The dose of noradrenaline required to increase systolic BP by 10 mmHg was significantly higher in NT than in BHT subjects (5.13±0.42 vs 3.50±0.57 µg · min^–1). No difference between NT and BHT subjects was found in the dose of isoprenaline required to increase heart rate by 20 beats · min^–1 (1.21±0.12 vs 1.09±0.11 µg · min^–1). Resting salivary flow was significantly lower in BHT than in NT subjects (0.39±0.06 vs 0.98±0.06 g · min^–1), suggesting decreased parasympathetic activity in the former group. The enhanced pressor effect of noradrenaline, together with the decreased parasympathetic activity, could explain the elevated blood pressure and heart rate in subjects with borderline hypertension.     

异丙肾上腺素调节窦房结起搏细胞延迟整流钾通道信号传递机制的研究

采用全细胞膜片钳技术研究β-受体激动剂异丙肾上腺素调节窦房结起搏细胞延迟整流钾通道信号传递机制。结果发现 ,采用 c AMP-依赖性蛋白激酶抑制剂 (H- 89)选择性阻断 c AMP-依赖性蛋白激酶磷酸化途径后 ,异丙肾上腺素依赖性 Ik 激活被抑制 ,而用选择性蛋白激酶 C抑制剂 Bisindolymaleim ide(磷酸化途径 )后则异丙肾上腺素依赖性 Ik 激活未能被抑制。提示异丙肾上腺素调节 Ik 的信号传递机制主要通过 c AMP-依赖性蛋白激酶 (PKA)磷酸化途径。     

左旋精氨酸通过激活L-arg-NO通路对异丙肾上腺素致大鼠心力衰竭的作用

目的 探究左旋精氨酸( L-arg)通过激活L-arg-NO通路对异丙肾上腺素( ISO)导致的大鼠心力衰竭的保护作用.方法 雄性SD大鼠随机分为对照组、ISO组、L-arg干预组.腹腔注射ISO复制大鼠心力衰竭模型,灌胃给予L-arg. 30 d后监测血流动力学参数:心率( HR)、左室收缩压力( LVSP)、左室舒张末期压力( LVEDP )、左室压力最大上升或下降速率( ± dp/dtmax ) ,计算心肺系数,检测血清超氧化物歧化酶( SOD)、肿瘤坏死因子-α( TNF-α)、一氧化氮( NO)含量以及一氧化氮合酶( NOS)活性;HE染色观察心肌组细胞排列;Masson染色观察心肌胶原纤维并计算心肌胶原纤维容积分数( CVF). 结果 与对照组比较,ISO组大鼠血流动力学参数:HR、LVSP、+dp/dtmax降低,LVEDP、-dp/dtmax升高,心肺系数增加,血清TNF-α、SOD升高, NO、NOS降低,差异均有统计学意义(P<0. 05). L-arg干预组HR、LVSP、+dp/dtmax均高于ISO组,LVEDP、-dp/dtmax、心肺系数低于ISO组,血清SOD和TNF-α降低,NO和NOS增加,差异均有统计学意义(P<0. 05). HE染色显示对照组心肌细胞形态正常,间质无扩张充血,心肌细胞排列整齐;ISO组心肌细胞排列紊乱,炎性细胞浸润,而 L-arg 干预组心肌细胞接近对照组.ISO组Masson染色心肌细胞间可见大量蓝染的胶原纤维,而对照组观察不到蓝染区域, L-arg干预组在对照组与ISO组之间;ISO组CVF明显高于L-arg干预组(P<0. 05),L-arg干预组高于对照组( P<0. 05 ). 结论 L-arg可以通过激活L-arg-NO通路,增加机体内 NO 含量,改善血流,减轻心肌重构,产生对心力衰竭心肌的保护作用.     

Mechanisms involved in the regulation of bovine pulmonary vascular tone by the 5-HT1B receptor

Background and purpose:

5-HT_1B receptors may have a role in pulmonary hypertension. Their relationship with the activity of BK_Ca, a T-type voltage-operated calcium channel (VOCC) and cyclic nucleotide-mediated relaxation was examined.

Experimental approach:

Ring segments of bovine pulmonary arteries were mounted in organ baths in modified Krebs–Henseleit buffer (37^oC) under a tension of 20 mN and gassed with 95% O₂/5% CO₂. Isometric recordings were made using Chart 5 software.

Key results:

Contractile responses to 5-HT (10 nM–300 µM) were inhibited similarly by the 5-HT_1B receptor antagonist SB216641 (100 nM) and the T-type VOCC blockers mibefradil (10 µM) and NNC550396 (10 µM) with no additive effect between SB216641 and mibefradil. Inhibition by SB216641 was prevented by the potassium channel blocker, charybdotoxin (100 nM). 5-HT_1B receptor activation and charybdotoxin produced a mibefradil-sensitive potentiation of responses to U46619. Bradykinin (0.1 nM–30 µM), sodium nitroprusside (0.01 nM–3 µM), zaprinast (1 nM–3 µM), isoprenaline (0.1 nM–10 µM) and rolipram (1 nM–3 µM) produced 50% relaxation of arteries constricted with 5-HT (1–3 µM) or U46619 (30–50 nM) in the presence of 5-HT_1B receptor activation, but full relaxation of arteries constricted with U46619, the 5-HT_2A receptor agonist 2,5 dimethoxy-4 iodoamphetamine (1 µM) or 5-HT in the presence of 5-HT_1B receptor antagonism. Enhanced relaxation of 5-HT-constricted arteries by cGMP-dependent pathways, seen in the presence of the 5-HT_1B receptor antagonist, was reversed by charybdotoxin whereas cAMP-dependent relaxation was only partly reversed by charybdotoxin.

Conclusions and implications:

5-HT_1B receptors couple to inhibition of BK_Ca, thus increasing tissue sensitivity to contractile agonists by activating a T-type VOCC and impairing cGMP-mediated relaxation. Impaired cAMP-mediated relaxation was only partly mediated by inhibition of BK_Ca.     

大黄蛰虫丸对异丙肾上腺素诱导大鼠心肌纤维化的影响

目的:探讨大黄蛰虫丸抗心肌纤维化作用及其初步机制.方法:50只SD大鼠随机分为正常对照组,模型对照组,阳性对照组,大黄蛰虫丸高、低剂量组.除正常对照组外,其他4组大鼠背部皮下注射异丙肾上腺素( Iso)5 mg·kg-1,连续10 d,建立大鼠心肌纤维化模型.造模同时阳性对照组按照每日1 g·kg-1剂量灌胃给予丹参,大黄蛰虫丸高、低剂量组分别按照每日3.2,1.6 g·kg-1剂量灌胃给药,每天1次,连续28 d.正常对照组和模型对照组给予等体积的生理盐水.观察大黄蛰虫丸对大鼠心脏指数,心肌病理学变化,心肌组织中羟脯氨酸( Hyp)含量,超氧化物歧化酶(SOD)活性,丙二醛(MDA)含量等的影响.结果:与正常对照组比较,模型对照组心脏指数增加,心肌组织出现明显的胶原纤维增生,心肌组织Hyp含量明显增高,胶原容积积分(CVF)与血管周围胶原面积/血管腔横断面积(PVCA)显著升高(P＜0.01),SOD活性下降,MDA含量增高(P＜0.05).与模型对照组相比,大黄蛰虫丸高、低剂量组心肌纤维化病变减轻,心肌组织Hyp含量下降,CVF,PVCA减小(P＜0.05或P＜0.01),SOD活性与MDA含量无明显变化.结论:大黄蛰虫丸能够抑制心肌纤维化的发生发展,逆转心肌重构,但该作用可能与抗脂质过氧化作用无关.     

原发性痛经寒凝血瘀证药效评价模型的建立

目的建立原发性痛经寒凝血瘀证大鼠模型,并在模型大鼠上,确定异丙肾上腺素诱导产热的最适剂量及催产素诱导子宫痉挛性收缩的最适剂量。方法 36只大鼠切除背部棕色脂肪7d后,丙硫氧嘧啶连续灌胃42d,术后21d开始雌激素连续灌胃28d,建立痛经寒凝血瘀证模型。在中性环境温度(28℃)下,d40乙醚浅麻醉苏醒后,生物机能检测系统连续监测尾静脉推注等比剂量异丙肾上腺素前30min和给药后120min,计算单位时间的温度曲线下面积,以给药前后单位时间曲线下面积的变化率计算诱导产热的ED50;d42水合氯醛麻醉下,尾静脉推注等比剂量的催产素,生物机能检测系统连续监测给药前后各30min的大鼠宫腔压力曲线下面积,以给药前后的面积变化率计算诱导宫缩的ED50。结果成功建立了原发性痛经寒凝血瘀证的大鼠模型。异丙肾上腺素诱导该模型大鼠产热的ED50为0.210μg·g-1,95%置信区间为0.167～0.264μg·g-1;催产素诱导宫缩的ED50为0.028U·g-1,95%置信区间为0.012～0.066U·g-1。结论建立了原发性痛经寒凝血瘀证的大鼠模型;在造模大鼠上,确定了异丙肾上腺素诱导适应性产热和催产素诱导子宫痉挛的最适剂量,作为评价原发性痛经痉挛性疼痛程度及其受局部温度影响的准确指标及观察条件。     

依那普利抗异丙肾上腺素诱导的心肌纤维化作用及机制

目的观察依那普利(enalapril,Ena)抗异丙肾上腺素(Isoprenaline,Iso)诱导的心肌纤维化作用并探讨其作用机制。方法异丙肾上腺素皮下注射致心肌纤维化模型,经Ena低、中、高(2.5、5.0、10.0 mg.kg-1)3个剂量组和阳性对照药卡托普利(100.0 mg.kg-1)治疗后观察其对心肌组织胶原变化、心室重量(HW/BW)和心室重量指数(LVI)、羟脯氨酸含量及免疫组化和Western blot检测TGF-β1表达的影响。结果Ena不同剂量组均能够降低心肌组织胶原含量(P<0.05或P<0.01),降低HW/BW和LVI(P<0.05或P<0.01),降低羟脯氨酸含量(P<0.05或P<0.01),减少TGF-β1在心肌组织中的表达(P<0.05或P<0.01),减轻心肌纤维化。结论Ena通过抑制TGF-β1表达抗Iso诱导的心肌纤维化。     

胍丁胺对异丙肾上腺素诱发人心房纤维迟后除极的影响(英文)

用标准微电极技术研究胍丁胺对异丙肾上腺素 ( Iso)诱发人心房纤维迟后除极的影响 .结果如下 :( 1 )胍丁胺 ( 1 - 1 0 mmol· L-1)以浓度依赖地方式明显抑制 Iso( 2 0 nmol· L-1)诱发人心房纤维的迟后除极 ;( 2 )预先应用咪唑啉受体和 α2 肾上腺素受体拮抗剂咪唑克生 ( 0 .1 mmol· L-1)可阻断胍丁胺 ( 1 0 mmol· L-1)对 Iso( 2 0 nmol· L-1)诱发迟后除极的抑制作用 ;( 3)预先应用一氧化氮合酶抑制剂硝基 - L-精氨酸甲酯 ( 0 .5mmol· L-1) ,不影响胍丁胺 ( 1 0 mmol· L-1)对 Iso( 2 0 nmol· L-1)诱发迟后除极的抑制作用 .结果表明 ,胍丁胺对 Iso诱发人心房纤维迟后除极的抑制作用可能是由于咪唑啉受体和 α2 肾上腺素受体介导钙内流减少所致 .     

Dyssynchrony of segment shortening in the anterior wall of the feline left ventricle

Non-uniformity of regional contraction may be both spatial and temporal. This study was undertaken to deal with the temporal aspects of shortening and to quantify non-uniformity with regard to timing. Nine cats were anaesthetized and artificially ventilated. Two pairs of ultrasonic crystals were situated in the anterior midwall of the left ventricle to measure regional shortening. One pair, longitudinal segment, was oriented to align with midwall fibres. The other pair, transverse segment, was placed perpendicular to the first one. Registrations in control state, during caval occlusion, and during aortic constriction were carried out with and without isoprenaline infusion. Cyclic events were analysed in terms of phase angle, 0–2π representing one heart cycle. Transverse segments showed marked shift of duration of shortening, from 1.19π± 0.06π (meanæM) in the control state to 0.40π± 0.14π during caval occlusion with isoprenaline infusion. Duration of shortening of longitudinal segments showed less prominent shift with mean values between 1.38π and 1.11π. Regional uniformity of timing, expressed as synchronization index, varied markedly with interventions (P < 0.0005). Dyssynchrony was most prominent during caval occlusion with mean values less than 0.6. A simple model of force generation for the two segments visualizes that segment shortening of the transverse segment is of shorter duration than the longitudinal segment and a common mechanism for temporal and spatial non-uniformity within a region could be elaborated. This study quantifies both the time course of shortening and temporal non-uniformity of two cross-oriented segments within the same myocardial region.     

Mechanism underlying the reduced positive inotropic effects of the phosphodiesterase III inhibitors pimobendan,adibendan and saterinone in failing as compared to nonfailing human cardiac muscle preparations

Summary The present study was performed to compare the effects of the new positive inotropic phosphodiesterase III inhibitors pimobendan, adibendan, and saterinone on the isometric force of contraction in electrically driven ventricular trabeculae carneae isolated from explanted failing (end-stage myocardial failure) with those from nonfailing (prospective organ donors) human hearts. In preparations from nonfailing hearts the phosphodiesterase inhibitors, as well as the a-adrenoceptor agonist isoprenaline, the cardiac glycoside dihydroouabain, and calcium, which were studied for comparison, revealed pronounced positive inotropic effects. The maximal effects of pimobendan, adibendan, and saterinone amounted to 56%, 36% and 45%, respectively, of the maximal effect of calcium. In contrast, in preparations from failing hearts the phosphodiesterase III inhibitors failed to significantly increase the force of contraction and the effect of isoprenaline was markedly reduced. The effects of dihydroouabain and calcium were almost unaltered. The diminished effects of isoprenaline were restored by the concomitant application of phosphodiesterase inhibitors.To elucidate the underlying mechanism of the lack of effect of the phosphodiesterase III inhibitors in the failing heart we also investigated the inhibitory effects of these compounds on the activities of the phosphodiesterase isoenzymes I–III separated by DEAE-cellulose chromatography from both kinds of myocardial tissue. Furthermore, the effects of pimobendan and isoprenaline on the content of cyclic adenosine monophosphate (determined by radioimmunoassays) of intact contracting trabeculae were studied. The lack of effect of the phosphodiesterase inhibitors in failing human hearts could not be explained by an altered phosphodiesterase inhibition, since the properties of the phosphodiesterase isoenzymes I–III and also the inhibitory effects of the phosphodiesterase inhibitors on these isoenzymes did not differ between failing and nonfailing human myocardial tissue. Instead, it may be due to a diminished formation of cyclic adenosine monophosphate in failing hearts, presumably caused mainly by a defect in receptor-adenylate cyclase coupling at least in idiopathic dilated cardiomyopathy. Both the basal and the pimobendan-stimulated or isoprenaline-stimulated contents of cyclic adenosine monophosphate of intact contracting trabeculae from failing hearts were decreased compared with the levels in nonfailing hearts. However, under the combined action of isoprenaline and pimobendan the cyclic adenosine monophosphate level reached values as high as with each compound alone in nonfailing preparations, and in addition the positive inotropic effect of isoprenaline was restored.These findings may have important clinical implications. Along with the elevated levels of circulating catecholamines the positive inotropic effects of the phosphodiesterase inhibitors may be maintained in patients with heart failure. Furthermore, the concomitant application of a -adrenoceptor agonist and a phosphodiesterase inhibitor might be beneficial in terminal heart failure refractory to conventional therapeutic regimens.Some of the results reported in this paper have already been presented in abstract form at the 61 st Session of the American Heart Association, Washington, DC, Nov. 1988 (von der Leyen et al., Circulation 78 (Suppl II): 11-360, 1988), at the Fall Meeting of the German Society of Pharmacology and Toxicology, Sept. 1988 (Schmitz et al., Naunyn-Schmiedeberg's Arch Pharmacol 338 (Suppl): R 16, 1988), at the 30th Spring Meeting of the German Society of Pharmacology and Toxicology, March 1989 (Meyer et al., Naunyn-Schmiedeberg's Arch Pharmacol 339 (Suppl): R 53, 1989), and at the XIII Congress of the International Society For Heart Research, Ann Arbor, MI, May 1989 (Meyer et al., J Mol Cell Cardiol 21 (Suppl 11): S. 50, 1989) mis|Send offprint requests to Wilfried Meyer at the above address