芒柄花素磺酸钠在脑缺血再灌注大鼠体内的药动学研究

目的建立芒柄花素磺酸钠血浆样品的高效液相色谱(HPLC)分析方法,并应用该方法对正常大鼠和模型大鼠体内的芒柄花素磺酸钠进行药动学分析;明确芒柄花素磺酸钠在正常、模型大鼠血浆中的吸收分布情况。方法采用Venusil MP C_(18)色谱柱(250 mm×4.6 mm,5μm),流动相乙腈–水(30∶70,水相中加0.1%甲酸),柱温30℃,进样量20.0μL,体积流量1.0 mL/min,检测波长250 nm。制备大鼠脑缺血再灌注模型,将SD大鼠随机分为10组,每组5只大鼠。于大鼠脑缺血1 h及再灌注3.5 h按20 mg/kg ip芒柄花素磺酸钠注射液,并于给药后15、30、45、60、90、120、150、180、240、300 min腹主动脉取血。正常组大鼠分别于给药后5、10、15、30、45、60、90、120、150、180、240、300、480、720min目内眦取血。样品经处理后,采用HPLC法检测各时间点血浆中的芒柄花素磺酸钠浓度。采用药动学软件WinNonLin 6.3进行数据分析,计算药动学参数。结果芒柄花素磺酸钠在0.25～100.0μg/mL线性关系良好。定量下限RSD值为12.15%。日内精密度RSD值均5.0%,日间精密度RSD值均10.0%。提取回收率均80%,RSD值均5.0%。芒柄花素磺酸钠在正常大鼠、模型大鼠血浆内药动学参数为:t_(1/2)分别为(173.13±13.12)min、(117.86±45.05)min,C_(max)分别为(67.23±4.04)μg/mL、(75.22±10.57)μg/mL,AUC_(0-t)分别为(2 493.69±216.98)min·μg/mL、(6 094.52±250.81)min·μg/mL,Vd分别为(1 981.97±134.12)mL/kg、(484.56±167.93)mL/kg,Cl分别为(7.96±0.73)mL·min/kg、(2.87±0.14)mL·min/kg,MRT_(0-t)分别为(76.92±1.54)min、(89.06±0.77)min。结论应用HPLC法测定芒柄花素磺酸钠的血药浓度定量准确、灵敏,芒柄花素磺酸钠在模型大鼠血浆中吸收的量多,单位时间内消除的量少,滞留时间长。     

微透析技术结合液质联用的不同剂量黄芪的补阳还五汤在脑缺血损伤大鼠脑药动学研究（英文）

探讨不同剂量组的补阳还五汤益气组与活血组有效成分在MCAO大鼠体内的药动学特征。复制大鼠脑缺血再灌注动物模型,建立补阳还五汤微透析样品的液质联用检测方法,研究补阳还五汤益气组低、中、高剂(3.09,6.1712.34 g/Kg),活血组注射液给药剂量为2.32 g/Kg,股静脉给药后脑缺血再灌注损失大鼠中有效成分的药动学特征。补阳还五汤不同给药组中芒柄花素和芍药苷药动学过程符合一房室模型模型,低剂量益气组和活血组中芒柄花素和芍药苷的t_1/2分别为(88.43±3.82,69.18±0.11) min,MRT分别为(138.56±4.83,113.62±2.42) min,AUC_0-t分别为(28 488.35±4800.32140 614.80±23 954.05) ng/mL·min;中剂量益气组和活血组中芒柄花素和芍药苷的t_1/2分别为(82.16±1.78,67.08±3.69) min,MRT分别为(127.95±2.70,116.58±4.13) min,AUC_0-t(48 619.25±...     

芒柄花素对脑缺血再灌注后血脑屏障完整性影响

目的:基于脑缺血再灌注后,血脑屏障通透性随时间变化具有一定规律,进一步考查芒柄花素磺酸钠(Sul-F)对大鼠脑缺血再灌注后血脑屏障(BBB)完整性的影响.方法:将模型大鼠分为溶剂组(n=5)和给药组(n=5),另设假手术组(n=5).于相应时间点前0.5 h尾静脉注射2％伊文思兰(EB)(内含Sul-F),心脏灌流后取...     

微透析技术结合液质联用的不同黄芪剂量的补阳还五汤在脑缺血损伤大鼠血药动学研究

目的：探讨不同黄芪剂量的补阳还五汤益气组与活血组有效成分在MCAO大鼠体内的药动学特征。方法：复制大鼠脑缺血再灌注动物模型，建立补阳还五汤微透析样品的液质联用检测方法，研究补阳还五汤益气组低、中、高剂量（3.09，6.17，12.34 g·kg^-1），活血组注射液给药剂量为2.32 g·kg^-1，股静脉给药后脑缺血再灌注损失大鼠中有效成分的药动学特征。结果：补阳还五汤不同给药组中芒柄花素和芍药苷血液药动学过程符合一房室模型，低剂量益气组和活血组中芒柄花素和芍药苷的半衰期（t_1/2）分别为（46.89±1.77），（25.47±1.43）min，平均滞留时间（MRT）分别为（67.66±2.55），（36.74±2.07）min，药-时曲线下面积（AUC_0-t）分别为（39 325.21±7 411.43），（225 496.40±24 990.38）ng·mL^-1·min；中剂量益气组和活血组中芒柄花素和芍药苷的t_1/2分别为（43.73±0.47），（26.24±1.10）min，MRT分别为（63.09±0.68，37.85±1.59）min，AUC_0-t（67 556.41±7 043.40），（242 206.10±19 296.12）ng·mL^-1·min；高剂量益气组和活血组中芒柄花素和芍药苷的t_1/2分别为（43.34±5.70），（29.37±2.23）min，MRT分别为（62.54±8.22），（42.37±3.22）min，AUC_0-t分别为（145 611.50±24 607.85），（259 667.70±27 544.71）ng·mL^-1·min。结论：不同黄芪剂量组中芒柄花素的MRT及t_1/2均无明显差异。高剂量益气组能延长芍药苷t_1/2、MRT，能延缓芍药苷在体内被代谢，有利于芍药苷在体内维持更持久的作用时间。     

β-七叶皂苷钠在家兔体内的药动学研究

目的:建立家兔血液中七叶皂苷钠的测定方法。方法:应用酶联免疫吸附分析(ELISA)方法,测定正常家兔与脑缺血再灌注模型家兔静脉注射β-七叶皂苷钠(5mg/kg)后的血药浓度,并对其药动学参数进行分析。结果:正常家兔与模型家兔静脉注射β-七叶皂苷钠后,主要药动学参数t1/2α分别为(0.343±0.061)、(0.854±0.079)h,t1/2β分别为(23.325±10.36)、(34.283±13.74)h,CL分别为(1.600±1.206)、(0.718±0.428)L/h,Vd分别为(53.827±36.42)、(14.799±10.15)L,AUC0-24h分别为(2.919±0.981)、(26.417±9.207)μg(/h.L),AUC0-∞分别为(3.126±1.253)、(27.848±8.745)μg(/h.L),cmax分别为(4.126±0.927)、(7.905±1.054)mg/L。结论:β-七叶皂苷钠在脑缺血再灌注模型大鼠体内的消除较正常大鼠慢,在体内停留的时间较长。提示β-七叶皂苷钠在临床对症治疗时应考虑其药动学特点。     

雷公藤甲素在正常大鼠和佐剂性关节炎模型大鼠体内的药动学研究

目的:研究雷公藤多苷片中活性成分雷公藤甲素在正常大鼠和佐剂性关节炎模型大鼠体内的药动学特征,为其临床合理用药提供参考。方法:将12只SD大鼠随机分为正常组和模型组,每组6只。模型组大鼠sc完全弗氏佐剂0.1 m L复制佐剂性关节炎模型,正常组大鼠sc等体积生理盐水。造模14 d后,两组大鼠均ig雷公藤多苷片混悬液96 mg/kg,分别于给药前及给药后10、30、45、60、90、120、150、180、240、300、420 min眼眶取血0.4 m L,采用高效液相色谱法测定雷公藤甲素的血药浓度;采用DAS 2.0药动学软件计算药动学参数,并进行比较。结果:雷公藤甲素在正常组、模型组大鼠体内的c_(max)分别为(1.139±0.114)、(0.916±0.103)μg/m L,t_(max)分别为(2.167±0.606)、(3.083±0.801)h,t_(1/2α)分别为(5.500±3.610)、(5.593±1.795)h,AUC_(0-7 h)分别为(5.052±0.371)、(4.707±0.347)μg·h/m L,MRT_(0-7 h)分别为(3.224±0.119)、(3.429±0.139)h,CL分别为(11.616±2.986)、(11.246±2.638)m L/h。与正常组比较,模型组大鼠c_(max)显著减小,t_(max)和MRT_(0-7 h)显著延长(P<0.05)。结论:佐剂性关节炎会影响大鼠体内雷公藤甲素的药动学特征,其可促进大鼠体内雷公藤甲素的吸收与消除。     

灯盏花素对脑缺血再灌注损伤的保护作用和治疗时间窗

目的 :研究灯盏花素对脑缺血再灌注损伤的保护作用和治疗时间窗。方法 :线栓法制备大鼠大脑中动脉阻断 (MCAO)局灶性脑缺血模型 ,缺血前给予灯盏花素 5 0、75mg·kg- 1 ,ig,qd× 7d。末次给药 1h制备MCAO模型 ,缺血 2h ,再灌注 3h ,评价神经功能状态、脑水肿和脑梗死范围 ;放免法测定血清IL 8的含量和分光光度法测定脑组织中伊文思蓝 (EB)的含量 ;灯盏花素的治疗时间窗研究 ,采用MCAO局灶性脑缺血 2h,再灌注 2 4h模型 ,分别在缺血开始 3、4.5、6h腹腔注射灯盏花素 75mg·kg- 1 ,再灌注 2 2h,重复给药 1次 ,再灌注 2 4h ,评价神经功能状态、脑水肿和脑梗死范围。结果 :灯盏花素75mg·kg- 1 ,ig,qd× 7d能改善大鼠脑缺血再灌注后神经功能评分 ,减轻脑水肿和减少脑梗死范围 ,降低血清IL 8的含量和降低大鼠脑组织中EB的含量 ;在缺血后 3h治疗用药 ,能有效改善大鼠脑缺血再灌注后神经功能评分 ,减轻脑水肿和减少脑梗死范围 ,4.5h开始用药 ,疗效下降 ,6h开始用药 ,上述各指标有下降趋势 ,但无统计学差异。结论 :灯盏花素对脑缺血再灌注损伤有保护作用 ,有效治疗时机在缺血 4.5h内     

芒柄花素对脂多糖诱导的肺泡上皮细胞凋亡及炎症反应的抑制作用

目的 基于磷脂酰肌醇3激酶/蛋白激酶B(PI3K/Akt)信号通路，探讨芒柄花素对脂多糖（LPS）诱导的肺泡上皮细胞凋亡及炎症反应的抑制作用。方法 体外培养肺癌人肺泡基底上皮细胞A549，分为对照组（不干预）、模型组（1μg/mL LPS）、芒柄花素不同浓度组（1μg/mL LPS+6.25、12.5、25、50μmol/L芒柄花素），检测各组细胞培养液中炎症因子（白细胞介素8、肿瘤坏死因子α）水平和细胞活力。另取A549细胞分为对照组、模型组（1μg/mL LPS）、LPS+25组（1μg/mL LPS+25μmol/L芒柄花素）、抑制剂组（1μg/mL LPS+20μmol/L LY294002）、芒柄花素+抑制剂组（1μg/mL LPS+25μmol/L芒柄花素+20μmol/L LY294002）和芒柄花素+激活剂组（1μg/mL LPS+25μmol/L芒柄花素+10μmol/L SC79），检测各组细胞炎症因子分泌水平和mRNA表达水平、细胞凋亡情况和PI3K/Akt信号通路关键蛋白表达情况。结果 与模型组比较，25μmol/L的芒柄花素能显著降低细胞培养液中炎症因子水平，...     

芒柄花素磺化物的合成、溶解性能及降脂保肝活性

以芒柄花素为先导化合物, 利用磺化反应合成了具有降脂保肝活性的水溶性新化合物芒柄花素-3′-磺酸钠,通过IR、NMR、元素分析对其结构进行了表征。采用紫外分光光度法测定了芒柄花素-3′-磺酸钠的溶解度和正辛醇/水分配系数;采用高脂饮食诱导大鼠高脂模型,进行了降脂保肝的药理活性试验。实验结果表明芒柄花素-3′-磺酸钠不仅具有良好的水溶性,而且具有好的降脂保肝活性。
     

齿痛消炎灵颗粒中5种成分在大鼠体内的药动学研究

目的 研究齿痛消炎灵颗粒中芍药苷、橙皮苷、柚皮素、芒柄花素和甘草次酸5种成分在大鼠体内的药动学。方法 取6只雄性SD大鼠，禁食不禁水12 h后一次性灌胃齿痛消炎灵颗粒（5.0 g/kg），分别于给药后的不同时间点经眼内眦取血。血浆样品经乙腈沉淀蛋白预处理后（磺胺甲噁唑为内标），采用液相色谱-串联质谱（LC-MS/MS）法检测血浆中5种成分的浓度；采用DAS 3.0软件，计算各成分的药动学参数。结果 大鼠灌胃齿痛消炎灵颗粒后，5种成分中芒柄花素的tmax、t1/2均最短（分别为0.25、0.39 h）；柚皮素和甘草次酸的tmax较短，但t1/2较长，且柚皮素的药-时曲线出现了双峰现象；与其他3个成分相比，芍药苷和橙皮苷的cmax、AUC与体外成分含量高低不成正比。结论 齿痛消炎灵颗粒中芒柄花素、柚皮素、甘草次酸均在大鼠体内迅速吸收，芍药苷、橙皮苷均吸收较慢。     

RP-HPLC测定4，5，2’-三吗啉酰氧基-2，5'-二氯二苯甲酮原料药的含量及有关物质

目的 建立测定原料药4,5,2''-三吗啉酰氧基-2,5''-二氯二苯甲酮（LF1）的含量及有关物质的RP-HPLC方法。方法 采用Diamonsil C₁₈（250 mm×4.6 mm,5 μm）色谱柱,乙腈-磷酸水（60：40,pH3.0）为流动相,检测波长230 nm,体积流量1 mL/min,柱温25℃。结果 主峰与杂质峰分离良好,LF1和杂质A分别在质量浓度1.0~100（r=0.999 8）和0.2~2.4 mg/L （r=0.999 6）线性关系良好,最低检测限分别为1和2 ng/mL,平均回收率分别为100.7%和102.0%。结论 本法简便、快速、准确,可用于LF1原料药的含量及有关物质的测定。     

Effects of local anesthetics on calmodulin-dependent guanylate cyclase in the plasma membrane of Tetrahymena pyriformis

A highly purified preparation of Tetrahymena calmodulin activated a membrane-bound guanylate cyclase by more than 40-fold. This activation of guanylate cyclase by calmodulin was inhibited completely by local anesthetics such as dibucaine, tetracaine, lidocaine and procaine at concentrations that had no appreciable effect on the activities of basal guanylate cyclase (without calmodulin) and adenylate cyclase. The inhibition by dibucaine of calmodulin-mediated activation of the enzyme activity was not reversed by calcium but was partially overcome by increasing the concentration of calmodulin. Kinetic analysis of local anesthetic-induced inhibition of activation of guanylate cyclase demonstrated a mixed type of antagonism. These results suggest the possibility that the inhibition of calmodulin-dependent guanylate cyclase resulted, in part, from interaction of the drugs with calmodulin.     

2',4'-二羟基-3'-甲基-3-甲氧基查耳酮上调p21抑制人肝癌HepG2细胞的生长

目的 探讨2'',4''-二羟基-3''-甲基-3-甲氧基查耳酮(C20)对人肝癌HepG2细胞的体外抗肿瘤作用及其潜在的作用机制。方法 通过CCK-8法、集落形成实验、5-乙炔基-2''-脱氧尿苷(EdU)染色法检测C20对人肝癌HepG2细胞增殖的影响;通过彗星实验检测C20(10 μmol·L^-1)对HepG2细胞DNA损伤的影响;通过流式细胞术检测C20(5、10 μmol·L^-1)对HepG2细胞周期阻滞的影响;通过Hoechst染色和流式细胞术检测C20(5、10 μmol·L^-1)对HepG2细胞凋亡的影响。借助Western blotting法检测C20(5、10 μmol·L^-1)处理对HepG2细胞中与凋亡、DNA损伤、细胞周期阻滞相关蛋白表达水平的调控作用。结果 与对照组比较,C20显著抑制HepG2细胞的活力(P<0.001),给药48 h的半数抑制浓度(IC₅₀)为7.937 μmol·L^-1;5 μmol·L^-1 C20能够显著抑制HepG2细胞的集落形成能力(P<0.01);EdU染色结果显示5、10 μmol·L^-1的C20能够抑制人肝癌HepG2细胞的增殖能力;5、10 μmol·L^-1的C20显著诱导HepG2细胞G₂/M期阻滞(P<0.001);5、10 μmol·L^-1的C20显著促进HepG2细胞凋亡(P<0.001),并显著上调Caspas-3、Caspase-9以及PARP的剪切水平(P<0.01);10 μmol·L^-1的C20能够诱导HepG2细胞发生DNA损伤,并且5、10 μmol·L^-1的C20显著上调γH2AX、p21的蛋白水平(P<0.01)。结论 C20能够造成HepG2细胞发生DNA损伤,上调p21蛋白水平,导致细胞G₂/M期阻滞,并进一步诱发凋亡,发挥体外抗肝癌作用。     

Structural analogs of 5'-methylthioadenosine as substrates and inhibitors of 5'-methylthioadenosine phosphorylase and as inhibitors of human lymphocyte transformation

5'-Deoxy-5'-methylthioadenosine (MTA) phosphorylase was purified 13.4-fold from human peripheral lymphocytes. The enzyme demonstrated normal Michaelis-Menten kinetics with Km values of 26 microM and 7.5 mM for the two substrates, MTA and phosphate, respectively. The rate of MTA degradation was temperature dependent, 47 degrees being the optimum temperature. Five structural analogs served as alternative substrates with Km values ranging from 31 to 53 microM while two compounds, 5'-deoxy-5'-methylthiotubercidin (MTT) (Ki = 31 microM) and adenine (Ki = 172 microM), were inhibitory. These same analogs were examined as inhibitors of mitogen-induced human lymphocyte blastogenesis. MTT was found to be the most effective inhibitor of lymphocyte transformation with an I50 of 80 microM.     

UPLC-TOF-MS法鉴定胀果甘草药渣中黄酮类成分

目的建立胀果甘草药渣中黄酮类成分的超高效液相色谱-高分辨飞行时间质谱(UPLC-TOF-MS)定性分析方法。方法 AgilentSB-C18柱(100mm×4.6mm,1.8μm);流动相乙腈-0.1%甲酸水溶液,梯度洗脱;体积流量0.4mL/min;柱温25℃;检测波长254nm。ESI离子源,飞行时间质谱检测器。对比自制对照品进行鉴别。结果共鉴定出8个黄酮类成分,分别为2’,4,4’-三羟基查耳酮、甘草查耳酮D、甘草查耳酮甲、4’-羟基-2’’,2’’-二甲基吡喃[5’’,6’’,6,7]黄酮、甘草黄酮C、光甘草酮、甘草黄酮B和kanzonolE。结论建立了一种简单、可靠的UPLC-TOF-MS方法对胀果甘草药渣中黄酮类成分进行了鉴定,对胀果甘草药渣综合利用有一定参考价值。     

Stimulatory effect of ionophores on adenosine 3',5'-monophosphate content in human mononuclear leukocytes

Ionophores A23187 and bromo-lasalocid ethanolate enhanced the cyclic AMP content in human mononuclear leukocytes. The maximum effect of A23187 with a 10-min incubation was found with 0.3–1.0μM concentrations with or without l-isoproterenol (1 μM) or prostaglandin E ₁ (pge ₁) (0.3 μM). The maximum effect after 5 min of incubation at 37° was observed with 0.05, 0.2 and 1 μm A23187. The effect of ionophore A23187 was enhanced by both aminophylline (1 mM) and isobutyl-methylxanthine (1 mM). Calcium (1 mM). aspirin (1 mM) and indomethacin (100 μM) decreased the stimulatory action of A23187. Bromo-lasalocid ethanolate increased cyclic AMP content in cells maximally at a 3 μM concentration with or without 0.3 μM pge ₁.     

HPLC测定当归中1-(3',4'-dihydroxycinnamoyl)-cyclopentane-2,3-diol的含量

目的 建立HPLC测定当归中1-（3'',4''-dihydroxycinnamoyl）-cyclopentane-2,3-diol含量的方法。方法 采用Inertsil ODS-3 C₁₈柱（4.6 mm×250 mm,5 μm）,流动相为乙腈-0.05%三氟乙酸水溶液梯度洗脱,流速为1.0 mL·min^-1,检测波长为325 nm,柱温为30℃。结果 1-（3'',4''-dihydroxycinnamoyl）-cyclopentane-2,3-diol进样量在0.023 36~1.168 0 μg（r=1.000 0）内与峰面积呈良好的线性关系,平均回收率为95.33%,RSD为1.88%。结论 该方法简便、准确、重复性好,可为当归药材的质量控制提供参考。     

Effects of phenothiazines on the membrane-bound guanylate and adenylate cyclase in tetrahymena pyriformis

The particulate-bound guanylate cyclase activity of Tetrahymena pyriformis was shown previously to be Ca²⁺-dependent and to be activated by an endogenous calmodulin-like protein (Tetrahymena Ca²⁺-binding protein, TCBP) [S. Nagao, Y. Suzuki, Y. Watanabe and Y. Nozawa, Biochem. biophys. Res. Commum.90, 261 (1979)]. Phenothiazine derivatives, such as chlorpromazine and trifluoperazine, that interact with calmodulin were found to inhibit the Ca²⁺-dependent guanylate cyclase activity and the TCBP-induced activation of the guanylate cyclase activity. Ethylene glycol-bis (β-aminoethyl ether)-N, N'-tetraacetic acid (EGTA), a Ca²⁺ chelator, also inhibited the activation of guanylate cyclase. However, the mechanisms by which EGTA and trifluoperazine act were different. The EGTA-induced inhibition could not be overcome by increasing the concentration of TCBP, whereas the trifluoperazine-induced inhibition could be overcome by increasing the concentration of TCBP, but not by increasing the concentration of Ca²⁺. These findings suggest that the mechanism by which trifluoperazine inhibits the activation of guanylate cyclase involves competition with TCBP.     

Increased thymidylate synthetase in 5-fluorodeoxyuridine resistant cultured hepatoma cells

A FdUrd resistant line of cultured mouse hepatoma cells has been obtained. The resistant cell line had 6- to 10-fold higher levels of thymidylate synthetase, but dihydrofolate reductase and thymidine kinase were unchanged. No impairment of FdUrd incorporation by the resistant cell line could be detected. The increased thymidylate synthetase in resistant cells had the same turnover number and I₅₀ for FdUMP as the enzyme found in sensitive cells, making it unlikely that a new gene product had been obtained. Sensitive cells could be completely rescued by the addition of thymidine, suggesting that the primary mode of drug action is to diminish thymidine metabolites. Resistant cells, removed from FdUrd for several generations, did not proliferate immediately upon reintroduction of the drug; however, loss of sensitivity was much more rapid than upon initial exposure. These results are interpreted in terms of a mechanism for resistance.     

Age related changes in cardiac and aortic phosphodiesterase activities in normotensive and hypertensive rats.

The activities of cAMP¹ and cGMP phosphodiesterase were studied in the aorta (freed of adventitia layer) and in the heart (ventricles) of normotensive and mincralocorticoid hypertensive rats of 8 or 16 weeks of age. The enzyme activities were determined at low (1 μM) and high (100 μM) substrate concentrations. The changes in activity were compared to the changes in organ weight, protein and DNA content. The increase in organ weight that occurred with both age and hypertensive treatment corresponded mostly to a marked elevation in protein content in the aorta, but not in the heart, where the DNA content increased without any significant variation in protein content. In both tissues. eGMP phosphodiesterase activity measured at low substrate concentration was sensitive to endogenous Ca²⁺-dependent activation and markedly increased with age. This increase was proportionally larger than the variations in DNA content of the tissues, but lower than those of total protein in the aorta. It could not be ascribed to an increase in the activator content of the tissues, which was in excess. By contrast. cGMP phosphodiesterase activity measured at high substrate concentration and cAMP phosphodiesterase activity, measured at either substrate concentration, were not sensitive to the Ca²⁺-dependent activation and did not undergo large changes with age except for a significant decrease in cAMP phosphodiesterase activity at high substrate concentration per mg heart cytosol protein. No relationship could be found between the elevation of blood pressure, due to age or to the influence of the mineralocorticoid treatment, and phosphodiesterase activities, which varied in a similar manner in control and hypertensive rats. The results are consistent with the view that a cGMP phosphodiesterase. which is sensitive to Ca²⁺-dependent endogenous activation, increases in aorta and heart cells with the age of the rat.