Adrenal gland-released vasostatin-I is a myocardial depressant factor.

Pheochromocytoma crisis is an exceptional consequence of the release of storage vesicles of the adrenal medulla. It is complicated by fulminant adrenergic myocarditis. It offers a unique opportunity to detect inotropic negative factors from neuroendocrine origin. Our objectives were (a) to describe a pheochromocytoma crisis, (b) to investigate in vivo myocardial depressant activities for the N-terminal 1-76 Chromogranin A-derived peptide, vasostatin-I (VS-I). A patient with a pheochromocytoma crisis was treated, including extracorporeal membrane oxygenation, until mass resection. Plasma concentrations of VS-I were time-dependently assessed with a specific immunoassay; correlations with invasive cardiovascular parameters were investigated. Increased VS-I concentrations were observed over 7 days until tumour resection. VS-I concentrations correlated positively with Chromogranin A levels, negatively with cardiac output and left ventricular stroke work index, but not with heart rate. This case illustrates the pharmacokinetics of VS-I in a pheochromocytoma crisis. It highlights myocardial depressant activity for this peptide at high concentrations.

Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.

BACKGROUND: Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. METHODS: We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. FINDINGS: We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. INTERPRETATION: Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.

Soluble substances released from postischemic reperfused rat hearts reduce calcium transient and contractility by blocking the L-type calcium channel.

OBJECTIVES: This study was designed to investigate the effects of cardiodepressant substances released from postischemic myocardial tissue on myocardial calcium-regulating pathways. BACKGROUND: We have recently reported that new cardiodepressant substances are released from isolated hearts during reperfusion after myocardial ischemia. METHODS: After 10 min of global ischemia, isolated rat hearts were reperfused, and the coronary effluent was collected for 30 s. We tested the effects of the postischemic coronary effluent on cell contraction, Ca2+ transients and Ca2+ currents of isolated rat cardiomyocytes by applying fluorescence microscopy and the whole-cell, voltage-clamp technique. Changes in intracellular phosphorylation mechanisms were studied by measuring tissue concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), as well as activities of cAMP-dependent protein kinase (cAMP-dPK) and protein kinase C (PKC). RESULTS: The postischemic coronary effluent, diluted with experimental buffer, caused a concentration-dependent reduction of cell shortening and Ca2+ transient in the field-stimulated isolated cardiomyocytes of rats, as well as a reduction in peak L-type Ca2+ current in voltage-clamped cardiomyocytes. The current reduction resulted from reduced maximal conductance--not from changes in voltage- and time-dependent gating of the L-type Ca2+ channel. The postischemic coronary effluent modified neither the tissue concentrations of cAMP or cGMP nor the activities of cAMP-dPK and PKC. However, the effluent completely eliminated the activation of glycogen phosphorylase after beta-adrenergic stimulation. CONCLUSIONS: Negative inotropic substances released from isolated postischemic hearts reduce Ca2+ transient and cell contraction through cAMP-independent and cGMP-independent blockage of L-type Ca2+ channels.

Burn-induced impairment of cardiac contractile function is due to gut-derived factors transported in mesenteric lymph.

Neither the source nor the cause of burn-induced myocardial dysfunction is known. Because scald burns have been shown to cause cardiac contractile dysfunction, the purpose of this study was to test the hypothesis that gut-derived myocardial depressant factors were responsible for burn-induced cardiac contractile dysfunction. Male rats were subjected to laparotomy with or without mesenteric lymph duct ligation (LDL). After LDL or sham-LDL, the rats were randomized to receive sham or scald burn (43% TBSA full thickness) after which they were resuscitated for 24 h with 4 mL/kg/%burn of Ringers lactate solution, and then killed, and the hearts removed. Cardiac function was assessed by measuring the left ventricular pressure (LVP) and maximal rate of LVP rise and fall (+/-dP/dt) in response to increases either in 1) preload, 2) coronary flow rate, or 3) perfusate calcium. At 24 h after burn or sham burn and before killing, the mean arterial pressure of the burn group was less than the burn + LDL or the sham burn groups (P < 0.05). Pre-burn LDL significantly prevented burn-induced depression in LVP and +/-dP/dt (P < 0.05). In addition, the hearts harvested from the burn group showed a significant impairment in contraction and relaxation when preload, coronary flow, or perfusate calcium was increased compared with the burn + LDL and sham groups (P < 0.05). Burn-induced cardiac dysfunction, manifested by impaired contraction and relaxation, is prevented by pre-burn lymph duct ligation. These results indicate that gut-derived myocardial depressant factors transported in mesenteric lymph contribute to burn-induced impairment of cardiac contractile function, because burn-induced cardiac dysfunction can be totally abrogated by pre-burn mesenteric lymph duct ligation.

Plasma activation during splanchnic arterial occlusion shock.

During circulatory shock, activating factors for cells in the microcirculation can be detected in plasma. But the source of such activators has remained uncertain. We have demonstrated recently that homogenates derived from the pancreas but not other peritoneal organs activate naive leukocytes. Production of such activating factors can be blocked by a serine protease inhibitor. Thus, factors generated by pancreatic proteases may possibly produce cellular activation in vivo. Rats were subjected to 90 min of superior mesenteric and celiac artery occlusion followed by reperfusion (SAO shock). In addition, rats were subjected to SAO shock for 120 min, after a 60-min pretreatment prior to occlusion with either saline or the serine protease inhibitor Futhan (nafamostat mesilate, 3.3 mg/kg b.w.). A sham SAO protocol was carried out as a control. Cellular activation was tested by neutrophil pseudopod formation and NBT reduction. Plasma from SAO-shocked animals but not sham shock rats exhibited a significant increase (P < 0.001) in the activation of naive leukocytes. Futhan-treated animals subjected to SAO shock exhibited a significantly higher post-reperfusion blood pressure than non-treated animals (P < 0.005 for all time points greater than 120 minutes), as well as significantly greater survival (P < 0.001). Neutrophil pseudopod formation and plasma peroxide production, an additional index of cellular activation, were significantly lower in Futhan-treated SAO shock plasma (P < 0.05) than levels in non-treated SAO shock animals. These results demonstrate that activating factors for leukocyte are released in SAO shock and can be mitigated by pretreatment with the serine protease inhibitor Futhan. Proteolytically derived plasma factors released during SAO shock may contribute to leukocyte activation and ensuing organ dysfunction.

A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock.

Using spontaneously beating rat myocardial cells as an in vitro model of myocardial depression, recent studies demonstrated that septic shock patients' sera frequently contain a myocardial depressant substance (MDS) that is associated with a reversible decrease in left ventricular ejection fraction (LVEF). To further characterize MDS, 50 consecutive patients with possible septic shock were studied serially from shock onset until recovery or death. Thirty-four patients had criteria diagnostic of septic shock, and 16 had a nonseptic critical illness. Of the 34, 14 met strict criteria for circulating MDS, with a mean inhibition of 35 percent (range 20 percent to 62 percent). Compared with those patients not exhibiting significant MDS activity, the 14 MDS-positive patients had a lower mean minimal EF (28 percent vs 39 percent, p less than 0.01), a greater mean decrease in EF (22.1 percent vs 8.8 percent, p = 0.002), a higher pulmonary artery wedge pressure (16.8 vs 11.9 mm Hg, p less than 0.01), greater LV dilatation (162 vs 118 ml/m2, p = 0.02), and a higher circulating mean peak lactic acid (6.9 vs 2.7 mmol/L, p less than 0.01). In the 14 MDS-positive patients, the in vitro myocardial cell depression had a negative correlation with the in vivo EF (r = -060, p less than 0.05). These findings suggest that a circulating MDS is a cause of the myocardial depression frequently accompanying human septic shock.

Impaired venous return causes circulatory failure in experimental pancreatitic shock in dogs.

The haemodynamic effects in the early phase of canine acute experimental pancreatitis (AP) were studied using a cardiac catheterization technique. AP was induced in anaesthetized dogs with an infusion of trypsin-sodium-taurocholate into the pancreatic duct. The initial haemodynamic measurements were performed after the preparation of the animal and 5 min after the induction of AP. Thereafter, pressure and volume parameters were measured at 10 min intervals. AP induced significant increases in heart rate, dP/dtmax and mean arterial pressure, but a decrease in Vmax 5 min after the induction of AP. After the initial phase, the heart rate remained significantly increased, while constant and significant decreases of stroke volume, cardiac output, end-diastolic volume and end-diastolic pressure developed. The parameters of the contractility of the left ventricle were not affected to the same extent. It is suggested that the circulatory failure observed in AP, characterised by a prompt reduction of cardiac output, was primarily due to a heavy reduction in preload. This supports the theory that cardiac output is primarily affected by impaired venous return with consequently decreased preload rather than by a loss of ventricular contractility. Hence, the existence of a myocardial depressant factor in the early phase of experimental AP does not gain support from the present results.

Lack of effect of thyrotropin releasing hormone (TRH) in circulatory shock.

Thyrotropin releasing hormone (TRH) has been reported to reverse hypotension induced by a variety of agents and thus it has been suggested to be of therapeutic value in circulatory shock. We have investigated TRH (2 mg/kg bolus plus 2 mg/kg/hr infusion) in both hemorrhagic (cats) and traumatic shock (rats). TRH induced a pressor effect of 23 +/- 8 mm Hg (p less than 0.05) in cats and 19 +/- 3 mm Hg (p less than 0.01) in rats during hypotension. However, this transient (10-15 min) response did not result in any sustained improvement in the cardiovascular status of the animals in either shock model when compared to the vehicle. In addition, TRH did not attenuate any of the biochemical indices of the severity of the shock state (i.e., plasma amino-nitrogen concentrations, or plasma cathepsin D and MDF activities) nor did it improve survival time in traumatic shock (2.8 +/- 0.4 vs. 2.0 +/- 0.2 hours). Furthermore, TRH resulted in a significant blunting of the maximum post-reinfusion superior mesenteric artery flow and enhanced beta-glucuronidase release from liver lysosomal preparations in vitro. These potentially detrimental effects in conjunction with the lack of any overt protective effect under the conditions existing in these two shock models, do not provide evidence that TRH is beneficial as a therapeutic agent in circulatory shock.

Acute effects of unsaturated fatty acids in splanchnic artery occlusion shock.

Diets enriched with omega-3 unsaturated fatty acids are associated with decreased hypercholesterolemia and decreased risk of ischemic and atherosclerotic diseases. We studied the acute intravascular effects of some of these unsaturated fatty acids (i.e., eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) along with omega-6 unsaturated fatty acids, (i.e., linoleic and linolenic acid) in splanchnic artery occlusion (SAO) shock in rats. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes followed by reperfusion usually resulted in a fatal outcome 90-120 minutes after releasing the clamps. SAO shock rats treated with the omega-3 unsaturated fatty acid, EPA, exhibited an improved survival time and rate (p less than 0.05 from vehicle) compared to those receiving only vehicle (i.e., 50% ethanol). EPA and DHA treated SAO rats also exhibited lower plasma activities of the lysosomal protease, cathepsin D, free amino-nitrogen compounds, and the cardiotoxic peptide, myocardial depressant factor. These results indicate that omega-3 unsaturated fatty acids, especially EPA, have some acute beneficial effects in SAO shock in rats.

Use of a novel peptide leukotriene receptor antagonist, Ly-163443, in splanchnic artery occlusion shock.

We studied the effects of LY-163443, a novel selective receptor antagonist of LTD4 and LTE4, in splanchic artery occlusion (SAO) shock. LY-163443 antagonized the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats. Anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 minutes developed a severe shock state usually resulting in a fatal outcome within two hours after release of the occlusion. SAO shock rats pre-treated with LY-163443 before the occlusion of the splanchnic arteries maintained post-release MABP at significantly higher values compared to rats receiving either the vehicle or LY-163443 as a post-treatment 15 min after occlusion (final MABP 96 +/- 8 vs 51 +/- 1, p less than 0.01 and 53 +/- 3, p less than 0.01, respectively). Pre-treatment with LY-163443 attenuated the release of the lysosomal hydrolase, cathepsin D (p less than 0.01 from vehicle and p less than 0.05 from post-treatment groups), and the plasma accumulation of free amino-nitrogen compounds (p less than 0.05 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in the pre-treatment group than in the vehicle group (27 +/- 3 vs 51 +/- 6 U/ml, p less than 0.01). SAO shock rats pretreated with LY-163443 also exhibited significantly higher survival rates (p less than 0.01 from vehicle and post-treatment groups), and prolonged survival times (p less than 0.01 from vehicle and post-treatment groups).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Platelet activating factor interaction with tumor necrosis factor and myocardial depressant factor in splanchnic artery occlusion shock.

Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the celiac trunk for 45 min, developed a severe shock state (splanchnic artery occlusion shock) resulting in a fatal outcome within 75-90 min after release of the occlusion. Shocked rats, treated with an intravenous bolus of L-659,989, a specific platelet activating factor (PAF) receptor antagonist (12.5, 25 or 50 nmol/kg, 4 min after reperfusion followed, 8 min thereafter, by a continuous infusion of 125, 250 or 500 nmol/kg for 30 min), maintained post-release mean arterial blood pressure at significantly higher values than did rats receiving the vehicle. Treatment with L-659,989 significantly increased survival rate, blunted the rise in plasma myocardial depressant factor activity and lowered serum and macrophage levels of tumor necrosis factor (TNF-alpha). In addition, the drug completely restored macrophage phagocytosis, improved macrophage killing and significantly inhibited leukopenia. To investigate the interaction between PAF, TNF-alpha and myocardial depressant factor, the blood levels of these three mediators were evaluated: shocked rats exhibited increased PAF levels with a peak at 30 min. The plasma levels of PAF peaked earlier than did either serum TNF-alpha or plasma myocardial depressant factor. Both peaks occurred 75 min after the release of occlusion. The results of this study therefore suggest that PAF is a key mediator of splanchnic artery occlusion shock and plays a permissive role in inducing the release of other factors (i.e. TNF-alpha and myocardial depressant factor) that are relevant to shock.

Beneficial effects of a specific leukotriene receptor antagonist in splanchnic artery occlusion shock.

The purpose of this study was to examine the effects of a new potent peptidoleukotriene receptor antagonist, SK&F 104353, in splanchnic artery occlusion shock. SK&F 104353 was administered as a 1 mg/kg initial bolus followed by an infusion of 3 mg/kg per h for the entire 2 h post-reperfusion observation period. In a group of conscious rats, this dose of SK&F 104353 shifted the LTD4 dose response curve rightward 10-fold, indicating effective antagonism of peptidoleukotriene responses in the rat. Anesthetized rats subjected to splanchnic artery occlusion shock survived an average of only 98 +/- 8 min whereas all animals receiving SK&F 104353 survived the 2 h reperfusion period (P less than 0.02 from vehicle). Therefore, the survival rate of the splanchnic artery occlusion shock group of rats receiving SK&F 104353 was improved to 100% compared with 50% survival for the vehicle-treated splanchnic artery occlusion shock group (P less than 0.025). In the splanchnic artery occlusion shock + SK&F 104353 group the increase in the plasma activities of the lysosomal hydrolase, cathepsin D, and the cardiotoxic peptide, myocardial depressant factor, were significantly attenuated in comparison to the splanchnic artery occlusion shock + vehicle group (P less than 0.025). These data indicate that the peptidoleukotriene receptor antagonist, SK&F 104353 is beneficial in splanchnic artery occlusion shock, and furthermore suggests that it may be a therapeutically useful agent in bowel ischemic 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.

Protective effects of KW-3635, a novel thromboxane A2 antagonist, in murine traumatic shock.

Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, increases in plasma cathepsin D (9.6-fold), free amino-nitrogen (4.0-fold), and myocardial depressant factor (5.2-fold) activities, and a survival time of 1.90 +/- 0.23 h. Following the induction of traumatic shock, plasma thromboxane B2 (TxB2) concentrations significantly increased from 3.12 +/- 0.68 to 6.78 +/- 0.27 pmol/ml. Treatment with the thromboxane receptor antagonist KW-3635 10 min post-trauma (2 mg/kg + 2 mg/kg per h, i.v.) prolonged survival time to 3.30 +/- 0.39 h (P less than 0.01) and attenuated the accumulation of cathepsin D compared to untreated trauma rats (6.6 +/- 1.1 and 13.6 +/- 1.3 U/ml, P less than 0.01), free amino-nitrogen (6.4 +/- 1.1 and 14.3 +/- 1.2 U/ml, P less than 0.01), and myocardial depressant factor (45 +/- 5 and 94 +/- 13 U/ml, P less than 0.02). However, KW-3635 did not prevent the increase in plasma TxB2 concentration, suggesting a lack of thromboxane synthetase inhibitory activity of this drug. The beneficial effects of thromboxane A2 (TxA2) antagonism in the present study are highly significant, and consistent with the concept that TxA2 is involved in the pathogenesis of traumatic shock.

Protective effects of a specific platelet activating factor (PAF) antagonist, WEB 2086, in traumatic shock.

We have investigated the role of platelet activating factor (PAF) in the pathogenesis of a murine model of traumatic shock using WEB 2086, a specific antagonist of PAF. WEB 2086 (0.5 mg/kg) significantly reversed the decrease in mean arterial blood pressure (MABP) induced by PAF (0.3 micrograms/kg) in anesthetized rats. Anesthetized rats were subjected to Noble-Collip drum trauma. Traumatized rats treated with WEB 2086 (0.5 mg/kg bolus followed by infusion at 0.5 mg/kg/hr) maintained a higher MABP than those receiving only the vehicle (0.9% NaCl). Improvement in MABP paralleled a significant increase in overall survival time (p less than 0.01) in rats receiving WEB 2086 (0.5 mg/kg). WEB 2086 also significantly attenuated the plasma accumulation of the lysosomal hydrolase, cathepsin D and of free amino-nitrogen compounds, compared to shocked rats receiving only the vehicle. Furthermore, the production of the cardiotoxic peptide, myocardial depressant factor (MDF) was also blunted by WEB 2086. These results suggest that PAF may be an important mediator in the pathogenesis of traumatic shock in rats. Furthermore, PAF receptor antagonists may be useful as therapeutic agents when given early in the course of ischemic and shock states.

Beneficial effect of anisodamine in hemorrhagic shock.

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 hemorrhagic 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 less than 0.001). Anisodamine treated shock cats exhibited significantly lower cathepsin D activity (P less than 0.02) and amino-nitrogen concentration (P less than 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 less than 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.

Efficacy of a combination thromboxane receptor antagonist and lipoxygenase inhibitor in traumatic shock.

The effects of a thromboxane receptor antagonist having lipoxygenase inhibitory activity, L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) (1 mg/kg per h) were studied in a standardized model of traumatic shock. Pentobarbital (35 mg/kg) anesthetized rats subjected to Noble-Collip drum trauma were characterized by a 82 +/- 12 min survival time, a 20-fold increase in plasma cathepsin D activity, and a 6-fold increase in plasma myocardial depressant factor (MDF) activity. L-655,240 significantly attenuated the accumulation of MDF activity in the plasma (74 +/- 3 vs. 46 +/- 4 units/ml), vehicle vs. drug, respectively, and significantly (P less than 0.01) prolonged survival time to 206 +/- 26 min. However, plasma cathepsin D was not significantly altered with L-655,240 administration during traumatic shock. L-655,240 at 20 micrograms/ml markedly attenuated minced rat lung fragments from producing LTC4 and LTD4.L-655,240 exhibited significant anti-proteolytic activity in pancreatic homogenates. Therefore, L-655,2340 does not stabilize lysosomal membranes directly, but exerts an anti-proteolytic action which appears to curtail the production of a myocardial depressant factor by the ischemic pancreas, thus protecting during traumatic shock. A combination anti-eicosanoid drug such as L-655,240 may therefore prove to be an important therapeutic agent in acute ischemic disorders including traumatic shock.

Effects of fructose 1,6-diphosphate on splanchnic artery occlusion shock in the rat.

Splanchnic artery occlusion (SAO) shock, produced by clamping splanchnic arteries for 45 min followed by the release of occlusion, was induced in male rats, treated 15 min before surgery, with fructose 1,6-diphosphate (FDP) or with equivalent doses of fructose or inorganic phosphate. Survival rate, peritoneal macrophage phagocytosis and plasma levels of myocardial depressant factor (MDF) were measured. Shocked animals pretreated with vehicle exhibited 24.6 +/- 0.9% phagocytic activity, 110 +/- 3.9 units/ml MDF plasma levels and 0% survival. Sham animals showed the following values: survival 100%; phagocytosis, 49.5 +/- 1.3%; MDF, 22 +/- 2.9 units/ml. Pretreatment with FDP (25 mg/kg/i.v.) significantly improved survival rate (50%) and macrophage phagocytosis (37.9 +/- 0.4%) and reduced plasma MDF levels (77 +/- 3 units/ml). Equivalent doses of fructose and inorganic phosphate did not improve survival, as well as lower doses of FDP. These results suggest a beneficial effect of FDP in SAO shock.