Activity of the short-acting thromboxane receptor antagonist, SQ 30,741, in thrombolytic and vasospastic models in monkeys

The effects of the thromboxane receptor antagonist SQ 30,741 (1 mg/kg) on reflow after thrombolysis and on vasoconstrictor responses to the thromboxane agonist U-46,619 was determined in cynomolgus monkeys. SQ 30,741 (n = 5) or vehicle (n = 4) was administered to anesthetized monkeys upon reocclusion of a stenotic and electrically injured carotid artery, which had been recanalized successfully with streptokinase and heparin. Once blood flow again decreased to zero the treatment was repeated. SQ 30,741 significantly (P less than .05) enhanced reflow by 113% after the first administration and by 150% after the second administration. The respective times to each reocclusion were greater after SQ30,741 (49 +/- 9 and 61 +/- 23 min; P less than .01 and P less than .05) than with vehicle (10 +/- 3 and 15 +/- 2 min). The potency of SQ 30,741 was demonstrated in other anesthetized monkeys by a 8.5 +/- 1.1-fold (n = 3) shift to the right in the U-46,619 dose-response for renal vasoconstriction. The effect of SQ 30,741 (n = 5) on pre-existing renal vasoconstriction was determined using conscious monkeys in which an individually tailored dose of U-46,619 was chosen to sustain an average 82% reduction in blood flow. An arterial injection of SQ 30,741 rapidly returned flow to base-line values, but this antagonism was limited in duration, and flow again reached the nadir within 46 +/- 7 min of continuous U-46,619 infusion. The abbreviated duration of the biological activity of SQ 30,741 in vivo was consistent with its short plasma T1/2 (9.5 +/- 1.3 min; n = 3) determined in separate unanesthetized monkeys by a radioreceptor assay.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of diltiazem on infarct size, reperfusion flow and flow reserve: the effect of timing of treatment

This study was performed to determine if improved subendocardial reflow seen with diltiazem pretreatment after left circumflex coronary (LCX) occlusion is due to a direct vasodilatory effect of diltiazem on the reperfused bed or due to an increased flow maximum or reserve. In the first part of this study anesthetized dogs were subjected to saline or diltiazem (infused starting before, 10 min after LCX occlusion or 2 min before reperfusion; 0.18 mg/kg + 0.45 mg/kg/hr i.v. for all groups) treatment with a 90-min LCX occlusion and 5-hr reperfusion and myocardial blood flow and infarct size were determined at the end of the experiment. In the second part, maximal flow using intracoronary adenosine was determined at 1 and 3 hr postreperfusion in the ischemic bed when pretreated with saline or diltiazem. Myocardial infarct size was reduced significantly only in animals pretreated with diltiazem compared to saline-treated animals. At 1-hr postreperfusion, subendocardial flow (microspheres) was significantly higher only with diltiazem pretreatment compared to the saline group (100 +/- 17 vs. 54 +/- 8 ml/min/100 g, respectively) and subendocardial reperfusion flows were negatively correlated to infarct size (r = 0.97, P less than .05). Thus, diltiazem only improves reflow and infarct size when infused before occlusion and this improved reflow does not occur via a direct vasodilator action of diltiazem. When maximal vasodilating doses of adenosine were given, flow in the ischemic region was nearly identical for saline and diltiazem pretreated groups despite higher preadenosine flows in the diltiazem group (higher resting flow occurred at the expense of the existing flow reserve).(ABSTRACT TRUNCATED AT 250 WORDS)     

BM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist,prevents pig myocardial infarction induced by coronary thrombosis

The aim of this study was to characterize the effects of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual thromboxane A2 receptor antagonist and thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals (n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 +/- 2.2 and 36.9 +/- 2.1% of the left ventricular mass, respectively. In the BM-573-treated group (n = 6), a drug infusion (10 mg. kg-1. h-1) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction.     

A selective cysteinyl leukotriene receptor 2 antagonist blocks myocardial ischemia/reperfusion injury and vascular permeability in mice

Cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators that predominantly exert their effects by binding to cysteinyl leukotriene receptors of the G protein-coupled receptor family. CysLT receptor 2 (CysLT(2)R), expressed in endothelial cells of some vascular beds, has been implicated in a variety of cardiovascular functions. Endothelium-specific overexpression of human CysLT(2)R in transgenic mice (hEC-CysLT(2)R) greatly increases myocardial infarction damage. Investigation of this receptor, however, has been hindered by the lack of selective pharmacological antagonists. Here, we describe the characterization of 3-(((3-carboxycyclohexyl)amino)carbonyl)-4-(3-(4-(4-phenoxybutoxy)phenyl)-propoxy)benzoic acid (BayCysLT(2)) and explore the selective effects of this compound in attenuating myocardial ischemia/reperfusion damage and vascular leakage. Using a recently developed β-galactosidase-β-arrestin complementation assay for CysLT(2)R activity (Mol Pharmacol 79:270-278, 2011), we determined BayCysLT(2) to be ～20-fold more potent than the nonselective dual CysLT receptor 1 (CysLT(1)R)/CysLT(2)R antagonist 4-(((1R,2E,4E,6Z,9Z)-1-((1S)-4-carboxy-1-hydroxybutyl)-2,4,6,9-pentadecatetraen-1-yl)thio)benzoic acid (Bay-u9773) (IC(50) 274 nM versus 4.6 μM, respectively). Intracellular calcium mobilization in response to cysteinyl leukotriene administration showed that BayCysLT(2) was >500-fold more selective for CysLT(2)R compared with CysLT(1)R. Intraperitoneal injection of BayCysLT(2) in mice significantly attenuated leukotriene D(4)-induced Evans blue dye leakage in the murine ear vasculature. BayCysLT(2) administration either before or after ischemia/reperfusion attenuated the aforementioned increased myocardial infarction damage in hEC-CysLT(2)R mice. Finally, decreased neutrophil infiltration and leukocyte adhesion molecule mRNA expression were observed in mice treated with antagonist compared with untreated controls. In conclusion, we present the characterization of a potent and selective antagonist for CysLT(2)R that is useful for discerning biological activities of this receptor.     

Pharmacological characterization of potent, long-acting thromboxane receptor antagonists, SQ 33,261 and SQ 33,552.

SQ 33,261 ([1S-[1 alpha,2 alpha(Z),3 alpha,4 alpha]]-6-[3-[[2- [(phenylamino)carbonyl]hydrazono]methyl]-7-oxabicyclo[2.2.1]hept-2 - yl]-4-hexenoic acid) and SQ 33,552 ([1S-[1 alpha,2 alpha(Z),3 alpha,4 alpha]]-6-[3-[[[[(4- chlorophenyl)amino]carbonyl]hydrazono]methyl]-7- oxabicyclo[2.2.1]hept-2-yl]-4-hexenoic acid) are potent thromboxane (Tx) A2 receptor antagonists. They inhibited platelet aggregation in platelet-rich plasma induced by the TxA2 mimetic, U-46,619 (10 microM), with IC50 values of 200 and 70 nM, respectively. Neither compound inhibited ADP (20 microM)-induced platelet aggregation (IC50 greater than 1000 microM). SQ 33,261 and SQ 33,552 competitively antagonized U-46,619-induced contraction of rat aortic strips with respective pA2 values of 9.0 and 10.1 and KB values of 1.2 and 0.1 nM. They also competitively antagonized U-46,619-induced contraction of guinea pig tracheal strips with pA2 values of 8.9 and 9.9 and KB values of 1.9 and 0.4 nM, respectively. SQ 33,261 and SQ 33,552 (p.o.) were potent inhibitors of U-46,619 (2 mg/kg i.v.)-induced death in mice with ID50 values of 8 and 1 micrograms/kg, respectively. SQ 33,261 and SQ 33,552 (0.2 mg/kg p.o.), also had long duration of action in this assay with 50% survival times of 7 and 15 hr, respectively. SQ 33,261 at 0.01 and 1.0 mg/kg i.v., inhibited arachidonic acid-induced bronchoconstriction and reversed arachidonic acid-induced hypertension to a hypotensive response. SQ 33,552 inhibited TxA2 synthase at high concentrations (IC50 = 307 microM), whereas SQ 33,261 was inactive. Neither compound inhibited cyclooxygenase or caused an elevation of platelet cyclic AMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

内洋地黄素拮抗剂减轻心肌缺血再灌注损伤的实验研究

目的 观察心肌缺血再灌注(myocardial isehemia reperfusion，MIR)时心肌组织内洋地黄素水平的变化和内洋地黄索特异性拮抗剂地高辛抗血清对MIR的影响，证明内洋地黄素是介导MIR损伤的重要介质之一。方法 采用左冠状动脉前降支结扎30min，复灌45min建立在体大鼠MIR、模型。SD大鼠随机分成7组：假手术组，模型组，生理盐水组，维拉帕米组，小剂量、中剂量、大剂量地高辛抗血清组。连续记录Ⅱ导联心电图，于再灌注45min后立即取左室心尖部缺血区心肌，检测心肌匀浆中内洋地黄素含量、心肌细胞膜Na^ -K^ -ATP酶和线粒体内Ca^2 含量。结果MiR损伤时，心肌组织内洋地黄素水平明显升高。心肌细胞膜Na^ -K^ -ATP酶活性显著下降，线粒体内Ca^2 含量升高；心电图ST段显著抬高，再灌注时发生明显的室性心律失常。地高辛抗血清组可显著降低心肌组织内洋地黄素水平，恢复细胞膜Na^ -K^ -ATP酶活性，降低线粒体内Ca^2 含量；显著改善MIR所致ST段抬高和再灌注心律失常的发生率。结论 MIR时，心肌组织内洋地黄素水平显著升高，是介导MIR损伤的重要物质之一。地高辛抗血清通过拮抗内洋地黄素的生物学作用，减轻MIR损伤。     

心肌梗死前心绞痛病史时程对梗死面积的影响及再灌注治疗的作用

目的　探讨心肌梗死前心绞痛病史时程对梗死面积的影响及再灌注治疗在其中的作用。方法　 381例首次发作急性心肌梗死患者 ,分组比较发病前心绞痛和既往心绞痛对肌酸激酶 (CK)和肌酸激酶同工酶 (CK MB)峰值及Wagner心电图QRS记分值的影响 ,并观察早期再灌注治疗的作用。 结果　①分组 :381例患者中 ,仅有发病前心绞痛者 77例 (A组 ,占 2 0 .2 % ) ,仅有既往心绞痛者 130例 (B组 ,占 34.1% ) ,兼有发病前心绞痛和既往心绞痛者 73例(C组 ,占 19.2 % ) ,心肌梗死前无心绞痛者 10 1例 (D组 ,占 2 6 .5 % )。②CK、CK MB峰值及QRS记分值 :A组、B组和C组显著低于D组 (P均 <0 .0 5 ) ;③再灌注对CK、CK MB峰值及QRS记分值的影响 :各组内有再灌注 (+)亚组显著低于无再灌注 (- )亚组 (P均 <0 .0 0 1)。A(+)亚组和C(+)亚组显著低于D(+)亚组 (P均 <0 .0 5 ) ,而B(+)亚组和D(+)亚组间比较差异无统计学意义 (P均 >0 .0 5 )。B(- )亚组和C(- )亚组均显著低于D(- )亚组 (P均 <0 .0 5 ) ,而A(- )亚组和D(- )亚组间差异均无统计学意义 (P均 >0 .0 5 )。结论　既往心绞痛可明显保护严重缺血的心肌 ,减少梗死面积 ,其作用不依赖于再灌注治疗 ,可能与侧支循环形成有关 ;而发病前心绞痛可能通过缺血预适应机制延长心肌对严重     

舒芬太尼预处理对缺血再灌注大鼠心肌梗死范围及心肌酶的影响

目的:探讨舒芬太尼预处理(SPC)对缺血再灌注(IR)大鼠心肌的保护作用.方法:采用结扎左冠状动脉前降支法制备心肌IR模型,评价IR前后各实验组不同时间点心功能变化,再灌注心律失常严重程度,并计算心肌梗死范围(IS/AAR),测定血清心肌酶CK、CK.MB、LDH及观察心肌组织病理学改变.结果:再灌注后SPC组和缺血预处理(IPC)组心律失常严重程度评分及IS/AAR,心肌酶均低于I/R组(P＜0.05或0.01).且心肌组织超微结构损伤轻微.但与假手术组比较心肌酶浓度则有不同程度升高(P＜0.05或0.01).结论:舒芬太尼预处理具有IPC样减轻大鼠心肌缺血再灌注损伤的作用.     

双羟基黄酮醇对心肌再灌注损伤中局部心肌血流量影响的实验研究

目的:评价双羟基黄酮醇对缺血后冠脉内皮功能的作用以及评价其对致死性心肌缺血再灌注损伤的防治效果。方法:测定意识清醒、无应激状态下绵羊的冠状血管对不同浓度静脉输注的乙酰胆碱的反应,闭塞冠状动脉1 h然后进行7 d的连续再灌注,再灌注的同时进行双羟基黄酮醇或vehicle的治疗,测定缺血状态下和再灌注开始后的血液动力学指数和局部心肌收缩力,评估冠脉血管对乙酰胆碱的反应,并心脏测量梗死面积。结果:(1)双羟基黄酮醇处理后可预防心率上升,显著降低左室舒张末压在再灌注过程中的升高幅度;(2)乙酰胆碱引起的浓度依赖性心率、心搏出量和外周血管传导力的上升并不受到双羟基黄酮醇的处理和心肌缺血/再灌注的影响;(3)双羟基黄酮醇处理后梗死面积显著缩小;(4)双羟基黄酮醇处理可以显著改善危险心肌边缘区域的局部心肌血流。结论:双羟基黄酮醇可显著缩小心肌梗死面积,延长缺血后心肌再灌注中可显著改善内皮功能,可显著减弱危险心肌边缘区局部血流量的进行性损伤。     

冠状动脉血流显像分析冠状动脉左前降支心肌桥血流储备

目的 应用彩色多普勒冠状动脉血流显像(CFI)测量冠状动脉左前降支心肌桥冠状动脉血流速度储备(CFVR),分析前降支心肌桥冠状动脉血流动力学变化及其临床意义.方法 对连续110例怀疑或已知冠心病患者行冠状动脉造影(CA)、冠状动脉血管内超声(IVUS)和冠状动脉内多普勒(ICD)检查,确诊为冠状动脉左前降支心肌桥的11例患者和9例正常者(对照组)利用CFI检测基础状态和经静脉注射腺苷140 μg·kg-1·min-1达到最大充血反应状态时左冠状动脉前降支血流,计算CFVR,并与ICD测值比较,分析CFI方法的准确性.结果 心肌桥的发生率为10%.7例患有稳定心绞痛.9例肌桥位于前降支中段,2例位于中远段.2例冠状动脉前降支狭窄>80%,其中1例同时合并回旋支狭窄(90%);9例CA显示冠状动脉无明显狭窄,IVUS显示前降支无明显斑块.CFI测量9例(病变组)无冠状动脉明显狭窄患者前降支远端冠状动脉血流,通过冠状动脉平均血流速度计算的CFVR与ICD测值的回归方程为Y=0.87 X+0.39,相关系数为0.81(P<0.001).心肌桥组最大充血反应状态下冠状动脉平均血流速度明显低于对照组,CFVR亦明显低于对照组(P<0.001).结论 CFI是一项准确测量CFVR的方法,心肌桥患者CFVR减低,可能是导致患者心绞痛的原因之一.     

The antianginal agent, ranolazine, reduces myocardial infarct size but does not alter anatomic no-reflow or regional myocardial blood flow in ischemia/reperfusion in the rabbit

It has been suggested that ranolazine protects the ischemic/reperfused heart by reducing diastolic wall pressure during ischemia. However, there is limited information regarding the effect of ranolazine on the anatomic zone of no-flow in a model of acute myocardial occlusion/reperfusion. Before coronary artery occlusion (CAO), open-chest anesthetized rabbits were assigned to vehicle or ranolazine. Hearts received 60 minutes of CAO and 3 hours reperfusion. Ischemic risk zone was comparable in the 2 groups. Ranolazine significantly reduced infarct size. There was a non-significant trend for the no-reflow defect to be smaller in the ranolazine group. Regional myocardial blood flow was similar in both groups in the risk zone during ischemia and at 3 hours reperfusion. Heart rates were similar in both groups, whereas mean arterial pressure was reduced in the ranolazine group. While ranolazine was effective in reducing myocardial infarct size, the mechanism by which it did this was independent of improving perfusion during either ischemia or reperfusion, suggesting that ranolazine's effect of reducing infarct size involves alternative mechanisms.     

Sustained reduction in myocardial reperfusion injury with an adenosine receptor antagonist: possible role of the neutrophil chemoattractant response

Recent studies have demonstrated that three membrane-permeant A(1) receptor antagonists reduced infarct size in a model of ischemia followed by brief reperfusion. However, it was not determined whether cardioprotection was mediated by nonspecific intracellular effects of these highly lipophilic drugs and whether the antagonists only delayed myocardial necrosis without affecting the ultimate infarct size. In the present study, closed-chest dogs were subjected to 90 min of left anterior descending coronary artery occlusion and 72 h of reperfusion and received either a nonmembrane-permeant adenosine receptor blocker that is devoid of direct intracellular effects and is 6-fold selective for the A(1) receptor [1, 3-dipropyl-8-p-sulfophenylxanthine (DPSPX); n = 11] or vehicle (n = 12). DPSPX was administered as three 200-mg boluses 60 min before and 30 and 120 min after reperfusion. The area of necrosis was determined histologically and expressed as a percentage of the area at risk. Baseline predictors of infarct size were similar in the two groups. The ratio of the area of necrosis to the area at risk was less in the DPSPX group (17.8 +/- 4.3% versus 35.0 +/- 1.9%; P =. 012), and DPSPX improved regional ventricular function. Under both basal and stimulated (formyl-Met-Leu-Phe) conditions, suspensions of human neutrophils generated extracellular adenosine levels (approximately 50 nM) sufficient to activate A(1) receptors. Moreover, both DPSPX and 1,3-dipropyl-8-cyclopentylxanthine, a selective A(1) receptor antagonist, significantly reduced the chemoattractant response of neutrophils to formyl-Met-Leu-Phe. We conclude that blockade of A(1) adenosine receptors attenuates myocardial ischemic/reperfusion injury, possibly in part by decreasing the chemoattractant response of neutrophils.     

Comparison of pyrroloquinoline quinone and/or metoprolol on myocardial infarct size and mitochondrial damage in a rat model of ischemia/reperfusion injury

The cardioprotective effectiveness of low-dose pyrroloquinoline quinone (PQQ, 3 mg/kg) was compared with metoprolol, a beta(1)-selective adrenoceptor antagonist. Rats underwent 30 minutes of left anterior descending coronary artery occlusion and 2 hours of reperfusion. Metoprolol and/or PQQ were given at the onset of reperfusion to mimic clinical treatment. Metoprolol and/or PQQ reduced infarct size and protected against ischemia-induced left ventricular dysfunction after 2 hours of reperfusion. Combined therapy augmented left ventricular developed pressure at the end of reperfusion. Metoprolol or PQQ alone enhanced mitochondrial respiratory ratios in ischemic and nonischemic myocardium. Although the PQQ/metoprolol combination therapy increased respiratory ratio values, the effects were small when compared with PQQ alone. Only PQQ decreased lipid peroxidation. Metoprolol and/or PQQ given at the onset of reperfusion reduce infarct size and improve cardiac function. Combination therapy further reduces infarct size. PQQ is superior to metoprolol in protecting mitochondria from ischemia/reperfusion oxidative damage.     

应用组织追踪和彩色多普勒冠状动脉血流显像结合多巴酚丁胺负荷试验评价缺血再灌注心肌的收缩储备和冠状动脉血流储备

目的应用组织追踪和彩色多普勒冠状动脉血流显像（CDCFI）结合多巴酚丁胺负荷试验分析不同时间的缺血再灌注对左室心肌收缩功能和冠状动脉血流的影响，以期为评估心肌存活性提供简便快捷的定量指标。方法健康杂种犬25条，随机分为顿抑组和梗死组。应用组织追踪和CDCFI技术观测顿抑组和梗死组缺血区（前间隔）于基础状态、再灌注30min以及再灌注90min多巴酚丁胺负荷前后二尖瓣环收缩期向心尖方向运动的最大位移（MVD）以及左前降支中远段舒张期冠状动脉血流储备（CFR）的动态变化。结果多巴酚丁胺负荷试验后，不同再灌注时间顿抑心肌和梗死心肌前间隔MVD的增加率（△D％）和左前降支的CFR值均明显低于基础状态（P〈0．001，P〈0．05），顿抑组的△D％以及CFR值均明显高于梗死心肌（P〈0．001，P〈0．05），并随再灌注时间延长，有逐渐好转趋势（P〈0．05，P〈0．05）；而梗死心肌则无此变化趋势（P〉0．05，P〉0．05）；CFR与二尖瓣环收缩期向心尖运动的最大位移变化率之间有良好的相关性（r=0．719，P〈0．05）。结论结合组织追踪技术和CDCFI技术动态观察缺血再灌注心肌多巴酚丁胺负荷后心肌收缩功能和冠状动脉血流动力学变化，可以提高判断存活心肌的准确率。     

基于冠状动脉CTA的血流储备分数评估心肌缺血Meta分析

目的 探讨基于冠状动脉CTA的血流储备分数(FFR_CT)评估心肌缺血的准确性。方法 检索2004年1月—2015年2月Pubmed、Cochrane图书馆、Embase、中国期刊全文数据库(CNKI)、中国生物医学文献数据库(CBM)、万方数据知识资源系统关于FFR_CT在评估心肌缺血准确性方面的文献,对符合纳入条件的文献行进一步质量评估以及异质性检验。汇总敏感度和特异度,通过汇总工作特征曲线(SROC)和曲线下面积(AUC)评价采用FFR_CT诊断心肌缺血的临床价值。结果 共纳入4篇文献,质量分级均为A级。纳入研究的总患者数为662例,血管1117条。FFR_CT在患者及血管水平汇总后的敏感度分别为0.90(95%CI 0.85~0.93)和0.83(95%CI 0.78~0.87);特异度分别为0.72(95%CI 0.67~0.76)和0.78(95%CI 0.75~0.81);诊断比值比(DOR)分别为24.34(95%CI 10.84~54.65)和21.09(95%CI 7.51~59.24),AUC分别为0.9415、0.9140。结论 FFR_CT能有效提高冠状动脉CTA对心肌缺血的诊断准确性。     

Effect of enalapril or the thromboxane receptor antagonist, daltroban, in rats with subtotal renal ablation

There is evidence to suggest that thromboxane synthesis inhibition will attenuate the hypertension and proteinuria associated with subtotal renal ablation. In the present study, the thromboxane receptor antagonist, daltroban, (30 mg/kg/day i.p.) or vehicle was administered to rats for 3 weeks starting 2 weeks after partial renal ablation (right uninephrectomy and ligation of approximately two-thirds of the blood supply to the left kidney). Renal ablation was associated with proteinuria and increased systolic blood pressure. Neither the proteinuria nor the hypertension was affected by daltroban administration. Histological examination of the remaining kidney demonstrated no beneficial effect of daltroban. In a second study, it was determined that, 2 weeks after renal ablation, urinary thromboxane excretion was significantly increased, and subsequent administration of daltroban for 2 weeks resulted in significant blockade of the effects of the thromboxane mimetic, U46619. In a third study, enalapril (50 mg/l in the drinking water) resulted in a significant attenuation of the proteinuria, hypertension and glomerular lesions associated with partial renal ablation. The data indicate that enalapril, but not daltroban, protects against the development of renal disease associated with reduced renal mass.     

Binding of a thromboxane A2/prostaglandin H2 receptor antagonist to washed human platelets

A binding site for the thromboxane A2/prostaglandin H2 (TXA2/PGH2) antagonist [125I]9,11-dimethylmethano-11, 12-methano-16-(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega-tetranor-TXA2 to washed human platelets was studied. 9,11-Dimethylmethano-11, 12-methano-16-(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega-tetranor-TXA2 competitively antagonized aggregation of washed human platelets induced by the TXA2/PGH2 mimetic U46619. A Schild analysis of the pharmacologic study revealed a pA2 of 8.08 and a slope of -1.12. The pA2 value yielded a Kd of 8 nM. The association rate constant (k1) for [125I]PTA-OH was 6.6 X 10(6)M-1 min-1 and the dissociation rate constant (k-1) was 1.82 X 10(-1), yielding a kinetically determined Kd (k-1/k1) of 27 nM. Scatchard analysis of [125I]PTA-OH binding to washed human platelets revealed one class of binding sites with a Kd of 21 +/- 5 nM and maximum binding of 42 +/- 6.4 fmol/10(7) platelets (N = 5) (2530 +/- 380 binding sites/platelet). Several TXA2/PGH2 receptor agonists and antagonists competed with [125I]PTA-OH for binding. For the four antagonists used in this study, the rank order of potency for displacing the ligand from its binding site correlated (r = 0.93) with the rank order of potency for their ability to inhibit U46619-induced aggregation in human platelet-rich plasma. The antiaggregatory prostaglandins prostaglandin F2 alpha, prostaglandin D2, and Iloprost also displaced the ligand, but only at concentrations considerably higher than that required to produce their pharmacologic effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of acute hyperhomocysteinemia on coronary flow reserve in healthy adults

BACKGROUND: B-mode ultrasound studies indicate that hyperhomocysteinemia is associated with preclinical structural and functional arterial abnormalities. This study was designed to evaluate the effect of elevated plasma homocysteine levels on coronary flow reserve (CFR). METHODS: A total of 20 healthy subjects aged 41 +/- 7 years were studied on 2 separate days, a week apart, before and after methionine load (100 mg/kg of body weight) or placebo in a double-blind crossover study. At each visit, homocysteine levels were measured by high performance liquid chromatography and CFR was determined by transthoracic Doppler echocardiography. RESULTS: After methionine load, plasma homocysteine increased from 10.7 +/- 2.8 mumol/L to 30.4 +/- 5.1 mumol/L ( P < .0001) and CFR decreased from 3.0 +/- 0.4 to 2.3 +/- 0.3 ( P < .001). CFR was inversely related to postload homocysteine levels ( r = -0.21, P = .02). After placebo, there was no change in CFR. CONCLUSION: In asymptomatic adults, acute hyperhomocysteinemia is associated with a significant reduction in CFR.