丁苄腈心安与心得安对大鼠心肌β肾上腺素受体亲和力比较

本文以~3H双氢心得舒(~3H—DHA)作为放射性配基,测定大鼠心肌上β肾上腺素受体的最大结合容量(B_(max))和平衡解离常数(K_D)分别为104.1±4.7fmol/mg蛋白质及10.1±2.7nM,Hill系数(nH)为1.007±0.002。丁苄腈心安和心得安对大白鼠心肌β肾上腺素能受体与~3H-DHA结合的半数抑制浓度(IC_(50))分别为3.30±0.74×10~(-8)M和3.87±0.66×10~(-7)M,表观解离常数各为2.20±0.49×10~(-8)及2.58±0.44×10~(-7)。故丁苄腈心得安对大鼠心肌β肾上腺素受体的亲和力约为心得安的11.7倍。     

用大鼠脑切片进行β—受体放射配体结合实验的方法学研究

本项研究探素了用氚标的β-受体拮抗剂~3H-双氢心得舒与大鼠中脑上丘平面冰冻切片进行结合实验的条件。实验得出配体与脑切片的最大特异性结合量为17.3±4.5 fmol/mg,组织干重,表观平衡解离常数为5.8±0.6nM,Hill系数为0.93±0.3,结合速率常数为0.112±0.025nM~(-1)·min~(-1),解离速率常数为0.69±0.07min~(-1),心得安与配体竞争结合的IC_(50)为1.00±0.15×10~(-8)M,心得宁的IC~(50)为167±0.22×10~(-8)M,异丙肾上慷素的IC_(50)为1.32±0.3×10~(-6)M。这些结果与用组织匀浆进行结合实验所得结果近似,表明在合适的条件下用冰冻组织切片进行β-受体结合实验是可行的。     

苯乙烯吸入染毒在家兔体内的毒物动力学

家兔iv 36.4 mg/kg和inh 3.6 g/m~3苯乙烯,分别符合三室开放模型和零级吸收二室开放模型。毒物动力学基本特征是:经呼吸道的吸收率稳定为56.3％,k_0=0.79±0.20 mg·kg~(-1)·min~(-1),iv和inh染毒在家兔体内分布和消除过程相同;分布快,α=0.138±0.097min~(-1) ,t_(1/2α)=6.8± 3.6min;呈周身分布;消除快,t_(1/2β)=84±69min,Cl_t=36.8ml·kg~(-1)·min~(-1);存在肾外途径消除。inh染毒时呼出气中苯乙烯浓度的动态变化与血相平行。     

脂质体携载前列腺素E_1抗心肌缺血再灌注损伤

目的　研究脂质体携载前列腺素E1(Lipo PGE1)减轻心肌再灌注损伤的机理。方法　 2 4只家兔随机分成Lipo PGE1组 ,PGE1组及对照组 ,每组 8只。以家兔左冠脉前降支 (LAD)结扎 6 0min ,再灌注 12 0min为缺血再灌注模型 ,于再灌注前 10min分别自耳缘静脉静注Lipo PGE1(2 μg·kg-1PGE1) ,PGE1(2 μg·kg-1)及等容量的脂肪乳剂 (Lipo PGE1的溶剂 ) ,以Evans蓝及氯化三苯基四氮唑 (TTC)双重染色确定缺血心肌及梗塞心肌范围 ,通过测定心肌组织髓过氧化物酶 (MPO)活性反应缺血心肌中性粒细胞浸润程度。结果　Lipo PGE1组梗塞心肌占危险区心肌重量百分比(32 2 0 %± 4 70 % )比较对照组 (44 5 7%± 5 46 % )及PGE1(42 0 9%± 6 93% )降低 (P <0 0 1) ;Lipo PGE1治疗组缺血区心肌组织MPO活性〔(1 9± 1 2 )U·g-1〕较对照组〔(5 3± 2 4)U·g-1〕及PGE1组〔(4 2± 2 0 )U·g-1〕均降低 ,边缘区心肌组织MPO活性〔(1 4± 1 1)U·g-1〕较对照组〔(3 3± 1 5 )U·g-1〕也降低 (P <0 0 5 )。结论　Lipo PGE1能有效抑制再灌注心肌中性粒细胞的浸润 ,减轻心肌再灌注损伤。     

L-芝麻素对代谢综合征大鼠心肌损伤的抑制作用

目的探讨L-芝麻素对代谢综合征大鼠心肌损伤是否有抑制作用。方法大鼠分正常组、模型组、L-芝麻素(30,60和120mg·kg-1)和辛伐他汀(5mg·kg-1)治疗组,除正常组给予正常饲料外,其余各组给予高脂高糖饲料诱导大鼠代谢综合征。至第9周时,各给药组给予含不同浓度L-芝麻素或辛伐他汀的高脂高糖饲料,每天1次。连续16周后,称体重(BW)、全心湿重(HWW)和左心室湿重(LVWW);取心肌组织测定心肌羟脯氨酸(HYP)、过氧化氢(H2O2)和一氧化氮(NO)含量,及超氧化物歧化酶(SOD)和过氧化氢酶(CAT)活性;HE染色观察心肌组织病理变化;免疫组化法检测心肌诱导型一氧化氮合酶(iNOS)表达和硝基酪氨酸(NT)含量。结果与正常组比较,模型组BW,HWW和LVWW明显增加,心肌H2O2,HYP和NO含量明显升高,SOD和CAT活性明显降低,iNOS表达和NT含量增多,并出现心肌纤维增粗肥大且排列紊乱、组织中大量炎症细胞和脂肪组织浸润等严重的病理性改变。与模型组比较,L-芝麻素60和120mg·kg-1组及辛伐他汀组BW〔(328±11),(313±10)和(310±10)vs(411±14)g〕,HWW〔(0.94±0.07),(0.86±0.11)和(0.85±0.12)vs(1.21±0.19)g〕和LVWW〔(0.77±0.08),(0.65±0.09)和(0.67±0.06)vs(1.03±0.22)g〕降低,心肌H2O2〔(239±50),(201±35)和(182±39)vs(302±41)mmol·L-1〕,HYP〔(1.09±0.09),(0.95±0.06)和(0.88±0.09)vs(1.21±0.07)mg·g-1蛋白〕和NO含量〔(1.51±0.46),(0.98±0.26)和(0.76±0.37)vs(2.61±0.41)μmol·L-1〕明显下降,SOD〔(71±12),(84±10)和(90±10)vs(49±8)μmo·lmin-1.L-1〕和CAT活性〔(27±8),(34±6)和(36±9)vs(20±4)μmol·L-1〕显著升高;心肌iNOS表达和NT含量减少,病理损伤明显减轻。结论L-芝麻素可抑制代谢综合征大鼠心肌损伤,该作用可能与其抑制氧化应激和提高抗氧化能力有关。     

盐酸阿芬太尼在手术病人中的药代动力学研究

本文进行了两组不同剂量的阿芬太尼在14例手术病人中药代动力学研究。7例一次性iv 80μg·kg~(-1)阿芬太尼,另7例一次性iv 40μg·kg~(-1)。用RIA方法测定0-8 h阿芬太尼的血浆浓度和0-48 h尿中的回收率。研究表明:阿芬太尼在两组病人体内的药代动力学过程均为3室模型。阿芬太尼的初级消除很快,给药后30 min内90％的原型药被消除。病人血浆浓度未发现2次上升现象。二者药-时曲线接近平行,说明阿芬太尼的代谢过程为1级消除。两组阿芬太尼的药代动力学数据经t检验无显著差异(P>0.05)。阿芬太尼的快、慢分布相和消除相的半衰期t_(1/2)π,t_(1/2)α和t_(1/2)β分别为0.71 min±s 0.37 min,11.66 min±s 3.46 min和86.12 min±s 19.15 min;平均总体和中心室的分布容积Vd、Vc分别为34.22L±s 8.27L和4.23L±s 1.72L;平均总体清除率Cl为0.29 L·min~(-1)±s 0.08L·min~(-1)。另外,k_(12)/k_(21)为1.5,k_(13)/k_(31)为3.5,k_(10)大于k_(31)。用药后48 h以内,40μg·kg~(-1)组和80μg·kg~(-1)组的病人尿中排出的原形阿芬太尼分别占总给药量的0.68％±s 0.72％和0.66％±s 0.54％。其肾清除率分别为0.0016 L·min~(-1)±s 0.0011 L·min~(-1)和0.0021 L·min~(-1)±s 0.0015 L·min~(-1)。     

胃复安在兔体内的药代动力学

本文报道胃复安在兔体内的药代动力学。按较大剂量(20mg·kg~(-1))快速静注后,血药浓度数据采用自编非线性算法和程序在Apple——Ⅱ微机上作曲线拟合后,依据最小残差平方和(Re)和AIC值作模型识别。5只兔均按二室模型拟合较为合适。算得参数:t_1/2α和t_1/2日分别为4.6±3.7和75.3±15.2min;Vc、Vd(area)和Vd(ss)分别为2.98±1.80、4.94±0.65和4.72±0.51L·kg~(-1);Cl为46.6±10.5ml·min.kg~(-1)。作统计矩分析,AUC、MRT和VRT分别为446±93μg·hr·ml~(-1)、104.5±19.6min和12062±4469min~2。     

槲皮素在兔体内的药代动力学

槲皮素为黄酮类化合物。兔iv槲皮素10m g·kg~(-1)后.血药浓度—时间曲线符合二室模型。T_(1/2)(α)为2.91 ±1.36min,T_(1/2)(β)183.78±82.67min,V_B为0.624±0.225 L·kg~(-1),CL为3.15±2.11 ml·kg~(-1)·min~(-1).槲皮素10mg·kg~(-1)ig后,生物利用度为42.7％,药峰浓度(C_(Dk))为10.9mg·L~(-1),药峰时间(t_(pk))为60min。iv槲皮素后.药物以原型和代谢产物两种形式经尿、胆汁排泄,消除较迅速。     

3,6-(二甲氨基)-二苯并碘杂六环葡萄糖酸盐对大鼠缺血再灌注心肌的保护作用

3 ,6 (二甲氨基 ) 二苯并碘杂六环葡萄糖酸盐 (3,6 dimethamidodibenzopyriodoniumgluconate ,IHC 93)是迄今本类药物中水溶性最好的药物。大鼠冠状动脉闭塞 4 0min ,再灌注 12 0min ,造成心肌缺血再灌注损伤(n =10 )。测定大鼠心肌梗死范围 (41± 4 ) % ,肿胀度 (81± 4 ) % ,血清肌酸激酶〔CK ,(5 .6± 0 .9)mmol·min- 1·L- 1〕和肌酸激酶同工酶〔CK MB ,(0 .88± 0 .0 9)mmol·min- 1·L- 1〕活性明显升高 ,血清内皮素 1〔ET 1,(0 .34± 0 .0 4 ) μg·L- 1〕水平明显升高。于冠脉结扎前和再灌注前 1min分别ivIHC 930 .12 5 ,0 .2 5和 0 .5mg·kg- 1(n =10～ 11) ,与缺血再灌组比 ,大鼠心肌梗死范围不同程度缩小 ,分别为 (38± 5 ) % ,(35± 4 ) %和(33± 3) % (中、大剂量组P <0 .0 1) ;心肌肿胀度有所减轻〔(78± 4 ) % ,(76± 3) %和 (77± 2 ) % ,中、大剂量组P <0 .0 1〕 ;CK活性降低〔(5 .1± 0 .8) ,(4.7± 1.0 )和 (4.4± 1.3)mmol·min- 1·L- 1,中、大剂量组P <0 .0 5〕 ;CK MB活性降低〔(0 .12± 0 .0 4 ) ,(0 .11± 0 .0 3)和 (0 .0 9± 0 .0 4 )mmol·min- 1·L- 1,均P <0 .0 1〕 ;ET 1水平降低〔(0 .2 6± 0 .0 3) ,(0 .2 6± 0 .0 3)和 (0 .2 7± 0 .0 3) μg·L- 1,均P <0 .0     

尼可地尔对豚鼠心肌细胞膜及线粒体膜电位的影响

研究KATP通道开放剂尼可地尔 (Nic)对豚鼠心肌细胞膜和线粒体膜电位的影响 .用激光共聚焦显微镜和特异性荧光探针 ,观察不同剂量的Nic及KATP通道阻滞剂格列本脲 (Gli)引起急性分离的豚鼠心肌细胞膜电位 ,线粒体膜电位荧光值的变化 .Nic1mmol·L- 1引起细胞膜电位在 1min内迅速超极化〔膜电位荧光值减少 ( 75± 12 ) %〕 ,Gli 3μmol·L- 1可阻断其变化 ;0 .1和 1mmol·L- 1Nic可使线粒体膜电位去极化和膜电位荧光值在 1,2 ,5min分别增加( 12± 3) %和 ( 32± 8) % ,( 2 5± 6) %和 ( 39± 9) % ,( 34± 6) %和 ( 4 5± 12 ) % ;3μmol·L- 1Gli可抑制其变化 .结果说明低浓度Nic只引起线粒体膜电位去极化 ,高浓度Nic还可使细胞膜电位发生超极化 ,引起KATP通道开放     

Forskolin-mediated activation of cardiac, liver and lung adenylate cyclase in the rat. Relation to [3H]forskolin binding sites

We investigated whether differences in binding sites for [3H]forskolin could account for the low potency of forskolin on adenylate cyclase (EC 4.6.1.1) from rat lung compared with heart or liver adenylate cyclase. Forskolin (0.1 mM) increased basal adenylate cyclase activity 41-fold in heart, 27-fold in liver, but only 3-fold in lung. The low potency in lung could not be accounted for by any lack of enzyme or stimulatory nucleotide-binding protein, since sodium fluoride (10 mM) increased basal activity 9-12-fold in all three tissues. The effectiveness of forskolin on adenylate cyclase appears to be related to the presence of specific [3H]forskolin binding sites. [3H]Forskolin binding in both heart and liver membranes was consistent with single binding sites with dissociation constants of 0.74 +/- 0.25 microM and 1.43 +/- 0.21 microM respectively. No such binding sites were detected in lung membranes. The binding was of low affinity (greater than 100 microM) and showed no tendency to saturate. These results are not consistent with the hypothesis that the nucleotide-binding protein influences stimulation of adenylate cyclase by forskolin, rather [3H]forskolin binding sites appear to be an important determinant of the effect of forskolin in different tissues.     

Mediation of the cardiac effects of forskolin by specific binding sites

The effects of forskolin and seven derivatives on cardiac functions were investigated by using the Langendorff technique and the results compared with the respective potencies obtained from adenylate cyclase and binding studies. In the isolated heart, forskolin increased all parameters measured in the same concentration range as demonstrated by identical EC50 values for increasing contractile force (270 nmol/L), heart rate (276 nmol/L), and coronary flow (249 nmol/L). Compared with its analogs, forskolin was the most potent agonist followed by 7-desacetylforskolin-7-ethylcarbonate, 7-desacetyl-7-propionylforskolin, 14,15-dihydroforskolin, and 7-desacetylforskolin. An identical order of potencies was obtained when these compounds were tested for their ability to inhibit [3H]forskolin binding and stimulate adenylate cyclase in a myocardial preparation. While the KI values derived from the binding experiments (386 nmol/L for forskolin) were similar to the respective EC50 values for the cardiac stimulatory effects, the ED50 values for adenylate cyclase stimulation were about 30-fold higher, e.g., 10 mumol/L for forskolin. Derivatives modified in position 9 of the molecule (1,9-dideoxyforskolin, 9,14-epoxy-15-hydroxyforskolin, and 7-desacetylforskolin-6,7:1,9-dicarbonate) had no effect on the isolated heart nor in adenylate cyclase or binding studies. This identical structure-activity profile observed in the three systems used suggests that the cardiac effects of forskolin are elicited by the one specific binding site described in this study.     

COMPARISON OF THE EFFECTS OF VASOACTIVE AGENTS ON ADENYLATE CYCLASE ACTIVITY IN ENDOTHELIAL AND SMOOTH MUSCLE CELLS FROM THE SAME SPECIMEN OF FETAL BOVINE AORTA

• 1 Adenylate cyclase activity in vascular endothelial cells (EC) has not been adequately defined. We compared adenylate cyclase activities in EC and smooth muscle cells (SMC) from the same specimen of fetal bovine aorta.
• 2 The basal adenylate cyclase activities of EC and SMC did not differ significantly (18.9 ± 0.8 and 21.4 ± 1.7 pmol/mg protein per min, n = 10, respectively).
• 3 The adenylate cyclase of EC responded dramatically to catecholamines, with the ED₅₀ value for isoproterenol being 0.036 μmol/L, and was also more sensitive to calcitonin gene-related peptide than that of SMC.
• 4 The adenylate cyclase of SMC was more sensitive to prostaglandins (with the ED₅₀ for PGI₂ being 0.024 μmol/L) and glucagon than that of EC, and responded modestly to catecholamines and was almost selectively sensitive to β₁-adrenoceptor agonists.
• 5 Maximum responses of adenylate cyclase to F^?, guanosine 5′-o-(3-thiotriphosphate) and forskolin were greater in SMC than in EC.
• 6 Based on these findings, it was concluded that EC and SMC differed significantly in adenylate cyclase responsiveness to agonists including hormones, prostaglandins, peptides and substances which may modify the effects of G proteins, although they shared a common developmental origin. Presumably, β-adrenoceptor agonists in EC and prostaglandins in SMC may appear to play an important role in cellular functions which are mediated by increases in cAMP.

     

Forskolin binding sites in rat liver and brain membranes

Using [3H]14,15-dihydroforskolin as a radioactive ligand, forskolin binding sites in rat liver and rat brain membranes were identified. Scatchard analysis of binding data revealed equilibrium dissociation constants of 1.6 microM in liver and 0.79 microM in brain membranes. The ligand could be displaced by either forskolin or dihydroforskolin. The maximal number of binding sites in liver and brain was 179 and 3.2 pmol/mg protein, respectively. The question whether these forskolin binding sites are related to the adenylate cyclase stimulating action of the diterpene remains open.     

Characterization of forskolin binding sites in rat brain membranes using [14,15-3H]14,15-dihydroforskolin as a ligand

Summary [14, 15-³H]14, 15-Dihydroforskolin ([³H]DHF) has been used as a radioactive ligand to identify forskolin binding sites in rat brain membranes. The binding was saturable and reversible. The binding sites showed positive cooperative properties as evident from an upward convex Scatchard plot and a Hill coefficient of 1.6. The equilibrium dissociation constants (K _D) were in the range between 10 M and 10 nM as estimated from the limiting slopes of the curved Scatchard plot. Half-maximal saturation of the binding sites was observed at a ligand concentration of 225 nM. The binding kinetics were very rapid: Binding equilibrium was reached in less than 2 min and a large excess of cold forskolin displaced 80% of the radioligand within 2 min. The dissociation reaction was not first order, characterized by a decreasing dissociation rate constant. Bound [³H]DHF could be displaced with forskolin (IC₅₀ 0.3 M), 14,15-dihydroforskolin (IC₅₀ 0.8 M) and 7-desacetylforskolin (IC₅₀ 3 M). However, nucleotides (ATP, GTP) and other receptor ligands (adenosine, isoproterenol) had no effect on the binding. Although the density of the forskolin binding sites (3.2 pmole/mg protein) is similar to those of other adenylate cyclase linked receptors, discrepancies between the K _D and the ED₅₀ obtained in adenylate cyclase studies and the finding that activation of the enzyme by forskolin is negative cooperative makes it difficult to clearly relate the binding sites to adenylate cyclase.     

A study of the H2-receptor for histamine stimulating adenylate cyclase in homogenates of guinea-pig lung parenchyma.

The effect of forskolin and several H2-agonists was investigated on the activity of adenylate cyclase in homogenates of guinea-pig lung parenchyma. Histamine, 0.1 microM to 1 mM, dimaprit, 1 microM to 10 mM, 4-methyl histamine, 0.1 microM to 10 mM, impromidine, 10 nM to 10 microM and forskolin, 1 nM to 100 microM, all produced a dose-dependent stimulation of adenylate cyclase activity above the basal level. The histamine H1-receptor antagonist mepyramine, 10 microM, and beta-adrenoceptor antagonist propranolol, 10 microM, had no effect on the stimulation by histamine of adenylate cyclase. The dose-response curve for stimulation by histamine of adenylate cyclase was shifted to the right in a dose-dependent manner by increasing concentrations of several H2-antagonists. Schild plots constructed for each H2-antagonist produced straight lines with slopes not significantly different from unity. The equilibrium dissociation constants obtained for the H2-antagonists in this study were similar to those previously reported for inhibition of dimaprit-induced relaxation of the pre-contracted lung strip, inhibition of [3H]-tiotidine binding to homogenates of guinea-pig lung parenchyma and inhibition of histamine-stimulated adenylate cyclase in guinea-pig gastric mucosa.     

Irreversible loss of [3H]forskolin binding sites in human platelets by alpha-haloacetyl analogs of forskolin

The 7-bromoacetyl-7-desacetyl (BrAcFsk) and 7-chloroacetyl-7-desacetyl (CIAcFsk) analogs of forskolin were synthesized as alkylating agents to study the high affinity binding sites for forskolin. BrAcFsk and CIAcFsk activated adenylate cyclase in human platelet membranes with EC50 values of about 20 and 12 microM, respectively. Both analogs increased cyclic AMP in human platelets; however, they were less potent that forskolin. Forskolin inhibited [3H]forskolin binding to human platelet membranes with an IC50 of 20 nM, whereas BrAcFsk and CIAcFsk inhibited [3H] forskolin binding with IC50 values of 0.1 microM. Pretreatment of intact platelets with 10 microM BrAcFsk caused a 90% irreversible loss in [3H]forskolin binding sites, whereas pretreatment with 10 microM CIAcFsk led to a loss of 55% of the binding sites. The loss of binding sites occurred within 5 min for BrAcFsk and within 30 min for CIAcFsk. The time required for the loss of binding sites produced by either alkylating agent was increased by the inclusion of 200 microM forskolin in the pretreatment buffer. The inactive bromoacetyl analog of forskolin 7-bromoacetyl-7-desacetyl-1.9-dideoxyforskolin (1,9-dideoxy-BrAcFsk) did not activate adenylate cyclase, inhibit [3H]forskolin binding, or cause an irreversible loss of [3H]forskolin binding sites. Adenylate cyclase was assayed in membranes from platelets treated with either 10 microM BrAcFsk or 10 microM 1,9-dideoxy-BrAcFsk. The stimulation of adenylate cyclase by prostaglandin E1, guanosine-5'-O-(3-thio)triphosphate, and AIF4 was inhibited by about 50% in membranes from platelets treated with BrAcFsk. However, the stimulation of adenylate cyclase by forskolin was unaffected by preincubation with BrAcFsk. Pretreatment of human platelets with 1,9-dideoxy-BrAcFsk had no effect on the stimulation of adenylate cyclase by prostaglandin E1, AIF4, or forskolin.     

Effect of thyroid status on beta-adrenergic receptor, adenylate cyclase activity and guanine, nucleotide regulatory unit in rat cardiac and erythrocyte membranes

The effect of thyroid hormone on the β-receptor coupled adenylate cyclase in rat crude cardiac membranes was analysed by measuring the number of DHA-binding sites, adenylate cyclase activity and the amount of cholera toxin catalysed ADP-ribosylation of a protein with a molecular weight of 42,000 in cardiac and erythrocyte membranes. In crude rat cardiac membranes, the number of DHA-binding sites (78 ± 15 fmole/mg protein in the euthyroid state) is increased to 158 ± 20 fmole/mg protein in the hyperthyroid state and decreased to 51 ± 6 fmole/mg protein in the hypothyroid state; the affinity of the binding sites remained unchanged (K_D 2.9?4.3 nM). l-Isoprenaline (10^?4 M)-stimulated adenylate cyclase activity varied in parallel to the number of DHA-binding sites in hyper- and euthyroidism. Thyroid hormone, however, did not influence GppNHp (10^?4 M)-stimulated adenylate cyclase activity. Cholera toxin catalysed ADP-ribosylation of normal crude cardiac membranes resulted in a 1.8 fold increase in adenylate cyclase activity in the presence of GTP (10^?4) and l-isoprenaline (10^?4M), presumably as a result of inhibition of GTPase. In crude cardiac membranes cholera toxin catalyses the ADP-ribosylation of one major protein, which comigrates on sodium dodecylsulfate-polyacrylamide gel electrophoresis with the putative regulatory component of adenylate cyclase (mol. wt 42,000). In different thyroid states the amount of the regulatory component (as determined by cholera toxin dependent labelling) was equal (112 fmole/mg protein in euthyroid crude cardiac membranes). Basal activity of adenylate cyclase showed a significant difference between activity in euthyroid (3.7 ± 0.2 pmole cAMP/mg protein/min) and hypothyroid (5.4 ± 0.2 pmole cAMP/mg protein/min), but not in hyperthyroid crude cardiac membranes (3.4 ± 0.2 pmole cAMP/mg protein/min). Our results indicate, that thyroid hormone regulates the number of DHA-binding sites and basal activity (in hypothyroidism) in crude cardiac membranes and thereby causes different results in l-isoprenaline-induced adenylate cyclase activity.     

Alterations in cardiac beta-adrenoceptor responsiveness and adenylate cyclase system by congestive heart failure in dogs

The effects of congestive heart failure on the physiological and biochemical functions of the cardiac beta-adrenoceptor-coupled adenylate cyclase system were studied in dogs with right heart failure produced by progressive pulmonary artery constriction and tricuspid avulsion. The cardiac inotropic response to dobutamine was attenuated in congestive heart failure, as determined by the right and left ventricular dP/dt responses. Adrenergic beta-receptor density, measured by [3H]dihydroalprenolol binding, was reduced in membrane fractions of the failing right ventricle, but not in the left ventricle. The functional activity of the adenylate cyclase system was studied in vitro by measuring the net cyclic AMP production following additions of isoproterenol, 5'-guanylylimidodiphosphate (Gpp(NH)p), forskolin, or manganese chloride, which act either directly on the beta-adrenergic receptors or on one of the post-receptor components of the adenylate cyclase system. Congestive heart failure reduced the net production of cyclic AMP by isoproterenol, Gpp(NH)p, and forskolin in both the right and left ventricles, but did not alter the effect of manganese chloride. Thus, beta-receptor down-regulation is chamber-specific, occurring only in the hemodynamically stressed right ventricle. In contrast, the post-receptor defect of the adenylate cyclase system occurred in both ventricles of the heart failure dogs. This decreased activation of adenylate cyclase by beta-agonists may be responsible, at least in part, for the diminished cardiac inotropic response to catecholamines in congestive heart failure.