Dual Inhibitory Action of ATP on Adrenergic Neuroeffector Transmission in Rabbit Pulmonary Artery

The aim of this study was to determine whether the inhibitory action of ATP on sympathetic neuroeffector transmission in the isolated pulmonary artery is due to ATP itself or one of its dephosphorylated breakdown products, ADP, AMP or adenosine. Furthermore, the mechanism of the inhibitory action was investigated. ATP (10^?6?3 × 10^?4 M), the degradation-resistant ATP-analogue, β, γ-methylene-5′-triphosphate (10^?5?3 × 10^?4 M), ADP (10^?6?3 × 10^?4 M), AMP (10^?5?3 × 10^?4 M), adenosine (10^?5?3 × 10^?4 M) and 2-chloroadenosine (10^?7?3 × 10^?4 M) reduced the contractions evoked by field-stimulation. This was also the case for prostaglandin E₂ (3 × 10^?9?3 × 10^?7 M), while prostaglandin F_2α(1.4 × 10^?8 M) slightly augmented the neurogenic response. The time course of the inhibitory effect of purinergic compounds on the stimulation evoked contractions was studied. In the case of ATP and ADP the inhibition was biphasic: an initial marked block (1 min. after drug addition) which in the continued presence of either compound recovered partially 10 min. later and then remained almost constant for another 90 min. The other purinergic agents caused a monophasic reduction. In the presence of indomethacin (5 × 10^?5 M), ATP and ADP also reduced the neurogenic contractions in a monophasic manner. Indomethacin did not alter the β,γ-methylene-5′-triphosphate-induced inhibition. Dilazep (3 × 10^?6 M) plus deoxycoformycin (3.6 × 10^?6 M), augmented the inhibitory effect of ATP. In contrast, theophylline (5 × 10^?5 M) did not alter the effect of ATP. The inhibitory effect of ATP (10^?4 M) on stimulation-evoked contractions was inversely proportional to the extracellular Ca²⁺ concentration (0.3–5.2 mM) and to frequency of stimulation (3–15 Hz). These results suggest that ATP initially causes a presynaptic inhibition of noradrenaline release evoked by field-stimulation. This phase I block is probably mainly due to an ADP-mediated short-lasting release of prostaglandins of the E type. The continuous inhibition (phase II) is probably due to ATP and its metabolites, possibly mainly adenosine. The phase II inhibition may possibly involve a decreased entry of Ca²⁺ into adrenergic nerve terminals during depolarization.     

Effect of Dopexamine Hydrochloride on Contractions of Rabbit Isolated Aorta Evoked by Various Agonists

The inhibitory affinity of dopexamine hydrochloride to postsynaptic adrenoceptors, cholinoceptors, 5-hydroxytryptamine and histamine receptors was studied in rabbit isolated aorta. Dopexamine (10^?7–10^?5M) antagonized competitively the contractions of rabbit aorta evoked by noradrenaline (pA₂: 6.60). Neither cocaine plus corticosterone nor cocaine, corticosterone plus propranolol altered the inhibition (pA₂: 6.77 and 6.63, respectively). The antagonism of dopexamine against noradrenaline-evoked contractions was the same after 1 and 4 hr of pretreatment with dopexamine. In the presence of cocaine plus corticosterone, dopexamine antagonized the contractions evoked by phenylephrine (pA₂: 6.94). Removal of endothelium did not influence this antagonism (pA₂: 7.06). Dopexamine (10^?7–10^?5M) did not antagonize the contractions of aorta evoked by histamine (3×10^?7–6 × 10^?5M) and by 5-hydroxytryptamine (3 × 10^?7 –3 × 10^?4M). Dopexamine (10^?8 and 10^?7M) did not alter the contractions of endothelium-free aorta evoked by carbachol. Dopexamine (10^?7–10^?5M) slightly enhanced the contractions of aorta evoked by potassium (10^?2–5.5 × 10^?2M). These results suggest that dopexamine is an α₁-adrenoceptor antagonist. Furthermore, dopexamine has no affinity to cholinoceptors, histamine and 5-hydroxytryptamine (5-HT₂) receptors and is apparently not a calcium antagonist.     

Dual Effect of the Muscarinic Agonist McN-A-343 on Vascular Neuroeffector Transmission

Abstract: The site and mechanism of action of McN-A-343 (4-m-chlorophenylcarbamoyloxy)-2-butynyltrime-thylammonium chloride) on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery was studied. Low concentrations (10^?6 — 3 × 10^?5 M) of McN-A-343 and cocaine enhanced (up to 210 and 236%, respectively) the contractions evoked by electrical-field stimulation, while higher concentrations (10^?4 — 3 × 10^?4 M) inhibited them. McN-A-343 (10^?4 M) caused an initial transitory potentiation (222% of control) of the stimulation-evoked contractions followed by an inhibition. In the presence of cocaine (3 × 10^?5 M), the potentiation caused by McN-A-343 was prolonged and the secondary inhibitory phase was thus abolished. Physostigmine (10^?5 — 10^?4 M), hexamethonium (10^?5 M), atropine (3 × 10^?7 M), suprofen (10^?5 M), and 4-aminopyridine did not alter the effect of McN-A-343 (10^?4 M). Cocaine (3 × 10^?5 M)and(+)-amphetamine (10^?5 M) reversed the McN-A-343-evoked block, while they did not alter the inhibition caused by tetracaine (3.2 × 10^?5 M). Atropine (3 × 10^?7 M) had no effect on the McN-A-343-induced block, while 4-aminopyridine (10^?4 M) caused a partial and transitory reversal. On the aorta McN-A-343 (10^?4 M) did not alter the contractile concentration-response curve of (—)-noradrenaline (10^?9 — 3 × 10^?4 M), while that of serotonin (10^?8 — 3 × 10^?5 M) was moved to the right in a competitive manner. McN-A-343 (10^?4 M) did not alter the contractions evoked by noradrenaline (10^?7 M) during the period corresponding to the stimulation-evoked enhancement and subsequent inhibition. McN-A-343 (10^?4 M) slightly antagonized the contractions caused by tyramine (10^?6 — 10^?3 M) and carbachol (10^?6 — 10^?3 M). It is concluded that McN-A-343 enhances stimulation-evoked transmitter release by a presynaptic facilitatory action mediated via receptors localized on the outer surface of adrenergic neurones and to a lesser extent by inhibition of noradrenaline re-uptake. The enhancement does not involve presynaptic nicotine or muscarine receptors. Furthermore, McN-A-343 inhibits transmitter release by acting as an adrenergic neurone blocking agent at an intraneuronal site. The inhibition does not involve presynaptic muscarine inhibitory receptors and is prostaglandin-independent.     

Calcium Channels Involved in Noradrenaline Release from Sympathetic Neurones in Rabbit Carotid Artery*

Abstract: Transmitter release from nerve terminals is dependent on the entry of Ca²⁺ through neuronal voltage‐gated calcium channels. In sympathetic neurones both N‐ and L‐type calcium channels are present. Potassium channel blockade increases Ca²⁺ entry into sympathetic neurones. We examined the participation of N‐ and L‐type calcium channels in the stimulation‐evoked release of noradrenaline from vascular sympathetic neurones. Rings of rabbit carotid artery were preincubated with [³H]‐noradrenaline. Electrical field stimulation was used to evoke ³H overflow. The selective N‐type calcium channel blocking agent ω‐conotoxin GVIA (single concentrations: 3×10^?10–10^?8 M) caused a slowly developing reduction of the stimulation‐evoked ³H overflow. At 3×10^?8 M, ω‐conotoxin GVIA caused an equilibrium block with a rapid (15 min.) onset. After 2 hr exposure to ω‐conotoxin the inhibition was steady (pIC₅₀ (‐log M): 9.43; E_max: 91%). The selective L‐type calcium blocking agents nifedipine (10^?7–10^?5 M) and nimodipine (10^?8–10^?5 M) had no effect on the stimulation‐evoked ³H overflow. The calcium channel opener Bay K 8644 (10^?6 M) likewise had no effect. The potassium channel blocking agent 4‐aminopyridine (10^?5–10^?3 M) enhanced the stimulation‐evoked ³H overflow up to 5 times. 4‐Aminopyridine (10^?4 M) did not alter the inhibitory effect of ω‐conotoxin GVIA (3×10^?8 M). In the presence of 4‐aminopyridine (10^?4 M), nifedipine (10^?5 M) and nimodipine (10^?6 M) enhanced the ³H overflow. We conclude that the stimulation‐evoked release of noradrenaline from sympathetic neurones in rabbit carotid artery is mediated by N‐type calcium channels and that L‐type channels are not involved even when potassium channels are blocked by 4‐aminopyridine.     

组织因子途径抑制物在急性肺栓塞家兔肺动脉内的表达

目的：探讨家兔急性肺栓塞后组织因子途径抑制物(TFPI)在肺动脉组织内的表达及其临床意义。方法：取栓塞3，8，24h后的急性肺栓塞动物模型的栓塞部位肺动脉和栓塞远端肺动脉，同时设实验对照组，取正常肺动脉，应用RT—PCR方法检测肺动脉组织内TFPI mRNA的表达水平。结果：肺栓塞后3h和8h组，栓塞远端肺动脉TFPI的表达显著低于栓塞部位肺动脉，并低于对照组的正常肺动脉(P＜0．01)；栓塞24h组，栓塞远端、栓塞部位和正常肺动脉之间比较差别无统计学意义。结论：栓塞部位肺动脉TFPI的表达水平短期内高于栓塞远端肺动脉，并可能对局部的凝血活性起调节作用，避免血栓的进一步延展。     

新活素治疗中重度肺动脉高压疗效观察

目的观察中重度肺动脉高压患者静脉应用新活素(重组人脑钠肽)的临床疗效。方法46例中重度肺动脉高压患者,常规治疗基础上静脉应用新活素组作为治疗组,其余作为对照组;观察并比较两组治疗前后肺动脉压力、6min步行试验、动脉血氧分压的变化。结果观察两周后,治疗组在肺动脉压力、6min步行距离、动脉血氧分压方面均明显改善,较对照组有统计学差异(P<0.05);治疗前后,对照组在肺动脉压力、动脉血氧分压无明显改善;但6min步行距离提高,有统计学差异。结论新活素可用于中重度肺动脉高压的治疗,快速有效,且不良反应少。     

Endothelium-dependent Relaxation in Response to Ethanol in the Porcine Isolated Pulmonary Artery

Many drugs cannot be dissolved in distilled water and so other solvents such as ethanol, dimethylsulphoxide and methanol are used. Because very little is known about the direct effects of these three solvents on the cardiovascular system, we have examined their effects on isolated pulmonary and coronary arteries from the pig. Increasing concentrations of ethanol, dimethylsulphoxide and methanol induced relaxation in porcine pulmonary (at 1·2% v/v, 59·9±9·0% (n = 9), 55·9±9·0% (n = 6) and 12·3±6·4% (n = 8), respectively, of U46619-induced tone) and coronary arteries (at 1·2% v/v, 69·9±7·1% (n = 10), 78·9±6·1% (n = 7) and 12·9±8·2% (n = 6) respectively, of U46619-induced tone). In the pulmonary arteries the relaxation in response to ethanol was found to be endothelium-dependent whereas the responses to dimethylsulphoxide and methanol were unaffected by removal of the endothelium. In the coronary arteries the relaxation to all three solvents was independent of the presence of the endothelium. Comparison of the sensitivity of the tissues to the solvents showed that ethanol and dimethylsulphoxide produced comparative responses in both the pulmonary and coronary arteries, whereas methanol was much less potent. The endothelium-dependent response to ethanol in the porcine pulmonary artery (maximum response, E_max, 67·1±9·3% of U46619-induced tone, n = 7) was attenuated by the cyclooxygenase inhibitor, flurbiprofen (E_max 31·9±12·0%, n = 7), the nitric oxide synthase inhibitor, L-NAME (N^G-nitro-L-arginine methyl ester; E_max 23·5±10·2%, n = 7)) and the combination of both inhibitors (E_max 18·3±7·8%, n = 7). The residual relaxatory response to ethanol was abolished, and converted into a contractile response, both by removal of the endothelium (at 1·7% v/v ethanol 27·3±11·5% of U46619-induced tone, n = 7) and by the addition of a low concentration of KCl (49·9±10·3%, n = 6), suggesting the release of a non-prostanoid, non-nitric oxide factor from the endothelium. This response, however, was not attenuated by the cannabinoid receptor-antagonist SR141716A (N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl; 52·5±4·3% relaxation, n = 8), suggesting that the factor released in this preparation by ethanol is not a cannabinoid. The results of this study indicate that many solvents commonly used in pharmacological experiments have pronounced vasoactive properties. Methanol might be the vehicle of choice, because it was the least active solvent, whereas high concentrations of ethanol might influence vascular function at both the level of the smooth muscle and the endothelium, with the action on the endothelium involving the release of endothelium-derived relaxing factors.     

Role of Cyclic AMP in Stimulation-Evoked Release of 3H-Noradrenaline from Rabbit Isolated Ear Artery

Abstract: The possible involvement of cyclic AMP in the stimulation-evoked ³H-overflow from rabbit isolated ear artery preloaded with ³H-noradrenaline was studied. Cyclic AMP (10^–5–3x10^–4M), 8–bromo-cyclic AMP (3x10^–4M) and adenosine (10^–5–3X10^–4M) enhanced stimulation-evoked ³H-overflow. Dibutyryl-cyclic AMP (10^–5–3x10^–4M) had no effect. Theophylline (3X10^–5M) and the phosphodiesterase inhibitor AH 21–132 (3X10^–5M) did not alter the enhancement of ³H-overflow caused by either cyclic AMP or adenosine. Forskolin (3X10^–6M) and the phosphodiesterase inhibitors ICI 63 197 (10^–4M) and AH 21–132 (3x10^–6–3x10^–5M) increased stimulation-evoked ³H-overflow. Forskolin (10^–6M) enhanced the effect of ICI 63 197 (3x10^–5M) but it did not alter the effect of AH 21–132. It is concluded that cyclic AMP is involved in the stimulation-evoked release of noradrenaline from postganglionic sympathetic nerves in the rabbit ear artery.     

雷洛昔芬对慢性低氧大鼠肺动脉血管重构的作用

目的 探讨雷洛昔芬对慢性低氧大鼠肺动脉结构重构的调节作用。方法 选取体质量180~200 g的健康SD大鼠40只,♂,随机分为常氧组、低氧组、低氧+17β-雌二醇组、常氧+雷洛昔芬组、低氧+雷洛昔芬组;原代培养大鼠肺动脉平滑肌细胞(pulmonary arterial smooth muscle cells,PASMC)分组同上。采用间断常压低氧法建立慢性低氧大鼠和细胞模型,采用免疫组织化学法检测肺动脉平滑肌的增殖情况,以蛋白免疫印迹法检测PASMC小窝蛋白(Caveolin-1,Cav-1)的表达,采用荧光探针法检测PASMC活性氧(ROS)的含量。结果 与常氧组相比,低氧组大鼠肺小动脉平滑肌增殖、中膜厚度及肌化程度明显增加(P<0.01),雷洛昔芬可显著抑制低氧诱导的肺动脉改变(P<0.05)。低氧组大鼠PASMC中ROS浓度增加(P<0.01),给予低氧组大鼠雷洛昔芬治疗,可下调ROS浓度(P<0.05)。低氧组大鼠PASMC中Cav-1表达显著降低(P<0.01),雷洛昔芬可改善其低表达(P<0.05)。雷洛昔芬的缓解肺动脉重构、上调Cav-1的表达、减少ROS的产生、抑制PASMC增殖的效果类似于17β-雌二醇。结论 雷洛昔芬可上调PASMC中Cav-1的表达,减少ROS的产生,抑制PASMC增殖,在缓解慢性低氧大鼠的肺动脉重构中发挥重要作用。     

瓜蒌提取物对离体家兔胸主动脉条收缩的影响

以兔离体主动脉条为实验材料,观察ＥＦＴ对去甲肾上腺素（ＮＥ）、氯化钾（ＫＣｌ）和氯化钙（ＣａＣｌ２）的剂量－效应曲线的影响及主动脉条的α受体及β受体的作用．观察了ＥＦＴ对ＮＥ引起的兔主动脉条２种收缩成分的影响．结果ＥＦＴ能舒张已被氯化钙、高钾和去甲肾上腺素收缩的兔主动脉条,使ＮＥ、ＫＣｌ、ＣａＣｌ２的剂量－效应曲线非平行右移,最大效应降低．ＥＦＴ松驰血管平滑肌的作用不依赖于阻断α受体或β受体．而与戊脉安（Ｖｅｒ）相似,是通过阻断钙通道实现的．但它们阻断钙通道的方式不同．ＥＦＴ可能无选择性阻断电位依赖性钙通道和受体操纵性钙通道,而Ｖｅｒ则只选择性阻断．因此,ＥＦＴ的扩血管机制与其对钙通道阻断作用有关     

Studies on the Effect of Histamine in Isolated Human Pulmonary Arteries and Veins

Abstract: The effect of histamine (0.01–200 μM) was studied in isolated human pulmonary vessels. Histamine induced concentration dependent contractions in both arteries and veins. In veins the maximal response to histamine was lower than in arteries. Histamine and 2-methyl-histamine had a dual action in both arteries and veins clearly demonstrated in vessels precontracted with potassium. In these vessels histamine and 2-methyl-histamine induced relaxation at low concentrations and contractions at high concentrations. Veins were more sensitive to the relaxant effect of histamine than arteries. Mepyramine eliminated the dual action of 2-methyl-histamine and histamine and unveiled a mepyramine resistant relaxation at the highest histamine concentrations used which was resistant to the effect of cimetidine and metiamide. The H₂ receptor agonist dimaprit (10–400 μM) induced a slight relaxation in both arteries and veins that could be eliminated by metiamide (100 μM). The results show that histamine has a dual action in human pulmonary vessels which includes a contractile effect mediated via H₁ receptors and a relaxant response partly mediated through H₁ receptors and partly via unspecific mechanisms. However, an H₂ mediated relaxant effect cannot be excluded.     

一氧化氮前体物逆转肺动脉胶原堆积的研究

目的 :研究一氧化氮前体L -精氨酸 (L -Arg)对高肺血流量所致肺动脉高压大鼠肺动脉胶原代谢的干预作用及其机制。方法 :在大鼠行腹主动脉 -下腔静脉分流造成的肺动脉高压模型基础上 ,给予L -Arg灌胃 ,11wk后 ,采用免疫组织化学法检测大鼠肺动脉Ⅰ、Ⅲ型胶原蛋白的表达。结果 :分流组大鼠肺中、小型肺动脉中Ⅰ、Ⅲ型胶原表达与对照组比较明显增加 (P<0 01) ;分流 +L -Arg 组大鼠肺中、小型肺动脉中Ⅰ、Ⅲ型胶原表达较分流组明显降低 (P<0 01)。结论 :L -Arg 对高肺血流量所致胶原堆积具有重要的逆转作用。     

葛根黄酮滴丸对离体豚鼠心脏冠脉血流量的影响

目的探讨葛根黄酮滴丸对离体豚鼠心脏冠脉血流量的影响。方法采用Langendorff氏法，给药后记录冠脉流量和心率变化。结果乐氏液1组与葛根黄酮滴丸低剂量（150mg／L）组冠脉流量分别为（5.80±0.75）mL／min和（7．82±0．66）mL／min，两组之间比较有显著性差异（P〈0．05）；乐氏液2组与葛根黄酮滴丸高剂量（250mg／L）组冠脉流量分别为（5．78±0．69）mL／min和（7．95±0．85）mL／min，两组之间比较有显著性差异（P〈0．05）：结论葛根黄酮滴丸使冠脉流量明显增加。     

肺心病患者血清对兔肺动脉内皮细胞分泌NO和ET的影响

目的：观察肺心病患者血清对兔肺动脉内皮细胞分泌一氧化氮(NO)、内皮素(ED的影响，以进一步探讨肺心病患者内皮细胞功能的变化。方法：用胶原酶-I消化分离获得兔肺动脉内皮细胞(RPAECs)，取生长稳定的4-6代细胞与含不同浓度肺心病患者或正常人血清的培养基共同孵育12h，弃掉更换为一般培养液，继续培养4h后收集细胞培养上清，测定细胞培养上清中的ET和NO。结果：当培养基中含10％、15％、20％肺心病患者血清时，细胞培养上清中的ET水平高于正常对照组，而NO水平低于正常对照组，两者的变化与培养基中患者血清的浓度相关。结论：高浓度肺心病患者血清抑制体外培养的兔内皮细胞分泌NO，同时促进ET的合成。     

支气管动脉灌注化疗及支气管动脉、肺动脉双介入治疗肺癌的疗效对比研究

目的：观察支气管动脉灌注化疗及支气管动脉、肺动脉双介入治疗肺癌的临床疗效,探讨其临床价值。方法选择2008年3月-2010年3月在本院诊治的肺癌患者80例为研究对象,将患者分成观察组和对照组,每组40例,对照组行支气管动脉灌注化疗,观察组行支气管动脉和肺动脉双介入治疗,比较两组患者治疗效果。结果观察组1-3年生存率分别为70.0%、52.5%、25.0%,对照组1-3年生存率分别为72.5%、50.5%、22.5%,两组患者1-3年生存率比较,差异无统计学意义（ P﹥0.05）;观察组和对照组3年平均生存时间分别为（26.8±12.5）个月、（25.4±12.8）个月,差异无统计学意义（ P﹥0.05）。结论支气管动脉和肺动脉双介入治疗肺癌未见显著疗效,相比支气管动脉单介入治疗方法,其不仅增加临床用药量,导致临床毒副作用增强,同时加大了临床治疗的难度,不利于保护患者的切身利益。     

Inhibitory Effect of Vanadium Compounds on Glutamate Dehydrogenase Activity in Mitochondria and Hepatocytes Isolated from Rabbit Liver

Abstract: The effect of orthovanadate, vanadyl sulphate and vanadyl acetylacetonate on glutamate dehydrogenase activity was studied in liver mitochondria and isolated hepatocytes of rabbit. In pcrmeabilized mitochondria with free access of substrates and drugs to glutamate dehydrogenase, orthovanadate and vanadyl sulphate at 200 μM concentrations decreased both glutamate synthesis and glutamate deamination by 80 and 50 %, respectively, while vanadyl acetylacetonate was less potent. In view of kinetic data obtained at various ammonium concentrations, orthovanadate appeared to be a competitive inhibitor (K_i= 40 × 3 μM), while vanadyl sulphate was a non–competitive one (K_i = 147 × 10 μM). In contrast to orthovanadate, vanadyl sulphate augmented the inhibitory action of increased above 0.5 mM 2–oxoglutarate concentrations. All these effects on the enzyme activity were partially reversed in the presence of L–leucine and ADR which are allosteric activators of glutamate dehydrogenase. Moreover, all compounds studied suppressed both glutamate formation and glutamate deamination in isolated hepatocytes incubated under various metabolic conditions, as concluded from decreased rates of glutamate and urea synthesis, respectively. In view of these observations it seems likely that vanadiumcontaining compounds may be potent inhibitors of glutamate metabolism in liver.     

Frequency-Dependence of 3H-Noradrenaline Release from Rabbit Pulmonary Artery: Effect of α-Adrenoceptor Antagonists and Inhibitors of Transmitter Inactivation

Abstract: The aim of this study was to examine the modulating role of presynaptic α₂-adrenoceptors on transmitter release from vascular sympathetic neurones. This was done by examining the influence of removal of inactivation pathways on the effect of α-adrenoceptor antagonists on the release of transmitter from noradrenergic neurones. The rabbit main pulmonary artery preloaded with ³H-noradrenaline (³H-NA) was used. The artery was stimulated with 300 pulses at various frequencies (1, 3, 10 and 30 Hz). Pargyline (3 × 10^?4M) increased the stimulation-evoked ³H-overflow at 1 and 3 Hz and decreased it at 30 Hz. U-0521 (3′,4′-dihydroxy-2-methylpropiophenone; 3 × 10^?6M) enhanced the overflow at 1 Hz and had no effect at 3–30 Hz. Corticosterone (4 × 10^?5M) did not alter the stimulation-evoked ³H-overflow at 1–30 Hz. Cocaine (3 × 10^?6M) enhanced the ³H-overflow slightly at 1–30 Hz. At 3 × 10^?5M, cocaine enhanced ³H-overflow at 1 Hz and reduced it at 30 Hz. Neither corticosterone (4 × 10^?5M) nor propranolol (10^?7M) modified this effect of cocaine. Propranolol (10^?7M) alone decreased the ³H-overflow at 30 Hz and had no effect at 1–10 Hz. Phenoxybenzamine (10^?6M) and chlorpromazine (3 × 10^?6M) potentiated the stimulation-evoked ³H-overflow at 1–30 Hz. Phentolamine (10^?6M) decreased the ³H-overflow at 1 Hz and enhanced it at 3–30 Hz. Rauwolscine (10^?6M) enhanced the stimulation-evoked ³H-overflow maximally at 10 Hz and had no effect at 1 and 30 Hz. Cocaine (3 × 10^?5M), cocaine (3 × 10^?5M) + corticosterone (4 × 10^?5M), pargyline (3 × 10^?4M) and U-0521 (3 × 10^?6M), but not corticosterone (4 × 10^?5M), increased the rauwolscine-induced enhancement at 1 and 3 Hz, but had no influence at 10 and 30 Hz. It is concluded that at a low frequency (1 Hz) of nerve stimulation, inhibition of either neuronal uptake, extraneuronal uptake, monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) causes an enhancement in transmitter overflow that is due to removal of inactivation pathways. The enhancement is not mediated via facilitatory β-adrenoceptors. At higher frequencies (3–30 Hz) inhibition of either neuronal uptake or MAO causes a sufficient amount of transmitter in the neuromuscular gap to activate the presynaptic α-adrenoceptor mediated negative feed-back system causing a decrease in transmitter release. α- Adrenoceptor antagonists enhance the stimulation-evoked release of ³H-NA only when the junctional gap concentration of transmitter is sufficient to trigger the presynaptic α-adrenoceptor auto-inhibitory system.     

The Vasodilatory Effects of Ketamine on Isolated Rabbit Portal Veins

Abstract: The vasodilation mechanism induced by ketamine was investigated in isolated smooth muscle strips of rabbit portal veins. Ketamine inhibited both the phasic and tonic components of K⁺-induced contraction at concentrations greater than 500 μM and 100 μM, respectively. This effect was reversible and concentration-dependent with concentrations up to 1 mM. These effects were similar to those producd by verapamil. In the presence of 60 mM K⁺, application of Ca²⁺ (2.5 mM) in the perfusing solution caused tonic contraction of the smooth muscle, and ketamine at concentrations larger than 10 μM strongly inhibited this Ca²⁺-induced contraction. Ketamine (100 μM) also inhibited the K⁺-induced contractions significantly in the absence and presence of guanethidine, tetrodotoxin and propranolol. Ketamine produced similar concentration-dependent relaxations in the tissues with and without endothelium. These results indicate that in rabbit portal vein, vasodilation produced by ketamine is not endothelium-dependent but is likely to be due to blockade of the voltage-gated influx of extracellular Ca²⁺.