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Diadenosine polyphosphates cause contraction and relaxation in isolated rat resistance arteries

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 1175-1181页

作者： Steinmetz, M Schlatter, E Boudier, HAJS Rahn, KH De Mey, JGR Univ Munster Med Poliklin D-48129 Munster Germany Univ Maastricht Cardiovasc Res Inst Maastricht Dept Pharmacol & Toxicol Maastricht Netherlands

The effects of diadenosine polyphosphates (APnA;n = 3-6) and adenine nucleotides on contractile reactivity of isolated rat mesenteric resistance arteries (MrA) and superior epigastric arteries (SEA), which display a dense and sparse autonomic innervation, respectively, were evaluated. All agonists examined, except adenosine and AMP, induced contractions. The rank order of potency was similar in both arteries: alpha,beta-methylene ATP (alpha,beta-meATP) > AP5A > AP6A > AP4A > ATP > ADP > APBA. Contractions were stable during several minutes in SEA but highly transient in MrA. They were reduced after exposure to 10 mu M alpha,beta-meATP and by 10 mu M of the P2X antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid. During phenylephrine (10 mu M)-induced contractions, the agonists induced a further contraction in SEA. In MrA, however, further contraction was followed by marked relaxation. The rank order of relaxing potency was comparable to that of the contractile potency of agonists. Also, the relaxing effects of APnA were blunted by 10 mu M pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid and after exposure to alpha,beta-meATP. In vitro and in vivo sympathectomy with 6-hydroxydopamine and removal of the endothelium did not modify the effects of APnA in MrA. Thus, the contractile effects of APnA in resistance arteries 1) are due to a P2X purinoceptor-mediated stimulation of the smooth muscle;2) depend on the length of the phosphate chain;acid 3) are followed by endothelium-independent relaxing effects in MrA but not SEA, which may involve receptors that are similar to those mediating contraction. The regional heterogeneity of APnA effects cannot be attributed to a direct neurogenic influence.

关键词：腺嘌呤核苷酸类/药理学腺嘌呤核苷酸类/生理学腺苷/药理学腺苷二磷酸/药理学腺苷一磷酸/药理学腺苷三磷酸/药理学二核苷磷酸类/药理学二核苷磷酸类/生理学内皮血管/生理学腹壁动脉/药物作用腹壁动脉/生理学肠系膜动脉/药物作用肠系膜动脉/生理学肌收缩/药物作用肌松弛/药物作用肌平滑血管/药物作用肌平滑血管/生理学磷酸吡哆醛/类似物和衍生物磷酸吡哆醛/药理学大鼠近交WKY 受体嘌呤能P2/拮抗剂和抑制剂受体嘌呤能P2/生理学交感神经切除术血管阻力动物男(雄)性大鼠

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Mechanisms underlying spontaneous rhythmical contractions in irideal arterioles of the rat

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第2期521卷 507-516页

作者： Hill, CE Eade, J Sandow, SL Australian Natl Univ John Curtin Sch Med Res Div Neurosci Canberra ACT 2601 Australia

1. Mechanisms underlying spontaneous rhythmical contractions hare been studied in irideal arterioles of the rat using video microscopy and electrophysiology. 2. Rhythmical contractions (4 min(-1)) were more common during the second and third postnatal weeks and were always preceded by large, slow depolarizations (5-40 mV). 3. Spontaneous contractions were unaffected by tetrodotoxin (1 mu M), neurotransmitter receptor antagonists, the sympathetic neurone blocker, guanethidine (5 mu M) or sensory neurotoxin, capsaicin (1 mu M). 4. Stimulation of sensory nerves inhibited spontaneous activity and this was not prevented by L-NAME (10 mu M). 5. L-NAME (10 mu M) caused an increase in frequency of spontaneous contractions, while forskolin (30 nM), in the presence of L-NAME, abolished spontaneous, but not nerve-mediated, contractions. 6. Spontaneous activity was not affected by felodipine (1 nM) or nifedipine (1 mu M), but was abolished by cadmium chloride (1 mu M) or superfusion with calcium-free solution. 7. Caffeine (1 mM), thapsigargin (2 mu M) and cyclopiazonic acid (3 mu M), but not ryanodine (3 mu M), abolished spontaneous and nerve-mediated contractions. After preincubation in L-NAME (10 mu M), cyclopiazonic acid abolished spontaneous contractions only. 8. Spontaneous depolarizations and contractions were abolished by 18 alpha-glycyrrhetinic acid (20 mu M) 9. Results suggest that spontaneous rhythmical contractions are myogenic and result from the cyclical release of calcium from intracellular stores, without a contribution from voltage-dependent calcium channels. Intercellular coupling through gap junctions appears to be essential for co-ordination of these events which could be modulated by nitric oxide and increases in cAMP. The possibility that different intracellular stores underly spontaneous and nerve-mediated contractions is discussed.

关键词：腺苷三磷酸/药理学年龄因素小动脉/生理学氯化镉/药理学咖啡因/药理学钙/药理学辣椒辣素/药理学中枢神经系统刺激剂/药理学环AMP/药理学二核苷磷酸类/药理学酶抑制剂/药理学非洛地平/药理学福司柯林/药理学缝隙接合部/生理学虹膜/血液供给膜电位/药物作用膜电位/生理学肌平滑血管/生理学 NG-硝基精氨酸甲酯/药理学神经肽Y/拮抗剂和抑制剂神经肽Y/药理学肽类环/药理学周期性血小板聚集抑制剂/药理学磷酸吡哆醛/类似物和衍生物磷酸吡哆醛/药理学大鼠 Wistar 兰尼碱/药理学毒胡萝卜内酯/药理学血管收缩/生理学血管舒张药/药理学动物女(雌)性男(雄)性大鼠

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Adenosine A₁ receptors modulate high voltage-activated Ca²⁺ currents and motor pattern generation in the Xenopus embryo

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期525卷 655-667页

作者： Brown, P Dale, N Univ St Andrews Sch Biol Sci St Andrews KY16 9TS Fife Scotland

1. Adenosine causes voltage- and non-voltage-dependent inhibition of high voltage-activated (HVA) Ca2+ currents in Xenopus laevis embryo spinal neurons. 2. As this inhibition can be blocked by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and mimicked by N-6-cyclopentyladenosine (CPA) it appears to be mediated by A(1) receptors. Agents active at A, receptors either were without effect or could be blocked by DPCPX. AMP had no agonist action on these receptors. 3. By using omega-conotoxin GVIA we found that adenosine inhibited an N-type Ca2+ current as well as a further unidentified HVA current that was insensitive to dihydropyridines, omega-agatoxin TK and omega-conotoxin MVIIC. Both types of current were subject to voltage- and non-voltage-dependent inhibition. 4. We used CPA and DPCPX to test whether A(1) receptors regulated spinal motor pattern generation in spinalized Xenopus embryos. DPCPX caused a near doubling of, while CPA greatly shortened, the length of swimming episodes. In addition, DPCPX slowed, while CPA greatly speeded up, the rate of run-down of motor activity. 5. Our results demonstrate a novel action of A(1) receptors in modulating spinal motor activity. Furthermore they confirm that adenosine is produced continually throughout swimming episodes and acts to cause the eventual termination of activity.

关键词：腺苷/药理学腺苷一磷酸/药理学钙/代谢钙通道阻滞药/药理学钙通道 N型/生理学二核苷磷酸类/药理学剂量效应关系药物电刺激胚胎非哺乳动物/细胞学酶抑制剂/药理学黄素类/药理学离子通道闸门/药物作用离子通道闸门/生理学膜电位/药物作用膜电位/生理学运动神经元/化学运动神经元/生理学膜片钳术受体嘌呤能P1/生理学脊神经根/细胞学游泳/生理学黄嘌呤类/药理学爪蟾属 ω蜗牛毒素GVIA/药理学动物

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Influence of purinoceptor antagonism on diadenosine pentaphosphate-induced hypotension in anesthetized rats

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 963-968页

作者： Steinmetz, M Le, VT Hollah, P Gabriëls, G Hohage, H Rahn, KH Schlatter, E Univ Munster Med Poliklin D-48149 Munster Germany

Diadenosine polyphosphates (ApnA;n = 3-6) are potent vasoactive agents in isolated vessels. Information on effects of ApnA in vivo is still limited despite the fact that these compounds are starting to be used in humans. This study was designed to compare the effects of ApnA and their possible metabolites on blood pressure in vivo and to functionally identify purinoceptors involved in their action. All four ApnA and their degradation products induced a sustained drop of mean arterial blood pressure during i.v. infusion, which was fully reversible. The rank order of potency was Ap4A greater than or equal to Ap6A > Ap5A = Ap3A = ATP = ADP > AMP greater than or equal to adenosine, suggesting that the hypotensive effect is predominantly evoked by the original dinucleotides and not by their degradation products. The hypotensive effect of Ap5A was reduced by the P2X and P2Y(1) purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, the A(1) purinoceptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, and the A(2) purinoceptor antagonist 3,7-dimethyl-1-propargylxanthine, The hypertensive effect by the prototype P2X receptor agonist alpha beta-methylene ATP was inhibited by pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid, too. Purinoceptor antagonists reduced the maximal effects of the agonists indicating a noncompetitive inhibition. In summary, the reported vasocontractile effect of ApnA seems to be limited to isolated preparations under resting tone conditions;however, the systemic cardiovascular effects of all four ApnA are hypotensive, also making them candidates for blood pressure reduction in humans. These effects are fast in onset and easily reversible. Activation of different purinoceptors in the vasculature (most probably P2Y(1) and A(2) receptors) contributes to the Ap5A-induced decrease of mean arterial blood pressure.

关键词：二核苷磷酸类/药理学低血压/病理生理学磷酸吡哆醛/类似物和衍生物磷酸吡哆醛/药理学大鼠 Wistar 受体嘌呤能P1/拮抗剂和抑制剂受体嘌呤能P2/拮抗剂和抑制剂可可碱/类似物和衍生物可可碱/药理学血管舒张药/药理学黄嘌呤类/药理学动物男(雄)性大鼠

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Voltage-independent calcium entry in hypoxic pulmonary vasoconstriction of intrapulmonary arteries of the rat

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JOURNAL OF PHYSIOLOGY-LONDON 2000年第3期525卷 669-680页

作者： Robertson, TP Hague, D Aaronson, PI Ward, JPT Univ London Kings Coll GKT Sch Med Dept Resp Med & Allergy London SE1 9RT England

1. It has been proposed that hypoxic pulmonary vasoconstriction (HPV) is mediated via K+ channel inhibition and Ca2+ influx through voltage-gated channels. HPV depends strongly on the degree of preconstriction, and Lte therefore examined thtr effect of Ca2+ channel blockade on tension and intracellular [Ca2+] ([Ca2+](i)) during HPV in rat intrapulmonary arteries (IPAs), whilst maintaining preconstriction constant. We also investigated the role of intracellular Ca2+ stores. 2. HPV demonstrated a transient constriction (phase I) superimposed on a sustained constriction (phase II). Nifedipine (1 mu M) partially inhibited phase I, but did not affect phase II. In arteries exposed to 80 mM K+ and nifedipine or diltiazem the rises in tension and [Ca2+](i) were blunted during phase I, but were unaffected during phase II. 3. At low concentrations (< 3 mu M), La3+ almost abolished the phase I constriction and rise in [Ca2+](i), but had no effect on phase II, or constriction in response to 80 mM K+. Phase II was inhibited by higher concentrations of La3+ (IC50 similar to 50 mu M). 4. IPA treated with thapsigargin (1 mu M) in Ca2+-free solution to deplete Ca2+ stores showed sustained constriction upon re-exposure to Ca2+ and an increase in the rate of Mn2+ influx, suggesting capacitative Ca2+ entry The concentration dependency of the block of constriction by La3+ was similar to that for phase I of HPV. Pretreatment of TPA with 30 mu M CPA reduced phase I by > 80%, but had no significant effect on phase II. 5. We conclude that depolarization-mediated Ca2+ influx plays at best a minor role in the transient phase I constriction of HPV, and is not involved in the sustained phase II constriction. Instead, phase I appears to be mainly dependent on capacitative Ca2+ entry related to release of thapsigargin-sensitive Ca2+ stores, whereas phase II is supported by Ca2+ entry via a separate voltage-independent pathway.

关键词：缺氧/病理生理学咖啡因/药理学钙/药代动力学钙通道阻滞药/药理学钙通道/生理学螯合剂/药理学地尔硫|艹卓|/药理学二核苷磷酸类/药理学依他酸/药理学电刺激酶抑制剂/药理学咪唑类/药理学离子通道闸门/药物作用离子通道闸门/生理学镧/药理学膜电位/药物作用膜电位/生理学硝苯地平/药理学磷酸二酯酶抑制剂/药理学肺动脉/化学肺动脉/生理学肺循环/生理学大鼠 Wistar 兰尼碱/药理学毒胡萝卜内酯/药理学血管收缩/药物作用血管收缩/生理学维拉帕米/药理学动物男(雄)性大鼠

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Heterogenous vascular effects of AP5A in different rat resistance arteries are due to heterogenous distribution of P2X and P2Y₁ purinoceptors

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第3期294卷 1182-1187页

作者： Steinmetz, M Bierer, S Hollah, P Rahn, KH Schlatter, E Univ Munster Med Poliklin D-48129 Munster Germany

In the accompanying article, we showed that AP5A displayed heterogenous vasoactive effects in rat resistance arteries, It induced a stable vasoconstriction in the superior epigastric artery (SEA) and a transient vasoconstriction in the mesenteric resistance artery (MrA). In the phenylephrine-precontracted MrA AP5A induced a marked vasorelaxation. In this study the noncompetitive inhibition of the AP5A-induced vasoconstriction with pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid was found to be significantly stronger in MrA than in SEA. The nonselective P2 purinoceptor antagonist suramin inhibited AP5A-induced vasoconstriction in MrA only. The vasoconstriction by the P2X purinoceptor agonist alpha,beta-methylene ATP was inhibited by with pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid and suramin similarly to that induced by AP5A. Thus, the AP5A-induced vasoconstriction is due to P2X receptor activation, but two different P2X receptors seem to be operational in the two different vessels. The AP5A-induced vasorelaxation of phenylephrine-precontracted MrA was inhibited by the P2Y(1) receptor antagonist ADP3'5'. The vasorelaxation induced by ADP beta S (P2Y(1) agonist) also was inhibited by ADP3'5', These findings suggest that AP5A-induced vasorelaxation of MrA is caused by P2Y(1) receptor activation, The P1 (A(2)) receptor antagonist 3,7-dimethyl-1-propargylxanthine only slightly inhibited AP5A-induced vasorelaxation at high concentrations. Adenosine and the A(2) receptor agonist CGS21680 failed to produce significant vasorelaxation, Therefore, vasorelaxation in MrA does not involve A(2) purinoceptor activation. AP5A-induced vasorelaxation was not inhibited by Ca2+- or ATP-dependent K+ channel blockade with clotrimazole, apamin, or glibenclamide. These data indicate that vasoconstriction in MrA and SEA by AP5A is due to different P2X receptors, and vasorelaxation in precontracted MrA is due to P2Y(1) receptor activation.

关键词：二核苷磷酸类/药理学二核苷磷酸类/生理学腹壁动脉/药物作用腹壁动脉/生理学肠系膜动脉/药物作用肠系膜动脉/生理学肌收缩/药物作用肌松弛/药物作用肌平滑血管/药物作用肌平滑血管/生理学钾通道阻滞剂大鼠 Wistar 受体嘌呤能P2/激动剂受体嘌呤能P2/拮抗剂和抑制剂受体嘌呤能P2/生理学尿苷三磷酸/药理学血管阻力动物男(雄)性大鼠

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Contribution of ecto-5′-nucleotidase to the inhibition of platelet aggregation by human endothelial cells

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BLOOD 2000年第6期96卷 2157-2162页

作者： Kawashima, Y Nagasawa, T Ninomiya, H Univ Tsukuba Coll Med Technol Tsukuba Ibaraki 3058577 Japan Univ Tsukuba Inst Clin Med Div Hematol Tsukuba Ibaraki 305 Japan

We studied the role of adenosine (Ado), which is generated from adenine nucleotides via the activity of ecto-5'-nucleotidase (ecta-5'-NT), in the inhibition of platelet aggregation by endothelial cells (ECs), The enzymatic activity of nucleotidases on human umbilical Vein endothelial cells (HUVECs) was examined with regard to (1) the inhibition of adenosine diphosphate (ADP)-induced platelet aggregation and (2) the liberation of inorganic phosphate from adenine nucleotides. Adenosine 5'-monophosphate (AMP) preincubated with HUVECs significantly inhibited ADP-induced platelet aggregation. This was completely blocked by the treatment of HUVECs with a specific inhibitor of ecto-5'-NT, 5'-[alpha beta-methylene] diphosphate (APCP), or by the addition of an A(2a) receptor antagonist. Neither nitric oxide nor prostacyclin was involved in this inhibitory activity, suggesting that Ado generated in the incubation medium by the activity of 5'-NT on HUVECs inhibited platelet aggregation. When ADP was incubated on HUVECs, it lost most of its agonistic activity for platelets. Pretreatment of HUVECs with APCP at a concentration that abolished ecto-5'-NT activity partially restored ADP-induced plate let aggregation. Ecto-5'-NT contributes to EC function by inhibiting platelet aggregation in cooperation with ATP diphosphohydrolase, which degrades ADP to AMP. (Blood. 2000;96:2157-2162) (C) 2000 by The American Society of Hematology.

关键词： 5'-核苷酸酶/生理学腺苷二磷酸/药理学腺苷一磷酸/药理学腺苷三磷酸双磷酸酶/生理学血小板/细胞学血小板/生理学细胞间通讯二核苷磷酸类/药理学内皮血管/细胞学内皮血管/生理学血小板聚集/药物作用人类

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Myocardial protection using diadenosine tetraphosphate with pharmacological preconditioning

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ANNALS OF THORACIC SURGERY 2000年第3期70卷 901-905页

作者： Ahmet, I Sawa, Y Nishimura, M Yamaguchi, T Kitakaze, M Matsuda, H Osaka Univ Sch Med Dept Surg 1 Suita Osaka 565 Japan Osaka Univ Sch Med Dept Med 1 Suita Osaka 565 Japan

Background. We have reported a similar cardioprotective effect and mechanism of diadenosine tetraphosphate (AP4A) and ischemic preconditioning in rat hearts. In this study, the applicability of AP4A administration to cardiac surgery was tested by using a canine cardiopulmonary bypass model. Methods. Hearts underwent 60 minutes of cardioplegic arrest (34 degrees C) by a single dose of cardioplegia. Cardioplegia contained either AP4A (40 mu mol/L;n = 6) or saline (n = 6). Beagles were weaned from cardiopulmonary bypass 30 minutes after reperfusion, and left ventricular function was evaluated after another 30 minutes by using the cardiac loop analysis system. Results. Administration of AP4A significantly improved the postischemic recovery of cardiac function and reduced the leakage of serum creatine kinase compared with saline. Systemic vascular resistance, mean aortic blood pressure, and the electrocardiographic indices were not significantly altered by AP4A administration. Conclusions. Administration of AP4A was cardioprotective without apparent adverse effects. Because the cardioprotective mechanism may be similar to that of ischemic preconditioning, the addition of AP4A into cardioplegia may be a novel safe method for clinical application of preconditioning cardioprotection. (Ann Thorac Surg 2000;70:901-5) (C) 2000 by The Society of Thoracic Surgeons.

关键词：腺苷/血液心肺转流术肌酸激酶/血液二核苷磷酸类/投药和剂量二核苷磷酸类/血液二核苷磷酸类/药理学心电描记术/药物作用心脏停搏人工缺血预处理心肌/方法心肌再灌注损伤/预防和控制动物狗女(雌)性

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