促甲状腺素释放激素抗休克与肾上腺素能受体及β-内啡肽的关系

用失血性休克大鼠离体心脏研究了促甲状腺素释放激素（Ｔｈｙｒｏｔｒｏｐｉｎ－ＲｅｌｅａｓｉｎｇＨｏｒｍｏｎｅ，ＴＲＨ）对肾上腺素能α，β，多巴胺（ＤＡ）受体激动剂正性肌力作用及β－内啡肽负性肌力作用的影响。结果表明ＴＲＨ可增强肾上腺素能β－受体及多巴胺受体激动剂的正性肌力作用，拮抗β－内啡肽的负性肌力作用，提示ＴＲＨ对休克大鼠心脏β－和ＤＡ受体具有一定的增敏作用，ＴＲＨ的抗休克作用与其增敏β－和ＤＡ受体，增加它们对其受体激动剂的反应性及拮抗β－内啡肽的心血管抑制作用有关。     

促甲状腺素释放激素对失血性休克大鼠脑μ、δ和K阿片受体的影响

本文用放射性相对选择性配体初步研究了促甲状腺素释放素（ＴＲＨ）对失血性休克大鼠脑μ、δ和Ｋ阿片受体的影响。结果显示失血性休克大鼠δ和ｋ阿片受体最大结合数（Ｂｍａｘ）显著升高，亲和力变化不大，μ阿片受体Ｂｍａｘ和亲和力无明显变化。ＴＲＨ（５ｍｇ·ｋｇ￣（－１））可使休克大鼠脑δ阿片受体Ｂｍａｘ降低，对其亲和力影响不大，对μ和ｋ受体无明显影响。这一结果提示ＴＲＨ减数调节失血性休克动物脑阿片受体数量可能是ＴＲＨ拮抗内阿片肽的心血管抑制作用，发挥抗休克作用的重要机理。     

促甲状腺素释放激素对失血性休克大鼠脑μ,δ和κ阿…

本用放射相对选择性配体初步研究了促甲状腺素释放素（ＴＲＨ）对失血性休克大鼠脑μ、δ和κ阿片受体的影响，结果提示ＴＲＨ减数调节失血性休克动物脑阿片受体数量可能是ＴＲＨ拮抗内阿片肽的心血管抑制作用，发挥抗休克作用的重要机理。     

心脏α受体及其生物学功能

<正> Wenzel等于1966年首先发现,预先阻断心脏β受体,α受体阻滞剂酚妥拉明可抑制肾上腺素受体激动剂对大鼠心室肌的正性肌力作用,认为大鼠心室肌存在α受体。此后许多实验结果也相继证实哺乳动物心脏存在α受体,而且对其生物     

α_1和α_2肾上腺素受体激动剂对大鼠左心房肌生理特性的影响

本文观察了选择性α_1肾上腺素受体激动剂苯福林和α_2肾上腺素受体激动剂B-HT933对大鼠左心房肌收缩性、兴奋性、自律性和功能性不应期的影响。苯福林在大鼠左心房肌标本上可致明显的正性肌力作用,同时可提高肾上腺素诱发的左房自律性、延长功能性不应期,这些作用可明显地被哌唑嗪所拮抗。但苯福林对大鼠左心房兴奋性无影响。B-HT933在同样实验条件下对大鼠左房收缩性、兴奋性、自律性和功能性不应期无影响。实验表明,突触后膜α受体兴奋所致的心脏作用由α_1亚型介导,但未能证实突触后膜α_2受体在大鼠左心房上具有功能性的作用。     

长期饮用普萘洛尔对大鼠心脏α_1肾上腺素受体亚型数量的影响

采用放射配体结合实验，离体左心房收缩功能实验及逆转录聚合酶链反应等方法观察大鼠长期饮用非选择性β肾上腺素受体拮抗剂普萘洛尔（７０ｍｇ·ｋｇ－１·ｄ－１，８ｗｋ）对心脏α１肾上腺素受体（α１－ＡＲ）亚型分布及其功能的影响．结果表明大鼠饮用普萘洛尔８ｗｋ后心脏α１－ＡＲ总数量无显著变化，ＷＢ４１０１和尼古地平竞争抑制曲线两位点分析结果显示３种亚型受体所占比例发生了明显变化，α１Ａ－ＡＲ数量不变，α１Ｂ－ＡＲ数量减少，α１Ｄ－ＡＲ数量增加，α１－ＡＲ亚型ｍＲＮＡ水平的改变为α１Ａ－ＡＲ和α１Ｄ－ＡＲ显著增加，α１Ｂ－ＡＲ明显减少．但α１－ＡＲ３种亚型介导去甲肾上腺素正性变力效应的作用无显著改变．     

Adrenoceptor agonists inhibit calcium-dependent potentials in rat stelate ganglion neurons

探索肾上腺素能受体激动剂对大鼠星状神经节细胞的作用及其作用机制．方法：离体交感神经节细胞内生物电记录．结果：去甲肾上腺素，可乐定（１０－３０μｍｏｌ·Ｌ－１）可逆地抑制细胞动作电位；依钙后超极化电位；在含ＴＴＸ与ＴＥＡ克氏液中记录到的钙锋电位及快兴奋性突触后电位．结论：肾上腺素受体激动剂对三种钙电位及快兴奋性突触后电位的抑制作用可能是其在突触前膜对钙内流的抑制所致．     

多巴酚丁胺和多巴胺在失血性休克治疗中的效果评价

失血性休克是临床上最常见的低血容量休克，首先应予以快速扩容治疗，若经过积极的液体输注，仍处于休克状态，常需要正性肌力药物支持。小剂量的多巴胺和多巴酚丁胺在临床上最为常用，多巴胺是α、β受体激动药；多巴酚丁胺主要兴奋心脏的β受体增加心肌收缩力，提高心排血量，对外周的作用很小，大剂量时也不出现α受体的强烈缩血管作用，在临床抗休克治疗时较为常用。为此，我们观察了多巴胺和多巴酚丁胺对失血性休克患者治疗后临床变化和血气分析结果，以评价两种药物的临床效果，指导临床应用。     

Urocortin对大鼠和兔离体心肌组织的选择性正性肌力效应

目的研究urocortin对心脏的作用。方法采用大鼠及兔离体右心房肌,左(大鼠),右(兔)心室乳头肌和大鼠离体右心室肌条标本,观察urocortin对心肌收缩力及心率的影响;采用细胞内微电极技术观察urocortin对大鼠离体乳头肌和左心房肌细胞动作电位的影响。结果Urocortin 1~30 nmol.L-1浓度依赖性地增强大鼠右心房心肌收缩力,urocortin10和30 nmol.L-1使收缩力分别增加(38±16)%和(61±17)%;urocortin的正性肌力作用明显强于同等浓度去甲肾上腺素的正性肌力作用。Urocortin不影响大鼠离体右心房的心率,左室乳头肌和右心室肌条的收缩力,对兔离体右心房和右室乳头肌亦无明显作用;β受体激动剂对上述标本则产生明显的正性频率作用和正性肌力作用。Urocortin 30~300nmol.L-1明显升高大鼠左心室乳头肌的动作电位幅值和超射值;urocortin 30~100 nmol.L-1明显升高大鼠左心房肌的动作电位幅值和超射值。结论Uro-cortin对大鼠离体心房具有很强的正性肌力作用。Urocortin的正性肌力作用具有明显的种属差异和组织学差异。     

三七皂甙单体Rb_1对心肌细胞Ca~（2＋）内流作用的研究

应用Ｆｕｒａ－２荧光技术及放射配基结合实验探讨三七皂甙单体Ｒｂ１对心肌细胞胞外Ｃａ２＋内流的作用。０．０４ｍｍｏｌ·Ｌ－１Ｒｂ１可以抑制高钾引起的大鼠心肌细胞胞浆Ｃａ２＋浓度的升高，且呈浓度依赖性；可以完全阻断高钾基础上的异丙肾上腺素的作用。其作用与钙通道拮抗剂维拉帕米类似。Ｒｂ１对大鼠心肌细胞膜上β受体亲和力和受体数均无明显影响。结果提示：Ｒｂ１对心肌细胞电压依赖性钙通道开放引起的胞内钙升高有抑制作用；对β受体相关联的钙通道开放引起的胞浆Ｃａ２＋升高也有抑制作用。而不影响β受体本身。     

促甲状腺素释放激素改善失血性休克心功能的作用机理

TRH iv后显著升高失血性休克家兔MAP,±dP/dt_(max),Vpm,V_(max)和血浆E。利血平预处理后,TRH的上述作用消失。β受体阻滞剂普萘洛尔预处理后,TRH增强±dP/dt_(max),Vpm和V_(max)的作用消失,并在iv TRH后20和30 min取消了TRH的升压作用。α受体阻滞剂酚苄明预处理后,TRH仍能升高MAP,±dP/dt_(max),Vpm和V_(max)。离体大鼠左心房实验证明TRH(0.1mmol/L)可显著增强异丙肾上腺素和多巴胺的正性肌力作用。     

钙增敏剂MCI-154抗休克作用及其机制

钙增敏剂MCI-154有明显的拮抗失血性休克及内毒素休克的作用,特别是对休克失代偿期有良好的疗效.与传统的加强心肌收缩的药物不同,本品不会明显增加休克动物心肌细胞内的钙超载,而主要通过增加心肌收缩蛋白对Ca2 的敏感性而改善休克动物的心功能,其增加心肌细胞内Ca2 水平及cAMP含量的作用明显比米力农弱.本品降低休克动物血管平滑肌细胞内游离Ca2 浓度,恢复钙调蛋白活性及c蛋白激酶C的表达,以及相对增加Calponin-α的表达,从而改善休克舒张功能.     

Negative inotropic effects of isoprenaline on isolated left atrial assays from aged transgenic mice with cardiac over-expression of human beta(2)-adrenoceptors

The action of isoprenaline has been evaluated in an isolated, left atrial assay, from aged transgenic mice with cardiac-specific over-expression of the beta(2)-adrenoceptor. In the assay, isoprenaline produced a negative inotropic concentration-response curve that was not altered by incubation with CGP-20712A (1 microM), a beta(1)-adrenoceptor antagonist. However, after incubation with ICI-118,551 (300 nM), a selective beta(2)-adrenoceptor antagonist, isoprenaline produced a positive inotropic concentration-effect curve that was located to the left of the negative inotropic curve. This suggests that the negative inotropic effect was mediated by a homogenous population of negatively-coupled beta(2)-adrenoceptors. In the presence of CGP-20712A (300 nM), the positive curve was shifted to the right, suggesting that the positive inotropic effect was mediated, at least in part, by beta(1)-adrenoceptors. These results differ substantially from those previously obtained in young transgenic mice. An outline of an explanatory model, based on a concept of over-expressed receptors 'stealing' G-proteins, is suggested.     

The effects of P1- and muscarinic-receptor agonists upon cAMP-dependent and independent inotropic responses of guinea-pig cardiac preparations.

1. The indirect negative inotropic effects of P1- and muscarinic-receptor agonists were compared by examining how the responses of isolated guinea-pig left atria and papillary muscles to positive inotropes were affected by the presence of the P1-receptor agonist, L-PIA or the muscarinic-receptor agonist, carbachol. 2. The indirect negative inotropic effects of L-PIA and carbachol were similar: both attenuated the responses of left atria more effectively than those of papillary muscles; and both more effectively attenuated responses to the cAMP-dependent positive inotropes, isoprenaline and forskolin. 3. However, there were differences: L-PIA, but not carbachol, was able at high concentrations to inhibit the responses of left atria to the calcium channel opener Bay K 8644; and at concentrations that produced similar direct negative inotropic effects, L-PIA consistently attenuated the positive inotropes more effectively than carbachol. 4. These findings are consistent with L-PIA being able to activate an additional negative inotropic mechanism that carbachol cannot.     

Human myocardial β-adrenoceptors: demonstration of both γ-adrenoceptors: mediating contractile responses to β-agonists on the isolated right atrium

On the isolated electrically driven muscle strip of human right atrial appendages the beta-adrenoceptor subtypes mediating the positive inotropic effects of isoprenaline, dobutamine and procaterol were characterized using the beta 1-selective antagonist bisoprolol and the beta 2-selective antagonist ICI 118,551. The three agonists induced concentration-dependent increases in force of contraction with an order of potency: procaterol (pD2-value: 8.03) greater than isoprenaline (pD2-value: 7.73) greater than dobutamine (pD2-value: 5.44). In saturating concentrations all three agonists produced the same maximum of developed tension. ICI 118,551 (10(-9)--10(-7) mol/l) and bisoprolol (10(-9)--10(-7) mol/l) were nearly equipotent in antagonizing the positive inotropic effects of isoprenaline and dobutamine. However, the slopes of the Schild-plots for both antagonists against both agonists were significantly less than 1.0 indicating interaction with beta 1- and beta 2-adrenoceptors. On the other hand, ICI 118,551 (10(-10)--10(-8) mol/l) was approximately 100 times more potent than bisoprolol (10(-8)--10(-6) mol/l) in antagonizing the positive inotropic effect of the highly selective beta 2-agonist procaterol. In addition, the slopes of the Schild-plots for antagonism of ICI 118,551 and bisoprolol against procaterol were not significantly different from unity indicating interaction with a homogeneous class of beta-adrenoceptors. The pA2-value for ICI 118,551 was 9.49, for bisoprolol it amounted to 6.99.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional evidence against the existence of β2-adrenoceptors mediating positive inotropic effects in guinea-pig right ventricular myocardium

In guinea-pig isolated papillary muscles we studied the positive inotropic effects of the β-adrenoceptor agonists isoprenaline, fenoterol and noradrenaline in the presence and absence of the β₁-selective antagonist atenolol and the β₂-adrenoceptor antagonist ICI 118.551. In Schild regression analysis pA₂ values for either atenolol (7.14–7.16) and ICI 118.551 (6.79–6.84) were independent of the agonists used. These results support the view that the inotropic response in guinea-pig ventricular myocardium is mediated by β₁-adrenoceptors only. Received: 2 May 1996 / Accepted: 21 August 1996     

alpha 1-adrenoceptor activation can increase heart rate directly or decrease it indirectly through parasympathetic activation.

1 The chronotropic effects of alpha- and beta-adrenoceptor agonists were investigated in the pithed rat. 2 The beta-adrenoceptor agonist, isoprenaline, produced only a positive chronotropic response. alpha 1-Adrenoceptor agonists, phenylephrine and amidephrine, produced positive and negative chronotropic effects. Part of the response to phenylephrine was beta-mediated. 3 A positive chronotropic response to amidephrine and phenylephrine was mediated directly through cardiac alpha 1-adrenoceptors and had a different time course from beta-adrenoceptor-mediated responses. 4 A negative chronotropic response to alpha-agonists was potentiated by neostigmine and blocked by atropine, tetrodotoxin or hexamethonium as well as by alpha 1-adrenoceptor antagonists. This may indicate alpha 1-adrenoceptors on preganglionic parasympathetic nerves, stimulation of these receptors causing release of acetylcholine. 5 The alpha 2-adrenoceptor agonist, xylazine, produced a direct negative chronotropic effect on the heart, independent of alpha-adrenoceptors. No evidence was found for functional post-junctional alpha 2-adrenoceptors. At high doses xylazine stimulated cardiac alpha 1-adrenoceptors.     

Cannabinoid CB1 and CB2 receptors antagonists AM251 and AM630 differentially modulate the chronotropic and inotropic effects of isoprenaline in isolated rat atria

Background

Drugs targeting CB₁ and CB₂ receptors have been suggested to possess therapeutic benefit in cardiovascular disorders associated with elevated sympathetic tone. Limited data suggest cannabinoid ligands interact with postsynaptic β-adrenoceptors. The aim of this study was to examine the effects of CB₁ and CB₂ antagonists, AM251 and AM630, respectively, at functional cardiac β-adrenoceptors.