Salutary consequences of blockade of platelet activating factor in hemorrhagic shock

We studied the effects of a potent, specific platelet activating factor (PAF) antagonist, CV-6209, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CV-6209 (1 mg/kg) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving either 0.9% NaCl or a lower dose (0.2 mg/kg) of CV-6209 (final MABP 88 +/- 4 vs. 57 +/- 4, vs. 61 +/- 7 mm Hg, respectively). CV-6209 (1 mg/kg) also significantly attenuated the increase in plasma cathepsin D activity following hemorrhage compared with hemorrhaged rats receiving only its vehicle (i.e. 0.9% NaCl). CV-6209 (1 mg/kg) also significantly decreased the plasma accumulation of free amino-nitrogen compounds and the plasma activity of a myocardial depressant factor (MDF) compared to hemorrhaged rats receiving 0.9% NaCl. Rats receiving CV-6209 (1 mg/kg) exhibited a significantly increased survival rate and survival time post-reinfusion compared to rats receiving only the vehicle. These data indicate that PAF is an important mediator of hemorrhagic shock in the rat and that PAF receptor antagonists may be useful in hemorrhagic shock states.     

Salutary effects of CG-4203, a novel, stable prostacyclin analog, in hemorrhagic shock

Prostacyclin (PGI2) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane-stabilizing agent that has been shown to exert beneficial effects in a variety of models of ischemia and circulatory shock. However, the use of PGI2 is limited by its instability and rapid biodegradation. We studied the effects of a novel, stable prostacyclin analog, CG-4203, in a murine model of hemorrhagic shock. Hemorrhaged rats treated with CG-4203 maintained postreinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (final MABP 101 +/- 3 vs. 75 +/- 5 mm Hg, p less than 0.01). CG-4203 was also found to attenuate the increase in plasma cathepsin D activity (p less than 0.01), as well as the plasma accumulation of free amino-nitrogen compounds (p less than 0.05). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in CG-4203-treated hemorrhaged rats than in rats receiving the vehicle (25 +/- 2 vs. 54 +/- 7 U/ml, p less than 0.01). In addition, CG-4203 exerted an anti-proteolytic action in pancreatic homogenates and inhibited platelet aggregation in platelet-rich plasma. However, CG-4203, at concentrations expected during treatment of shock, failed to have an immediate or delayed vasodilator effect in rat aortic rings, and thus vasodilation is not an important aspect of the antishock effects of CG-4203. Our results suggest that inhibition of platelet aggregation, as well as the antiproteolytic and membrane-stabilizing actions, could mediate the beneficial effects of CG-4203 in hemorrhagic shock.     

Beneficial actions of RO 15-1788, a benzodiazepine receptor antagonist, in hemorrhagic shock

We studied RO 15-1788, a new benzodiazepine receptor antagonist, [ethyl 8-fluoro-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo (1, 5a) (1, 4) benzodiazepine-3-carboxylate] to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with RO 15-1788 maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving only the vehicle (final MABP 114 +/- 4 vs 82 +/- 4 mmHg, p less than 0.001). Moreover, RO 15-1788 decreased the release of the lysosomal hydrolase, cathepsin D (p less than 0.02) into the circulation and blunted the plasma accumulation of free amino-nitrogen groups (p less than 0.01). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in RO 15-1788 treated rats subjected to hemorrhagic shock than in those given the vehicle (18 +/- 2 vs 42 +/- 4 U/ml, p less than 0.01). Additionally, in vitro analysis indicated that RO 15-1788 antagonizes PAF induced coronary vasoconstriction and cardiac depression observed in perfused rat hearts, as well as inhibiting PAF induced platelet aggregation in cat platelet rich plasma. Our results suggest that antagonism of PAF actions can contribute significantly to the beneficial effects of RO 15-1788 in hemorrhagic shock.     

Protective effects of thromboxane receptor blockade in splanchnic artery occlusion shock

Splanchnic artery occlusion (SAO) followed by release of the occlusive clamps produces circulatory shock characterized by an abrupt hypotension, cardiac depression and high lethality. We studied the effects of the thromboxane receptor antagonist, BM-13505, in rats during SAO shock. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion, usually resulting in death within 90-120 minutes of release of the occlusion. BM-13505 was started at reperfusion for 10 minutes. SAO shock rats treated with BM-13505 (1 mg/kg) maintained post-reperfusion mean arterial blood pressure (MABP) at significantly higher values compared to those receiving only the vehicle (0.9% NaCl). Treatment with BM-13505 attenuated the plasma activity of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and the plasma accumulation of free amino-nitrogen compounds (p less than 0.01 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in BM-13505 treated rats than in non-treated rats (p less than 0.01 from vehicle). SAO shock rats treated with BM-13505 also exhibited a higher survival rate than the vehicle group (75% vs. 20%). These results suggest an important role of thromboxane A2 in the pathophysiology of SAO shock.     

Salutary effects of nitrendipine, a new calcium entry blocker, in hemorrhagic shock

Intracellular accumulation of calcium is thought to play an integral role in the progression of ischemic injury and cell death. We infused the calcium entry blocker, nitrendipine (1.5 micrograms/kg per min), into cats in order to investigate the importance of extracellular Ca2+ influx during hemorrhagic shock. Nitrendipine proved to be a potent hypotensive agent in sham shock cats when infused over a 4 h period (156 +/- 9 to 90 +/- 5 mm Hg) (P less than 0.01). However, in hemorrhaged animals, nitrendipine treatment maintained the post-reinfusion MABP at a significantly higher (P less than 0.01) value than untreated controls (79 +/- 5 vs. 51 +/- 4 mm Hg, respectively). Superior mesenteric artery flow (SMAF) for hemorrhaged animals treated with nitrendipine was significantly higher (9.8 +/- 1.4 ml/min per kg) (P less than 0.01) than that for untreated cats (4.2 +/- 0.4 ml/min per kg), at 2 h post reinfusion. There was no significant increase in SMAF during oligemia in the nitrendipine-treated animals. Nitrendipine was also found to significantly retard the appearance of cathepsin D in the plasma of hemorrhaged cats as well as reduce plasma proteolysis to values not significantly different from sham shock animals. Furthermore, myocardial depressant factor (MDF) activity in the plasma of nitrendipine-treated shock cats was not significantly different from sham shock animals, while the plasma MDF activity for shock cats receiving vehicle increased 3-fold (P less than 0.001). The beneficial effects for nitrendipine in hemorrhagic shock are likely due to both its vasodilator function and its ability to reduce intracellular Ca2+ accumulation during ischemia, thereby reducing disruption of cell membrane systems.     

Beneficial action of a new opiate antagonist (Win 44,441-3) in hemorrhagic shock

The new opiate antagonist Win 44,441-3 (-)-isomer was infused intravenously in cats at a rate of 2 mg . kg-1 . h-1 to determine its effect in hemorrhagic shock. Hemorrhaged cats treated with Win 44,441-3 maintained post reinfusion mean arterial blood pressure (MABP) at a higher value compared to cats receiving only the vehicle. Final MABP was 70 +/- 11 mm Hg for cats receiving vehicle compared to 103 +/- 7 mm Hg for cats receiving Win 44,441-3. These values represent 60 +/- 9% and 85 +/- 6% of initial MABP for the vehicle- and Win 44,441-3-treated cats respectively. Win 44,441-2 (+)-isomer, the inactive stereoisomer of Win 44,441-3, was also infused at 2 mg . kg-1 . h-1 in cats subjected to hemorrhagic shock. The final pressure in this group was 72 +/- 8 mm Hg which is 61 +/- 8% of the initial pressure for this group. Win 44,441-3 and Win 44,441-2 were both ineffective in moderating increases in circulating lysosomal hydrolase activity in shocked cats. Neither isomer stabilized lysosomal membranes or retarded proteolysis in vitro. Plasma myocardial depressant factor was significantly reduced by the opiate antagonist, Win 44,441-3 during shock. Our results show that the systemic infusion of an opiate antagonist improves the hemodynamic state of cats subjected to hemorrhagic shock while the (+)-isomer which lacks opiate antagonist activity produces no such improvement.     

Protective effects of a novel nonglucocorticoid 21-aminosteroid (U74006F) during traumatic shock in rats.

The purpose of this study was to investigate the effect of the nonglucocorticoid steroid U74006F in the pathogenesis of a murine traumatic shock model. Pentobarbital-anesthetized (40 mg/kg) rats were subjected to Noble-Collip drum trauma and developed a lethal shock state characterized by a decreased mean arterial blood pressure (MABP) to 67 +/- 2 mm Hg and survival time (1.5 +/- 0.2 h). In contrast, sham trauma rats exhibited a MABP of 122 +/- 4 mm Hg at 5 h postanesthesia. Administration of U74006F at doses of 22.5 mg/kg at 15 to 20 min following trauma significantly maintained a higher MABP and prolonged survival compared to those trauma rats receiving only the vehicle for U74006F (0.002 N HCl). U74006F at 15 and 22.5 mg/kg prolonged survival time to 2.6 +/- 0.3 (p less than 0.05) and 3.1 +/- 0.6 h (p less than 0.02), respectively. U74006F also significantly attenuated the plasma accumulation of cathepsin D (p less than 0.02 to p less than 0.01) and free amino-nitrogen compounds (p less than 0.01) compared to the rats receiving only vehicle. Additionally, U74006F at 15 and 22.5 mg/kg blunted the production of the cardiotoxic peptide, myocardial depressant factor (MDF) (p less than 0.01 to p less than 0.001). Moreover, U74006F is a steroid without significant glucocorticoid or mineralocorticoid activity. These results suggest that U74006F may be useful as a therapeutic agent in traumatic shock.     

Salutary and detrimental effects of the (+)- and (-)enantiomers of meptazinol in anesthetized rats subjected to hemorrhagic shock

The effects of the two enantiomers of the opioid mixed agonist-antagonist meptazinol on mean arterial pressure (MABP), heart rate (HR), and survival time were investigated in pentobarbitone-anesthetized rats subjected to hemorrhagic shock. Following intravenous administration of (+)meptazinol (0.5 mg kg-1) to shocked animals (MABP, 30.0 +/- 0.2 mm Hg), there was significant and gradual elevation of MABP, which at the time the experiment was terminated did not differ significantly from preshock values. In addition, survival was prolonged by up to 7 days. Paradoxically, similar doses of (-)meptazinol produced further falls in MABP, significantly so at 60 min posttreatment. Likewise, the drug produced a slow progressive and significant decline in HR which culminated in premature death (mean survival time, 74.3 +/- 5.9 min, compared with a control value of 104.4 +/- 8.8 min; p less than 0.05). Our results demonstrate that the two enantiomers of meptazinol have opposing effects on hemorrhagic shock sequelae in the rat. It is surprising, in view of its known opioid antagonistic properties, that (-)meptazinol exerted a detrimental effect.     

Administration of polymerized bovine hemoglobin improves survival in a rat model of traumatic shock.

The ability of purified and modified hemoglobin solutions to expand blood volume and act as oxygen and carbon dioxide transporters with no apparent toxic side effects has lead to an increased interest in their utilization in shock conditions. Although hemoglobin solutions have been shown to provide beneficial effects in endotoxic and hemorrhagic shock, they have not been studied in whole body traumatic injury. We investigated the effects of a polymerized bovine hemoglobin solution (HBOC-201) in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, a survival time of 102 +/- 20 min, significant increases in intestinal myeloperoxidase (MPO) activity and splanchnic vascular endothelial dysfunction characterized by an impaired vasorelaxation of the superior mesenteric artery (SMA) to endothelium-dependent vasodilators. Traumatized rats were treated with HBOC-201 or an equal volume of vehicle corresponding to 5, 10 or 15% of the calculated blood volume. Treatment with HBOC-201 10 min posttrauma prolonged survival, normalized mean arterial blood pressure and attenuated endothelial dysfunction of the SMA. However, administration of HBOC-201 failed to significantly attenuate increases in intestinal MPO activity following trauma. No beneficial effects were observed with the administration the vehicle. These data indicate that HBOC-201 exerts significant beneficial effects in traumatic shock states by normalizing systemic blood pressure and attenuating vascular endothelial dysfunction. HBOC-201 may serve as a useful adjunctive agent in the early treatment of trauma.     

Novel mechanism of action of a prostacyclin enhancing agent in haemorrhagic shock

Summary Prostacyclin (PGI₂) is a potent vasodilator, an inhibitor of platelet aggregation, and a membrane stabilizing agent with beneficial effects in ischemia and shock. We studied defibrotide, a new agent which enhances PGI₂ release from vascular tissue, to determine its effects in a murine model of hemorrhagic shock. Hemorrhaged rats treated with defibrotide maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values compared to rats receiving the vehicle (final MABP, 100 ± 3 vs. 69 ± 7 mm Hg, p < 0.01). Defibrotide attenuated the release of the lysosomal hydrolase cathepsin D (p < 0.02), and the plasma accumulation of free amino-nitrogen groups (p < 0.02). The plasma activity of a myocardial depressant factor (MDF) was significantly lower in defibrotide treated shocked rats than in the vehicle group (29 ± 4 vs. 61 ± 8 U/ml, p < 0.01). Moreover, plasma i6-keto-PGF₁, concentrations increased 3-fold above haemorrhaged rats receiving only the vehicle. This, as well as the improved MABP, was abolished by indomethacin. Additionally, defibrotide exerts an anti-proteolytic action in pancreatic homogenates, and a lysosomal stabilizing effect in large granule fractions of rat liver homogenates. Moreover, defibrotide enhanced the recovery from norepinephrine induced vasoconstriction in rat aortic rings having an intact endothelium (p < 0.01 from vehicle), and augmented the release of i6-keto-PGF₁, the stable metabolite of PGI₂, from isolated rat aortae. Our results indicate that enhancement of endogenous vascular PGI₂ release coupled with direct, or PGI₂ mediated antiproteolytic and membrane stabilizing actions may be important physiological mechanisms counteracting the deleterious effects of hemorrhagic shock.Supported by Research Grant No. HL-25575 from the National Heart Lung and Blood Institute of the NIHResearch Fellow of the Ischemia-Shock Research Institute of Thomas Jefferson University. Send offprint requests to A. M. Lefer at the above address     

重组人内皮细胞衍生的白细胞介素—8对大鼠失血性休克的作用

目的：研究重组人内皮细胞衍生的白细胞介素－８（ＩＬ－８）对失血性休克的作用。方法：大鼠肌动脉放血至ＭＡＢＰ５．３２ｋＰａ，维持９０ｍｉｎ，复制晚期失血性休克模型。输血后，静脉注射ＩＬ－８ ２５０μｇ·ｋｇ＾－１。放免法测定血浆ＥＴ－１和６－ＫＰＧＦ１α含量。结果：给予ＩＬ－８周，ＭＡＢＰ显提高，休克状态改善，２ｈ存活率相应提高；休克晚期血浆ＥＴ－１水平比正常明显升高（２１±４ｖｓ８．２±１．８ｎ     

清醒大鼠重度失血性休克模型指标建立及有效性评价

目的:制作清醒大鼠重度失血性休克模型,评价模型的有效性,观察不同复苏液对重度失血性休克的疗效。方法:将37只SD大鼠在清醒状态下经股动脉释放其全身总血量的65%,制作重度失血性休克模型,随机分为3组,NaCl组(n=12)、全血组(n=12)和万汶组(羟乙基淀粉130/0.4氯化钠注射液,n=13),分别于放血前、放血末及输液后测定大鼠的平均动脉压(MBP)、呼吸频率(R)、体温(T)、动脉血气以及血乳酸盐(LD)。记录输液后24h与48h的存活率。结果:与放血前比较,各组大鼠放血末MBP、T、pH、二氧化碳分压[p(CO2)]、红细胞比容(HCT)及剩余碱(BE)明显降低,血氧分压[p(O2)]、血乳酸盐水平及氧饱和度升高。输液后2h与NaCl组相比,全血组和万汶组可以明显地改善大鼠的MBP、pH、p(CO2)及BE,降低动脉血乳酸,改善代谢性酸中毒,但全血组恢复效果更明显。结论:清醒大鼠重度失血性休克模型具有满意的重现性和有效性,适于不同复苏液抗休克性能的评价。     

Use of the novel cardiotonic and vasodilator agent pimobendan in traumatic shock

The effect of 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone (pimobendan, UD-CG 115 BS), a novel positive inotropic and vasodilator agent, was studied in a severe model of murine traumatic shock. Noble-Collip drum trauma produced a shock state characterized by a significantly reduced mean arterial blood pressure (MABP), a 5-fold increase in plasma cathepsin D and myocardial depressant factor (MDF) activities, and a survival time of 80 +/- 12 min. Administration of pimobendan (100 micrograms/kg, i.v. bolus) significantly prolonged the survival time to 175 +/- 24 min (p less than 0.01). Although plasma cathepsin D was not affected by pimobendan, this agent significantly attenuated the accumulation of MDF activity in the plasma when compared to animals receiving only its vehicle (37 +/- 6 vs 61 +/- 9 U/ml, p less than 0.05). Additionally, pimobendan inhibited platelet aggregation in cat platelet rich plasma, but failed to have an antiproteolytic effect in cat pancreatic homogenates. These results suggest that cardiotonic and vasodilator activities combined with inhibition of platelet aggregation could mediate the beneficial effects of pimobendan in traumatic shock.     

Novel beneficial mechanisms of defibrotide, a prostacyclin enhancing agent in splanchnic artery occlusion and reperfusion in rats.

To further clarify the protective mechanism(s) of defibrotide in splanchnic artery occlusion (SAO) shock, we observed the effect of defibrotide on polymorphonuclear leukocyte (PMN) accumulation in the intestinal tissue, gastric lysosomal hydrolases and endothelial function of the ischemia-reperfused superior mesenteric artery (SMA). Pentobarbital anesthetized rats were subjected to occlusion of both the celiac and superior mesenteric arteries for 90 min followed by 2 h reperfusion. The rats receiving only the vehicle for defibrotide exhibited a marked increase in intestinal myeloperoxidase (MPO) activity and a significant endothelial dysfunction manifested by the loss of endothelium-dependent vasorelaxation. Only 2 of 6 rats (33%) survived 2 h of reperfusion. In contrast, those rats treated with defibrotide exhibited significantly attenuated PMN accumulation in intestinal tissue, enhanced endothelium-dependent vasorelaxation in SMA rings, prolonged survival time and increased survival rate to 6 of 7 (i.e., 86%). However, addition of defibrotide in vitro had no direct effect on LTB4 activated PMN adherence to vascular endothelium. Moreover, defibrotide preserved gastric lysosomal membranes in vitro. These results indicate that the protective effect of intravenous administration of defibrotide on SAO shock may be related to its endothelial preserving effect reducing PMN adherence and protection of endothelial and lysosomal membrane integrity.     

Beneficial effect of anisodamine in hemorrhagic shock

Summary Anisodamine, an alkaloid extracted from Anisodus tanguticus, is widely used in China in the treatment of septic shock, but its mechanism of action is unknown. We studied its antishock action in cats in a well controlled model of hermorrhagic shock. A bolus dose of 1 mg/kg was given intravenously 20 min after MABP was stabilized at 40–45 mm Hg, followed by i.v. infusion of 2 mg/kg/h during the oligemic period. Two hours post-reinfusion, MABP was significantly higher (106±10 mm Hg) in the drug-treated group than in shock cats receiving only vehicle (53±6 mm Hg, P<0.001). Anisodamine treated shock cats exhibited significantly lower cathepsin D activity (P<0.02) and amino-nitrogen concentration (P<0.001) than untreated shock animals. Plasma myocardial depressant factor (MDF) activity was significantly increased in the untreated shock cats (61±6 Units/ml), but the plasma accumulation of MDF was significantly blunted by anisodamine (32±5 Units/ml, P<0.01). Anisodamine did not increase superior mesenteric artery flow (SMAF) in this model of hemorrhagic shock as there was no significant difference in SMAF between the two shocked groups. Thus, the beneficial effect of anisodamine probably is not due to vasodilation of the splanchnic vasculature. In vitro analysis indicates that the drug has a direct anti-proteolytic action in cat pancreatic homogenates. This may partly explain the mechanism of its action, which appears to be complex.Supported by the W. W. Smith Charitable Trust     

Reduction of infarct size and infiltration of polymorphonuclear leukocytes by a thromboxane synthetase inhibitor. Studies in a rabbit ischemic heart model.

The effect of sodium 6-(2-(1-(1H)-imidazolyl)methyl-4,5-dihydrobenzo(b) thiophene)carboxylate (RS-5186), a potent and long acting thromboxane synthetase inhibitor in vitro and in vivo, on infarct size and on the infiltration of polymorphonuclear leukocytes (PMNs), was studied in a rabbit coronary artery occlusion (1 h)--reperfusion (0.5 h or 3 h) model. The infarcted region was stained with triphenyltetrazolium, and the ratio of infarcted area/left ventricular area was calculated. The infiltration of PMNs into the infarcted region was determined by measuring the PMNs specific enzyme, myeloperoxidase (MPO) activity. In the vehicle treated group, infarct size and MPO activity were increased with increased reperfusion time from 0.5 h to 3 h (infarct size: 15.3 +/- 2.7 to 25.2 +/- 3.2%; MPO activity: 255 +/- 51 to 825.3 +/- 169.4 units/g wet weight). There was also a significant correlation (r = 0.90, p less than 0.01) between the infarct size and MPO activity. In contrast, in the RS-5186 treated group (2 mg/kg i.v.), both infarct size and MPO activity did not increase with prolongation of the reperfusion period (infarct size: 12.8 +/- 5.5 to 10.3 +/- 3.6%; MPO activity: 318.8 +/- 36.7 to 381.2 +/- 72.6 units/g wet weight). In 0.5 h reperfused samples, there was no significant difference in infarct size or in MPO activity between the vehicle treated group and RS-5186 treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-shock actions of the pyrimido-pyrimidine derivative, RA-642

The anti-shock actions of RA-642 were studied in traumatic shock in rats. The shock state was characterized by a significantly reduced mean arterial blood pressure (MABP), a five-fold increase in plasma cathepsin D activity, a three-fold increase in plasma myocardial depressant factor (MDF) activity, and a mean survival time of 1.6 +/- 0.3 h. Administration of 0.5 mg/kg of the pyrimido-pyrimidine derivative, RA-642, significantly prolonged survival time to 3.7 +/- 0.6 h (p less than 0.01). Plasma cathepsin D activity was not affected by RA-642 although accumulation of the cardiotoxic peptide MDF was significantly blunted (p less than 0.025). This effect on MDF accumulation may be related to the potent antiproteolytic action of RA-642 in vitro. Results indicate that RA-642 provides significant beneficial effects in a severe model of traumatic shock.     

The angiotensin II AT1-receptor antagonist candesartan improves functional recovery and reduces the no-reflow area in reperfused ischemic rat hearts.

It is not yet clear if cardiac angiotensin II is involved in the pathophysiology of myocardial ischemia/ reperfusion injury. The aim of this study was to investigate the effect of the angiotensin II AT1-receptor antagonist candesartan on myocardial functional recovery in isolated rat hearts subjected to ischemia and reperfusion. Three groups of hearts perfused in the Langendorff mode with Krebs-Henseleit buffer under constant pressure received either vehicle (n = 7), candesartan, 1 nM (n = 6), or 100 nM (n = 7) at the start of 30 min of global ischemia. The recovery of the double product was significantly higher in the candesartan, 100 nM, group (75+/-9.2%) than in the vehicle group (40+/-5.1%; p < 0.05). At the end of 30 min of reperfusion, left ventricular end diastolic pressure was lower in rats given candesartan, 100 nM, than in rats given vehicle (10+/-4.3 vs. 38+/-4.8 mm Hg; p < 0.05). After ischemia and reperfusion, there was a large no-reflow area in the vehicle group (28+/-3.1% of the left ventricle), which was reduced by candesartan, 100 nM (12+/-1.3%; p < 0.05). In rats given candesartan, 1 nM, there was a trend toward a higher recovery of the double product (73+/-13.4%), a lower left ventricular end-diastolic pressure (29+/-6.6 mm Hg), and a smaller no-reflow area (19+/-3.5% of the left ventricle) compared with the rats receiving vehicle. These trends did, however, not reach statistical significance. Our results demonstrate that candesartan reduces myocardial ischemia/reperfusion injury, thus indicating that endogenous cardiac angiotensin II is involved in the tissue injury after myocardial ischemia and reperfusion.     

Modulation of circulating endothelin levels in hypertension and endotoxemia in rats.

We have developed separate radioimmunoassays to measure circulating ET-1 and ET-3 levels in normotensive and different hypertensive rat models so that the role of endothelin in the regulation of vasomotor function can be studied. We also assessed the stimulatory effects of endotoxin on plasma and liver lymph ET-1 and ET-3 levels. The circulating ET-1 levels in normotensive rats, SHRs, and DOCA-salt hypertensive rats were 2.3 +/- 0.5, 2.1 +/- 0.4, and 2.1 +/- 0.9 pg/ml, respectively. Similarly, the plasma ET-3 levels in normotensive and different hypertensive rats were similar, ranging from 19.7 +/- 1.5 to 24.7 +/- 2.2 pg/ml. The data indicate that steady-state circulating levels of endothelins are a poor correlate of the hypertensive state. Endotoxin (30 mg/kg i.v. over 15 min) reduced blood pressure significantly and augmented plasma ET-1 levels by sevenfold (29.1 +/- 3.7 vs. 4.1 +/- 0.6 pg/ml in the vehicle group; p less than 0.05) and ET-3 levels by twofold (47.7 +/- 7.0 vs. 22.7 +/- 4.0 pg/ml in the vehicle group; p less than 0.05). Human TNF-alpha (30 ng/kg/min x 30 min), a putative mediator of endotoxin shock, enhanced plasma ET-1 (18.3 +/- 1.0 vs. 2.7 +/- 0.4 pg/ml in the vehicle group; p less than 0.05) by sevenfold and ET-3 levels by twofold (45.7 +/- 2.0 vs. 27.1 +/- 4.0 pg/ml in the vehicle group; p less than 0.05) without affecting blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ghrelin对败血症休克的影响(英文)

目的:研究ghrelin对大鼠晚期败血症休克的防治作用。方法:用盲肠结扎并穿刺法制备大鼠败血症休克模型,在术后即刻和8小时分别从股静脉和皮下注射ghrelin 10 nmol/kg。术后18h测定大鼠的血流动力学指标、血浆ghrelin、乳酸、葡萄糖浓度及心肌ATP含量。结果:与败血症休克组比较,ghrelin治疗组大鼠血压升高了33％,+LVdp/dt_(max)和-LVdp/dt_(max)值分别增加了27％和33％,而LVEDP降低了33％,血糖水平升高了54％,血浆乳酸浓度降低了40％,心肌ATP含量增加了22％(P<0.01)。死亡率由44％降到25％。败血症休克大鼠血浆ghrelin水平比假手术组(149±23)pmol/L增加了51％(P<0.01),血浆ghrelin水平与动脉血压和血糖值呈显著负相关(相关系数分别为-0.721和-0.811,P<0.01)。结论:ghrelin治疗可以部分纠正败血症休克大鼠的血流动力学紊乱和代谢障碍。