COMPARISON OF THE EFFECTS OF ENDRALLAZINE, HYDRALLAZINE AND VERAPAMIL ON HUMAN ISOLATED ARTERIES AND VEINS

1. The antagonist effects of endrallazine (BQ 22-708), hydralazine and verapamil have been studied on the contractile responses produced by various agonists on human digital arteries and metacarpal veins obtained post mortem. 2. Endrallazine and hydralazine antagonized the contractile responses to noradrenaline and serotonin in arteries by shifting the concentration-effect curves to the right and by reducing the maximum responses to both agonists. Neither drug had any effect on responses to BaCU in either tissue. 3. The same concentrations of endrallazine and hydralazine which antagonized responses to noradrenaline and serotonin in arteries, had no effect on concentration-effect curves to those agonists in veins. 4. Hydralazine was significantly more potent than endrallazine in reducing the maximum response to noradrenaline in arteries, and was less potent than endrallazine in reducing the maximum response to serotonin. 5. Verapamil antagonized the vasoconstrictor effect of all agonists tested in both arteries and veins. 6. It is concluded that in a similar manner to hydralazine, endrallazine has a direct effect on human vascular smooth muscle at concentrations which are probably similar to those occurring in vivo. Both hydralazine and endrallazine may produce selective arterio-dilatation by preventing the release of bound calcium from intracellular storage sites, an effect which is different to that of verapamil.     

REDUCED RESPONSES TO NORADRENALINE OF ISOLATED DIGITAL ARTERIES FROM HYPERTENSIVES

1. Strips of digital arteries obtained post-mortem from thirteen hypertensives have been compared with those from thirteen normotensives. 2. The strips from hypertensives and from males had a significantly greater response to 80 mmol/1 KCl, but this was due to the increased cross-sectional areas of the strips from hypertensives and from males. 3. The maximum responses to noradrenaline and serotonin, but not the pED₅₀ values, were significantly smaller in the strips from the hypertensives than in those from the normotensives, but there were no differences between the strips from hypertensives and normotensives in either the maximum response or pED₅₀ values to angiotensin or barium chloride. 4. It is concluded that these results suggest a decreased number of α-receptors are present in human hypertensive vascular smooth muscle and this is a sequel either of the increased pressure itself, or of increased exposure in vivo of the blood vessels from hypertensives to noradrenaline.     

ARE NEURONAL UPTAKE MECHANISMS RESPONSIBLE FOR THE DIFFERENCE IN SENSITIVITY TO NORADRENALINE BETWEEN HUMAN ARTERIES AND VEINS?

1. The sensitivity of human metacarpal veins and digital arteries obtained post-mortem to noradrenaline and phenylephrine has been tested. 2. ^pED₅₀ values for noradrenaline were significantly higher in the veins (699, s.e.m. = 008) than in the arteries (6.56, s.e.m. = 009), whereas _pED₅₀ values for phenylephrine in the two tissues were not significantly different (arteries: 6.24, s.e.m. = 009; veins: 6.26, s.e.m. = 005). 3. The addition of propranolol (4 × 10^?6 mol/l) alone, or in combination with hydrocortisone (4 × 10^?5 mol/l), did not affect the responses to either noradrenaline or phenylephrine. The further addition of cocaine (3 × 10^?5 mol/l) slightly shifted the noradrenaline and phenylephrine concentration-effect curves to the left in both arteries and veins, but veins were still found to be more sensitive than arteries to noradrenaline whilst there was still no difference in the sensitivity of veins and arteries to phenylephrine. 4. Cocaine also slightly potentiated responses to barium chloride, potassium chloride and serotonin. 5. It is concluded that the difference in sensitivity to noradrenaline between arteries and veins cannot be explained by differences in neuronal uptake and it is possible that there may be differences in the properties of the postsynaptic α-adrenoreceptors of the two tissues. It is also concluded that the potentiation of the contractile effect of noradrenaline produced by cocaine is not solely due to inhibition of neuronal uptake of amines.     

INTERACTION BETWEEN PLATELET-RELEASED SEROTONIN AND THROMBOXANE A2 ON HUMAN DIGITAL ARTERIES

Synergism between the contractile effects of platelet-derived serotonin (5HT) and thromboxane A2 (TXA2) on a human blood vessel has been investigated by incubating strips of digital arteries in subcontractile concentrations of either 5HT or the TXA2-mimetic agent U46619. Either agonist U46619 or 5HT, in subcontractile concentrations, significantly potentiated the contractile response to the other. The 5HT antagonist ketanserin (10 mumol/l), the Ca2+ antagonist drugs verapamil (3 mumol/l), or nifedipine (10 nmol/l), or a Ca2+-free bathing medium, reduced the contractile responses to 5HT, but had no effect on the potentiation mediated by U46619. The interaction between TXA2 and 5HT derived from platelets was studied by measuring responses to platelets 1 min after aggregation (in the absence or the presence of ketanserin 10 mumol/l), and 20 min after aggregation. The results indicated that the response to platelets mediated by TXA2 and 5HT was greater than the sum of those mediated by TXA2 or 5HT separately. It is concluded that synergism between the contractile effects of 5HT and U46619 occurs in human blood vessels; that this is mediated by enhanced utilization of intracellular, rather than extracellular calcium; and that synergism can also occur when 5HT and TXA2 are released from stimulated human platelets.     

脱水长春胺乙酯对离体犬基底动脉的作用

本文采用离体犬基底动脉实验。结果表明脱水长春胺乙酯能对抗5-HT和高钾所致基底动脉收缩,其对5-HT具二重拮抗作用,用Brink作图法求出pA₂为6.06,pD′₂为4.96。     

PHARMACOLOGICAL ANALYSIS OF 5-HYDROXYTRYPTAMINE EFFECTS ON HUMAN ISOLATED URETER

5-Hydroxytryptamine (5-HT) induced concentration-dependent contractions in human isolated ureteral strips in vivo. On the basis of available selective 5-HT agonists and antagonists, we have further investigated the receptors involved. At concentrations from 10 n m to 1 m m, 5-HT induced concentration-dependent contractions. Significant contractions were not observed with 5-HT1Aagonist 8-OH-DPAT (10(-9)-10(-4)m), 5-HT1Dalphaagonist sumatriptan (10(-9)-10(-4)m), 5-HT2agonist DOI (10(-9)-10(-4)m), 5-HT3agonist 2-methyl 5-HT (10(-9)-10(-3)m) and 5-HT4agonist renzapride (10(-9)-10(-3)m) on the human isolated ureter. On the other side, a 5-HT1-likeagonist 5-CT (10(-9)-10(-3)m) produced contractions on the isolated samples. The Emaxdeveloped by 5-CT was significantly smaller than that of the 5-HT (29% of 5-HT). Methithepin, the less selective 5-HT1/2antagonist (10(-9)-10(-6)m), 5-HT3antagonist, ondansetron (10(-9)-10(-5)m) and 5-HT4antagonist DAU 6285 (10(-8)-10(-6)m) did not antagonise the contractile responses to 5-HT. 10(-7)m ketanserin antagonised 5-HT induced contractile responses in ureteral strips. Additionally, combined administration of 5-HT4antagonist DAU 6285 (10(-6)m) and 5-HT1/2antagonist methithepin (10(-6)m) caused a rightward shift of the CRC of 5-HT yielding pEC50values of 4.68+/-0.15. 5-HT-induced contractile responses that were not abolished by TTX and atropine, thus supporting the suggestion that in the human, the contractile responses to cumulative addition of 5-HT of the ureter are not mediated by excitation of cholinergic neurons. In the present study the receptor mediating the contractile response to 5-HT in the human upper ureter could not be clearly designated 5-HT1-like, 5-HT2, 5-HT3or 5-HT4. This study suggests that contractile response to 5-HT in the upper segments of the human ureter appear to be mediated by an atypical 5-HT receptor subtype.     

IN VITRO CALCIUM DEPENDENCE OF ARTERIAL SMOOTH MUSCLE IN HUMAN HYPERTENSION

Digital arteries, removed at autopsy from 12 hypertensives and 11 normotensives, have been compared in vitro for the calcium dependence of contractures produced by potassium chloride and noradrenaline, and the potency of verapamil to antagonize contractures to noradrenaline. No significant differences were found between the vessels from the hypertensives and normotensives for the pD2 values or the maximum response to either potassium chloride or noradrenaline in bathing solutions containing 2.5, 1.0, 0.5 or 0 mmol/l calcium chloride. There were also no significant differences between the vessels, from the hypertensive or normotensives, in the pD2 values for the addition of calcium chloride to arteries exposed to potassium chloride or noradrenaline in a calcium free bathing medium, in the ability of verapamil to shift the pD2 values for noradrenaline, nor in the ability of verapamil to reduce the maximum responses to noradrenaline (except at the two highest concentrations of verapamil tested). It is concluded that it is unlikely to be a primary abnormality of the mechanisms regulating calcium ion entry and release in vascular smooth muscle in human hypertension.     

AUGMENTATION OF ANGIOTENSIN II RELEASE FROM ISOLATED MESENTERIC ARTERIES OF WISTAR-KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS FOLLOWING NEPHRECTOMY

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time-dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII). 2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy. 3. The mesenteric arteries from kidney-intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney-intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy. 4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR. 5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.     

五味子仁七种成分的一些药理作用比较

从北五味子乙醇提取物中得到七种单一成分,称为五味子甲素、乙素、丙素、醇甲、醇乙、酯甲、酯乙。这些成分能在不同程度上使CCL₄引起的高SGPT降低,其中酯乙与醇乙的作用最强;病理学观察也见到这些成分能或多或少地减轻肝细胞损伤,但与其降酶能力并不平行。进一步研究表明酯乙、醇乙等能明显降低肝组织GPT的活性,其原因可能是对于此酶的暂时性的可逆性抑制。醇乙、甲素、乙素、醇甲能明显促进外源葡萄糖生成肝糖元,此作用以醇乙最强(约与可的松相当)。由于在去肾上腺小鼠仍有此效,故其作用主要不是通过影响体内垂体-肾上腺系统。醇乙、乙素、酯乙对小鼠戊巴比妥睡眠时间有先延长、后抑制的双相性影响,但丙素只有延长作用。从动物实验看来,五味子这些成分的降SGPT作用可能部分地由于对肝内此酶的抑制,因此五味子治疗肝炎的临床效果应根据症状、体征及各种肝功化验综合评价,不宜单从降酶效果来判断。     

DISPOSITION OF PHENYTOIN AND PHENOBARBITONE IN THE ISOLATED PERFUSED HUMAN PLACENTA

1. The disposition of the anti-epileptic agents phenytoin (PHT) and phenobarbitone (PB) was investigated in lobules of term human placentae perfused using separate maternal and fetal circulations for 6 h periods. 2. No evidence for metabolism of PHT or PB to their p-hydroxylated or other derivatives was found either in perfused lobules or by incubation with placental microsomes. 3. Both PHT and PB were readily transferred across the placenta after administration to either the maternal or fetal perfusates. 4. PHT, unlike PB, showed considerable accumulation in placental tissue.     

盐酸小檗胺松弛离体兔肾动脉条作用原理的研究

盐酸小檗胺能松弛去甲肾上腺素、高钾和钙剂引起的兔肾动脉条的收缩,并使量效曲线右移,最大反应降低。它松弛肾动脉条的原理与维拉帕米相似,是通过拮抗钙而实现的。其拮抗参数pD’_2值为4.76,而维拉帕米为5.68,故可认为盐酸小檗胺为非竞争型钙拮抗剂,拮抗强度比维拉帕米弱。     

狗肠系膜动静脉平滑肌的亚细胞膜酶活性和钙—累积功能之比较

从狗肠系膜动静脉平滑肌分离出不同部分亚细胞膜。其中微粒体部分(MIC)与浆膜F_2部分富含质膜成分,其膜标记酶活性分别为粗膜的4～5倍及10～12倍。酶活性在动静间存在组织差异。静脉MIC与F_2有较强Ca~(2+)结合和较弱的Ca~(2+)转运能力。     

THE ACETYLCHOLINE PARADOX: A CONSTRICTOR OF HUMAN SMALL CORONARY ARTERIES EVEN IN THE PRESENCE OF ENDOTHELIUM

1. In animal experiments, acetylcholine is generally a vasodilator acting indirectly by releasing endothelium-derived relaxing factor (EDRF); for example, in dog and rabbit small coronaries mounted in a myograph, acetylcholine caused concentration-dependent relaxation. 2. In human small coronary arteries taken from the atrial appendage, however, acetylcholine caused concentration-dependent contraction with a functionally intact endothelium as shown by the relaxation in response to substance P, another stimulant of EDRF release. 3. We propose that coronary microvessels from various species have variable populations of acetylcholine receptors on the medial smooth muscle that cause contraction and on the endothelium that cause the release of EDRF. In humans, the medial smooth muscle receptors appear to predominate, and may thus play a role in coronary vasoconstriction.     

布洛芬口服液的相对生物利用度研究

用ＨＰＬＣ法测定布洛芬口服液在健康人体内的血药浓度，比较了布洛芬口服液和爱尔兰进口片剂在人体内的相对生物利用度，两者的ＡＵＣ０－∞无显著差异，Ｃｍａｘ、Ｔｍａｘ均有显著差异。布洛芬口服液在人体内具有明显的达峰时间快、峰浓度高的特点。     

COMPARISON OF THE VASCULAR EFFECTS OF ADENOSINE, AMP, ADP AND ATP ON ISOLATED BLOOD-PERFUSED INTERNAL AND EXTERNAL CAROTID ARTERIES OF DOGS

1. The effects of adenosine and adenine nucleotides were studied on arterial vasculature in blood-perfused arterial preparations of dogs which were isolated from the internal and external carotid arteries. Each compound was administered directly into the cannulated artery over a period of 4 s. 2. In both arterial preparations, adenosine produced a dose-related vasodilatation and was more potent than AMP. On the other hand, ATP produced a dose-related vasoconstriction and was more potent than ADP.     

γ-氨基丁酸对离体犬脑血管的作用

用离体犬脑血管(基底动脉)环标本,观察γ-氨基丁酸(GABA)对几种不同激动剂所致最大收缩反应的舒张作用。苯福林(PE)10μmol·L^-1,5-羟色胺(5-HT)10μmol·L^-1以及25mmol·L^-1的KCl均可使脑血管静息张力增加,GABA50μmol·L^-1对以上几种激动剂所致的收缩反应均有舒张作用。对较高浓度的KCI(45mmol·L^-1)所致的收缩无影响,但对由冷刺激(未预热的营养液,28℃)引起的收缩反应有明显的舒张作用。     

A COMPARISON OF LITHIUM EFFECTS ON HUMAN BRAIN AND RAT BRAIN NORADRENALINE-SENSITIVE ADENYLATE CYCLASE

Abstract: Lithium (Li) is a drug with numerous biochemical effects. Many of these biochemical effects occur only at high Li concentrations, or disappear after chronic Li treatment. Such effects are probably not related to Li's mechanism of therapeutic action. Inhibition of noradrenaline (NE)-sensitive adenylate cyclase has been proposed as a possible therapeutic mechanism of action for Li. Tolerance does not develop to this effect, which has been reported to occur reliably beginning at 2mM Li in rat cortex. Since 2mM Li is at the upper limit of therapeutic levels in humans, controversy has continued as to whether Li inhibition of NE-sensitive adenylate cyclase is a mechanism of Li's therapeutic action or a mechanism of Li toxicity. We hypothesized that human brain NE-sensitive adenylate cyclase may be more sensitive to Li inhibition than rat brain NE-sensitive adenylate cyclase. Fresh cortical human grey matter was obtained from the edges of surgically removed brain tumors in seven patients. Results showed significant inhibition of NE-sensitive adenylate cyclase at 1mM Li. These results support the possibility that inhibition of NE-sensitive adenylate cyclase is a mechanism of Li's therapeutic action.