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Milrinone improves intestinal villus blood flow during endotoxemia

CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE 2000年第7期47卷 673-679页

作者： Schmidt, W Tinelli, M Secchi, A Gebhard, MM Martin, E Schmidt, H Heidelberg Univ Dept Anesthesiol D-69120 Heidelberg Germany Heidelberg Univ Dept Expt Surg D-69120 Heidelberg Germany

Purpose: To determine whether the compromised intestinal villus blood flow in a rat model of endotoxemia could be improved by continuous infusion of the phosphodiesterase (PDE) inhibitor milrinone. Methods: Twenty-four anesthetized and ventilated rats were laparotomized and an ileal portion was exteriorized and opened by an antimesenteric incision. The ileal segment was fixed with the mucosal surface upward. Microcirculatory parameters were assessed by intravital videomicroscopy. The animals were randomly assigned to receive one of three treatments: infusion of Escherichia coli lipopolysaccharides without phosphodiesterase inhibitor pretreatment (= LPS group);or infusion of LPS with milrinone pretreatment (= milrinone group), or without infusion of LPS or milrinone (= control group). Macrohemodynamic parameters (MAP, HR) and microhemodynamic parameters of ileal mucosa (mean diameter of central arterioles = D-A and mean erythrocyte velocity within the arterioles = V-E) were measured 30 min before and at 0, 60, and 120 min after induction of endotoxemia. Mucosal villus blood flow was calculated from D-A and V-E. Results: In the milrinone group MAP decreased 60 min after induction of endotoxemia whereas it remained table in the control and the LPS group. In both groups given endotoxin V-E decreased after start of LPS infusion, in contrast, D-A decreased in the LPS group, but increased in the milrinone group after 120 min of endotoxemia. Thus, the endotoxin-induced decrease of intestinal villus blood flow was diminished but not fully restored by milrinone infusion. Conclusion: Our results indicate that milrinone has some beneficial microcirculatory effects during endotoxemia. Although it contributed to systemic hypotension, it attenuated intestinal mucosal hypoperfusion.

关键词：小动脉/药物作用小动脉/病理生理学血压/药物作用强心药/药理学内毒素血症/病理生理学红细胞/药物作用红细胞/生理学心率/药物作用回肠/血液供给回肠/药物作用肠黏膜/血液供给肠黏膜/药物作用脂多糖类米力农/药理学磷酸二酯酶抑制剂/药理学大鼠 Wistar 局部血流/药物作用血管舒张药/药理学动物男(雄)性大鼠

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Cerebrovascular effects of the TRH analogues pGlu-3-methyl-His-Pro amide and pGlu-Glu-Pro amide: A comparison with TRH

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UPSALA JOURNAL OF MEDICAL SCIENCES 2000年第1期105卷 73-83页

作者： Koskinen, LOD Koch, ML Svedberg, J Def Res Estab Div NBC Def Dept Biomed Umea Sweden

The goal of the study was to assess whether TRH analogues possess cerebrovascular effects similar to the native peptide. The neuropeptide thyrotropin releasing hormone (TRH) elicits cerebrovasodilation in several species under various conditions. The laser-Doppler method was employed to study the effects of TRH and the analogues pGlu-3-methyl-His-Pro amid (M-TRH) and pGlu-Glu-Pro amide. Intravenous (iv.) injection of 300 mu g kg(-1) of TRH elicited cerebrovasodilation and a 62% increase in blood flow within 1 minute. M-TRH, in a dose of 300 mu g kg(-1) iv., elicited a 80% increase in cerebral blood flow. Even a minute dose of M-TRH (625 ng kg(-1)) caused an increase in cerebral blood flow. No clear difference in effects on the cerebral blood flow was observed between spontaneously and mechanically ventilated animals. pGlu-Glu-Pro amide had no cerebrovascular effect.

关键词：血气分析脑血管循环/药物作用剂量效应关系药物血流动力学/药物作用激光多普勒流量测定分子结构吡咯烷酮羧酸/类似物和衍生物大鼠 Sprague-Dawley 促甲状腺素释放激素/类似物和衍生物促甲状腺素释放激素/药理学血管舒张药/药理学动物男(雄)性大鼠

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Blunting of pulmonary but not systemic vasodilator responses to dobutamine in newborn lambs

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PEDIATRIC RESEARCH 2000年第1期47卷 107-113页

作者： Smolich, JJ Sano, T Penny, DJ Monash Med Ctr Cardiol Unit Ctr Heart & Chest Res Dept Med Clayton Vic 3168 Australia Monash Med Ctr Inst Reprod & Dev Clayton Vic 3168 Australia Monash Univ Clayton Vic 3168 Australia Royal Childrens Hosp Dept Cardiol Parkville Vic 3052 Australia

Little is known about the changes in systemic and pulmonary vascular responses to dobutamine that occur during postnatal development. To address this question, vascular pressures and cardiac output were measured in anesthetized 1- to 2-d-old (n = 6), 7- to 10-d-old (n = 7), and 6- to 8-wk-old lambs (n = 6) while dobutamine was infused incrementally in the dose range of 0.5-40 mu ***(-1).min(-1). Dobutamine reduced pulmonary vascular resistance in the three age groups (all p < 0.005). However, although this reduction reached a plateau over the infusion range of 15-40 mu ***(-1).min(-1) at all ages, its magnitude was less (p < 0.02) in 1- to 2-d-old lambs (24 +/- 2%) than in 7- to 10-d-old (41 +/- 7%) or 6- to 8-wk-old lambs (42 +/- 6%). Over the same infusion range, dobutamine produced a fall in systemic vascular resistance (all p < 0.005) that was proportionally similar in 1- to 2-d-old (51 +/- 3%), 7- to 10-d-old (48 +/- 3%), and 6- to 8-wk-old lambs (42 +/- 6%). In separate subgroups of 1- to 2-d-old lambs, pulmonary and systemic responses to dobutamine were not affected by pretreatment with selective alpha(1)-, beta(1)-, or beta(2)-adrenoceptor antagonists. Taken together, these findings suggest that the pulmonary but not systemic vasodilator response to dobutamine in lambs is blunted in the initial days after birth, and that this pulmonary effect is not directly related to the adrenoceptor-stimulating properties of dobutamine.

关键词：肾上腺素能拮抗剂/药理学动物新生血管/药物作用血管/生理学多巴酚丁胺/药理学肺/血液供给绵羊血管阻力/药物作用血管舒张药/药理学动物

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Enoximone coupled to very low dose dobutamine echocardiography detects myocardial viability in akinetic and dyskinetic post-myocardial infarcted areas

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AMERICAN JOURNAL OF CARDIOLOGY 1999年第3期84卷 264-269页

作者： Mangieri, E Alessandri, N Tanzilli, G Barillà, F Puddu, PE Monti, F Canale, G Campa, PP Univ Rome La Sapienza Dept Cardiol 2 Inst Cardiac Surg Rome Italy

Dobutamine and enoximone stimulate independently inotropic reserve by increasing intracellular cyclic adenosine monophosphate. The potential of enoximone (0.75 mg/kg body weight over 10 minutes) followed by very low dose (2.5 mu g/kg/min) dobutamine echocardiography to predict recovery of ventricular function in akinetic and dyskinetic postinfarcted areas was studied. We enrolled 22 patients with previous Q-wave myocardial infarction and regional wall motion abnormalities related to left anterior descending arterial disease, left ventricular election fraction <40%, and all scheduled for myocardial revascularization. A 10 mu g/kg/min dobutamine test was performed 48 hours before the study protocol. Test images obtained at peak of pharmacodynamic effects were compared with those obtained at 4 months after myocardial revascularization, We used a 16-segment ventricular model and a 5-grade scoring system. Resting regional myocardial dysfunction graded greater than or equal to 2 was present in 267 of 352 segments evaluated. Contractile reserve (decrease in testing wall motion score greater than or equal to 2 grades) at peak effect of enoximone infusion was present in 34 of 112 severely hypokinetic, 42 of 117 akinetic, and 14 of 38 dyskinetic segments. The inotropic reserve evaluated after very low dose dobutamine was observed in 34 of 112 severely hypokinetic, 49 of 117 akinetic, and 20 of 38 dyskinetic segments. After revascularization, recovery of function was observed in 31 of 112 severely hypokinetic, 49 of 117 akinetic, and 21 of 38 dyskinetic segments. Overall, there was a significant correlation between absolute score changes of segments which were abnormal at baseline (n = 267) to enoximone peak effects (r = 0.49, p <0.001) to predict absolute changes after revascularization;after dobutamine there was progress toward identify (r = 0.62, p <0.001) and the difference wets significant among correlation slopes of dobutamine alone, enoximone alone, and enoximone plus v

关键词：强心药/投药和剂量强心药/药理学多巴酚丁胺/投药和剂量多巴酚丁胺/诊断应用超声心动描记术/方法依诺昔酮/药理学心肌梗死/并发症心肌梗死/超声检查试验预期值疾病严重程度指数血管舒张药/药理学心室功能障碍左/病因学心室功能障碍左/超声检查成年人女(雌)性人类男(雄)性中年人

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Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期295卷 578-585页

作者： Ratz, JD Fraser, AB Rees-Milton, KJ Adams, MA Bennett, BM Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC50 value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.

关键词：主动脉胸/药物作用主动脉胸/代谢主动脉胸/生理学结合竞争性生物转化血压/药物作用环GMP/代谢药物耐受性/生理学内皮缩血管肽1/拮抗剂和抑制剂内皮缩血管肽1/代谢内皮缩血管肽1/生理学肌收缩/药物作用肌松弛/药物作用硝酸甘油/药代动力学硝酸甘油/药理学吡嗪类/药理学大鼠 Sprague-Dawley 受体内皮素A 受体内皮缩血管肽/拮抗剂和抑制剂受体内皮缩血管肽/代谢磺胺类/药理学血管舒张药/药代动力学血管舒张药/药理学动物男(雄)性大鼠

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Pharmacological limitation of damage to renal medulla after cold storage and transplantation by trimetazidine

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第1期292卷 254-260页

作者： Hauet, T Baumert, H Ben Amor, I Gibelin, H Tallineau, C Eugene, M Tillement, JP Carretier, M INRA Dept Genet Anim Unite Transplantat Expt Lab Transplantat Expt F-17700 Surgeres France Fac Med EA 2624 Poitiers France Ctr Hosp Reg & Univ Poitiers Poitiers France Hop St Louis Lab Resonance Magnet Nucl & Explorat Fonct Paris France Ctr Hosp Reg & Univ Poitiers Biochim Lab Poitiers France Fac Med Pharmacol Lab Creteil France

Delayed graft function remains an important complication after renal transplantation. In this study, we investigated the influence of trimetazidine (TMZ), a cytoprotective agent, on renal medullary damage after prolonged preservation and autotransplantation. Pig kidneys were cold-flushed and preserved (48 h at 4 degrees C) with two standard renal preservation solutions Euro-Collins and University of Wisconsin supplemented or not with TMZ (10(-6) M). Analysis of plasma and urine from 48-h-cold-stored and autotransplanted kidneys was performed with biochemical methods and proton NMR spectroscopy. Histological study by light and electron microscopy was performed after reperfusion (30-40 min) and on day 14. The results showed that the preservation in either Euro-Collins or University of Wisconsin solution containing TMZ improved significantly glomerular filtration rate compared with kidneys preserved without TMZ. TMZ significantly reduced renal medullary damage, evidenced by decreased excretion of trimethylamine-N-oxide, dimethylamine, dimethylglycine, and acetate in urine. Proximal tubular injury in TMZ-free groups was assessed by significantly greater Na+ excretion, amino aciduria, and lactic aciduria than in TMZ-supplemented groups. Urinary concentrating ability was significantly improved in TMZ-preserved groups compared with TMZ-free groups. In TMZ-supplemented groups, there was also a greater excretion of citrate, which is a citric acid cycle metabolite. An extensive reduction in apical brush border of tubular cells, notably those of the proximal tubules, was noted in TMZ-free groups. This study clearly shows that TMZ has a beneficial action on in vivo renal preservation and its major impact is the vulnerable renal medulla.

关键词：生物学标记/尿柠檬酸/尿低温保存/方法肾小球滤过率/药物作用肾功能试验肾髓质/病理学肾移植/病理学磁共振波谱学微绒毛/药物作用微绒毛/病理学灌流前瞻性研究随机分配猪时间因素移植自体曲美他嗪/药理学血管舒张药/药理学动物男(雄)性

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INVITRO EFFECT OF THE CORONARY VASODILATOR DILTIAZEM ON HUMAN AND RABBIT PLATELETS

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THROMBOSIS RESEARCH 1978年第6期13卷 941-955页

作者： SHINJO, A SASAKI, Y INAMASU, M MORITA, T Pharmacological Research Laboratory Tanabe Seiyaku Co. Ltd. 2-2-50 Kawagishi Toda Saitama 335 Japan

In vitro effects of the new coronary vasodilator diltiazem on platelet function were examined in comparison with known inhibitors of platelet aggregation. Diltiazem inhibited ADP- and collagen-induced aggregation of human and rabbit platelets. It also inhibited collagen-induced release of adenine nucleotides from the platelets. It also inhibited collagen-induced release of adenine nucleotides from the platelets of both species. The inhibition of collagen-induced aggregation of washed rabbit platelets was overcome by increasing the Ca concentration of the suspending medium. Arachidonic acid-induced platelet aggregation was also inhibited by diltiazem, whereas the formation by the platelet lysate of aggregating substances from the added arachidonic acid was not inhibited.

关键词：腺苷二磷酸/药理学花生四烯酸类/药理学阿司匹林/药理学苯丙氮|艹卓|类/药理学血小板/药物作用钙/药理学胶原/药理学地尔硫|艹卓|/药理学依他酸/药理学吲哚美辛/药理学血小板聚集/药物作用血管舒张药/药理学动物人类男(雄)性兔

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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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Differential blockade of α,β-methylene-ATP, noradrenaline and electrically evoked contractions of the rat vas deferens

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JOURNAL OF AUTONOMIC PHARMACOLOGY 1999年第4期19卷 249-256页

作者： Boselli, C Grana, E Univ Pavia Fac Farm Ist Farmacol Pavia Italy

1 The present study was carried out compare the effects of nifedipine, verapamil, papaverine and chloroethylclonidine (CEC) on the electrically-induced contractions and on the contractions produced by exogenous noradrenaline and alpha,beta methylene-ATP in the epidydimal portion of rat vas deferens, 2 Nifedipine inhibited in a concentration-dependent fashion the purinergic component (phase I) of the electrically evoked response. Verapamil (10(-7) M-10(-5) M) did not inhibit significantly or even potentiated phase I of the contractile response to single-pulse field stimulation but inhibited the response to alpha,beta methylene-ATP. Papaverine left unaffected phase I but depressed the response to alpha,beta methylene-ATP. CEC significantly potentiated,the purinergic component of the electrically-evoked response and the response induced by alpha,beta methylene-ATP. 3 Nifedipine was devoid of any inhibitory action on the noradrenergic component (phase II) of the response to single shock. Verapamil at the highest concentration used (10(-5) M) was able to partially inhibit phase II. Papaverine abolished in a concentration-dependent manner the noradrenergic component of the response to single shock. CEC abolished the phase II of single shock while was devoid of any inhibitory action on exogenous noradrenaline. 4 The implications of these differences among the compounds studied in the present work are discussed in relation to roles of calcium channels.

关键词：肾上腺素能α拮抗剂/药理学可乐定/类似物和衍生物可乐定/药理学色满卡林/药理学药物相互作用电刺激硝苯地平/药理学去甲肾上腺素/拮抗剂和抑制剂去甲肾上腺素/药理学罂粟碱/药理学大鼠 Wistar 输精管/药物作用血管收缩药/拮抗剂和抑制剂血管收缩药/药理学血管舒张药/药理学维拉帕米/药理学动物男(雄)性大鼠

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Effects of the flavoprotein inhibitor, diphenyleneiodonium sulfate, on ex vivo organic nitrate tolerance in the rat

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JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 2000年第2期293卷 569-577页

作者： Ratz, JD McGuire, JJ Anderson, DJ Bennett, BM Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada

The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but not the L-enantiomer (L-IIDN), in isolated rat aorta via inhibition of the bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H oxidase, which also is inhibited by DPI, has been proposed to generate superoxide that quenches nitric oxide (NO) produced during GTN biotransformation, and increased oxidase levels are proposed to contribute to the phenomenon of organic nitrate tolerance. We examined the effect of DPI on isolated rat aorta using an in vivo model of organic nitrate tolerance. The EC50 values for GTN-, D-IIDN-, and L-IIDN-induced relaxation of aorta from GTN- tolerant rats were increased 4.5- to 7.5-fold. Treatment of blood vessels with DPI (0.3 mu M) increased the EC50 values for GTN and D-IIDN by the same magnitude in control and tolerant aortae, a result that would not be predicted if DPI and GTN tolerance affected common targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo tolerance was assessed by NADPH-dependent cytochrome c reductase activity of aortic microsomes, immunoblotting, and Northern analysis. By all three determinants, CPR expression was unchanged in aorta from GTN- tolerant rats. Superoxide dismutase-inhibitable NADPH-dependent cytochrome c reductase activity (a measure of superoxide generation) of tolerant rat aortic microsomes was not different from that of controls. Superoxide dismutase-inhibitable NADH-dependent cytochrome c reductase activity was detected only in microsomes from tolerant animals. DPI caused a modest increase in the sensitivity for relaxation by the NO donor DEA NONOate to an equal extent in tolerant and nontolerant tissues, whereas the superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), had no effect on the sensitivity for relaxation by GTN. These results would not be expected if tolerance-induced incr

关键词：主动脉胸/药物作用生物转化印迹法 RNA 药物耐受性酶抑制剂/药理学黄素蛋白类/拮抗剂和抑制剂谷胱甘肽/类似物和衍生物谷胱甘肽/药理学异山梨酯硝酸/拮抗剂和抑制剂异山梨酯硝酸/代谢异山梨酯硝酸/药理学微粒体/药物作用微粒体/代谢肌平滑血管/药物作用 NADPH高铁血红素蛋白还原酶/代谢硝酸盐类/拮抗剂和抑制剂硝酸盐类/代谢硝酸盐类/药理学一氧化氮供体/药理学一氧化氮合酶/拮抗剂和抑制剂硝酸甘油/拮抗剂和抑制剂硝酸甘油/代谢硝酸甘油/药理学亚硝基化合物/药理学鎓类化合物/药理学药物前体/代谢药物前体/药理学大鼠 Sprague-Dawley S-亚硝基谷胱甘肽立体异构现象超氧化物类/代谢血管舒张药/拮抗剂和抑制剂血管舒张药/代谢血管舒张药/药理学动物男(雄)性大鼠

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