RESUMEN
Tissue-type plasminogen activator is a new thrombolytic agent that dissolves intravascular thrombi in coronary and peripheral vessels with less pronounced systemic lysis than that produced by streptokinase. Plasminogen activator was shown to induce reperfusion, and to salvage ischemic myocardium, by lysing experimentally induced coronary artery thrombi. The effect of a melanoma cell-derived tissue-type plasminogen activator was studied in cat myocardium rendered ischemic by coronary artery ligation for 2 hours and reperfused for another 4 hours. Plasminogen activator was infused at a rate of 500 IU X kg-1 X min-1 for the first 30 minutes of reperfusion. The marked increase in plasma creatine kinase activity during reperfusion was significantly lower in plasminogen activator-treated cats at 4, 5 and 6 hours, with 7.7 +/- 1.5 X 10(-3) IU X mg protein-1 (n = 8) in the plasminogen activator group versus 17.8 +/- 3.5 X 10(-3) IU X mg protein-1 (n = 7) in the vehicle group at 6 hours (mean +/- SEM). The area at risk in the two ischemic groups was not different, being 14.6 +/- 1.5 and 16.6 +/- 1.4% of total left ventricular mass for the treated and untreated groups, respectively. However, the mass of necrotic tissue determined histochemically was significantly lower in the plasminogen activator-treated group, accounting for 29.5 +/- 3.9% of the area at risk compared with 46.8 +/- 4.2% of area at risk in cats receiving only the vehicle (p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Activador de Tejido Plasminógeno/uso terapéutico , Animales , Gatos , Enfermedad Coronaria/sangre , Enfermedad Coronaria/fisiopatología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Creatina Quinasa/sangre , Electrocardiografía , Fibrinógeno/análisis , Hemodinámica/efectos de los fármacos , Miocardio/patología , Tamaño de los ÓrganosRESUMEN
OBJECTIVE: The aim was to investigate the role of peptide leukotrienes in the pathophysiology of myocardial injury during reperfusion of previously ischaemic myocardium. METHODS: Adult male cats (2.9-5.4 kg) were subjected to left anterior descending coronary artery occlusion for 3 h followed by 3 h of reperfusion. The peptide leukotriene receptor antagonist, LY-171883, was given intravenously only during the reperfusion period (3 mg.kg-1 bolus; 3 mg.kg-1 x h-1 infusion). Ischaemic injury was assessed by nitroblue tetrazolium staining and tissue creatine kinase activity; neutrophil infiltration was determined by myeloperoxidase activity of myocardial homogenates. RESULTS: There was no significant difference at any time point in the experimental protocol between mean arterial blood pressure or pressure-rate index in cats given LY-171883 (3 mg.kg-1) and cats given vehicle. The area at risk of infarction (AAR) was 24(SEM 2)% for vehicle treated cats and 22(2)% for the drug treated cats. The necrotic area was 48(5)% of the AAR for the vehicle group but only 29(5)% of the AAR for the group given LY-171883 (p < 0.02). Left ventricular maximum +dP/dt tended to be higher with drug treatment compared to vehicle at the end of the reperfusion period. Tissue from the area at risk was assayed for creatine kinase activity and neutrophil specific myeloperoxidase activity as an index of the accumulation of neutrophils in this region. Creatine kinase activity was significantly higher (p < 0.05) in the AAR for drug nu vehicle treated cats following reperfusion, confirming the histochemical analysis. Myeloperoxidase activity increased approximately 12-fold in the AAR of cats receiving vehicle. LY-171883 did not reduce the myeloperoxidase activity significantly in the area at risk. CONCLUSIONS: LY-171883 has a protective effect in ischaemia-reperfusion injury to the myocardium. These findings suggest a role for peptide leukotrienes both in the extension of ischaemic damage and in post-ischaemic ventricular dysfunction during reperfusion.
Asunto(s)
Acetofenonas/farmacología , Leucotrienos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Tetrazoles/farmacología , Animales , Gatos , Modelos Animales de Enfermedad , Corazón/efectos de los fármacos , Masculino , Daño por Reperfusión Miocárdica/prevención & control , Receptores de LeucotrienosRESUMEN
Hepatic Kupffer cells and pulmonary alveolar macrophages together constitute a macrophage-axis involved in the regulation of regional and systemic inflammatory responses. Systemic inflammatory response syndrome induced by overproduced pro-inflammatory mediators is the major cause of adult respiratory distress syndrome. In the present study, we examined the anti-inflammatory role of nitric oxide (NO) in a rat model of acute lung injury induced by hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia by clamping the relevant branches of hepatic artery and portal vein, followed by a 4-h reperfusion achieved by removal of the vascular clamp. Four groups of animals were studied: sham control + saline; sham control + N(omega)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v., 10 min before reperfusion); HI/R + saline; HI/R + L-NAME. Results show that (1) administration of L-NAME to rats subjected to HI/R decreased plasma NO levels; however, the attenuation of NO increased plasma alanine aminotransferase (ALT) activity and superoxide generation in the ischemic lobes of liver, compared to HI/R alone. (2) Inhibition of NO synthesis with L-NAME in rats subjected to HI/R also enhanced systemic inflammatory response as assessed by the increase in the number of circulating leukocytes and levels of plasma tumor necrosis factor-alpha (TNFalpha) and interleukin 1-beta (IL-1beta). (3) The overwhelming systemic inflammatory response induced by administration of L-NAME in rats subjected to HI/R also augmented pulmonary vascular permeability and superoxide generation in the lung tissue. (4) Pulmonary alveolar macrophages isolated from rats subjected to HI/R + L-NAME produced higher levels of TNFalpha and IL-1beta in the supernatant of culture medium than that of rats subjected to HI/R alone. (5) There were no differences between the groups of sham + saline and sham + L-NAME in terms of plasma NO levels and ALT activity, circulating leukocytes, superoxide generation in the liver and lung, lavage protein levels, and TNFalpha and IL-1beta levels in plasma and bronchoalveolar lavage fluid. Our results suggest that inhibition of NO synthesis by L-NAME in rats subjected to HI/R not only augments ischemic liver injury, but also enhances the systemic inflammatory response and exacerbates remote lung injury. The increase in TNFalpha and IL-1beta production by alveolar macrophages may, in part, account for L-NAME-induced enhancement of acute lung injury.
Asunto(s)
Hígado/irrigación sanguínea , Pulmón/patología , Óxido Nítrico/biosíntesis , Daño por Reperfusión/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/patología , Síndrome de Respuesta Inflamatoria Sistémica/fisiopatología , Alanina Transaminasa/sangre , Alanina Transaminasa/efectos de los fármacos , Animales , Líquido del Lavado Bronquioalveolar , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Interleucina-1/metabolismo , Recuento de Leucocitos , Pulmón/fisiopatología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Nitratos/sangre , Nitritos/sangre , Proteínas/efectos de los fármacos , Proteínas/metabolismo , Ratas , Ratas Endogámicas F344 , Daño por Reperfusión/fisiopatología , Superóxidos/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The pathophysiology of experimental acute endotoxemia is a complex process involving both cardiovascular dysfunction and an inflammatory response. We have examined the correlation in hemodynamic changes and the pulmonary inflammatory response after lipopolysaccharide (LPS) administration with respect to time. Importantly, we have measured the lung and plasma levels of nitric oxide (NO) over time, as well as rapid generation of lung superoxide after LPS administration. In anesthetized rats given a bolus injection of LPS (10 mg/kg intravenously, from Salmonella enteritidis), mean arterial blood pressure dropped by 63-70% within 15 min, and cardiac output fell by 57-63% within 20 min compared with saline controls. Mean arterial blood pressure recovered slightly but was still 51, 30, and 25% less than that of saline controls 45, 105, and 165 min after LPS administration, respectively. Cardiac output remained depressed throughout the experimental period and was 35% lower than in saline controls 165 min after LPS treatment. There was a small increase in plasma nitrite/nitrate as an index of plasma NO production after 45 min and a 10-fold increase 165 min after LPS addition compared with controls, strongly suggesting that NO mediates the hypotension that occurs 165 min after LPS administration. Lung NO production increased twofold 105 min after LPS administration and remained higher than in saline controls. Histological sections showed that there was fluid accumulation and alveolar collapse in the lung 45 min after LPS, whereas after 165 min, there was extensive tissue damage and increased leukocyte accumulation compared with controls. These results suggest that there was no correlation between early (1 h) tissue damage and NO production. We found an increase in lung superoxide generation 15 min after injection of LPS that coincided with the alterations in cardiovascular function. These results suggest that early lung tissue damage and/or hemodynamic changes may be due to superoxide generation from the lung.
Asunto(s)
Sistema Cardiovascular/fisiopatología , Endotoxemia/fisiopatología , Neumonía Bacteriana/fisiopatología , Enfermedad Aguda , Animales , Líquido del Lavado Bronquioalveolar/química , Radicales Libres , Hemodinámica , Recuento de Leucocitos , Masculino , Neutrófilos/metabolismo , Nitratos/sangre , Óxido Nítrico/biosíntesis , Nitritos/sangre , Peroxidasa/metabolismo , Ratas , Ratas Sprague-Dawley , Salmonelosis Animal/fisiopatología , Salmonella enteritidis , Organismos Libres de Patógenos Específicos , Superóxidos/metabolismo , Factores de TiempoRESUMEN
Interferon-gamma (IFN-gamma) has been implicated in the mortality of animal models of endotoxemia. On the other hand, the specific role of IFN-gamma in the development of organ inflammation in a model of polymicrobial sepsis has not been elucidated. In this study, we hypothesized that IFN-gamma plays an important role in lung inflammation after cecal ligation and puncture (CLP). To verify this hypothesis, lung tissue was removed 5 h after CLP or from sham controls. The mRNA expression (by RT-PCR) of IFN-gamma was increased in lung homogenates of CLP rats compared to sham controls. Using immunohistochemistry, we show for the first time the increased presence of IFN-gamma staining cells in the lung following CLP. Only very small amounts of positive staining for IFN-gamma was observed in lungs of sham controls. The presence of IFN-gamma in the lung 5 h after CLP correlated with a twofold increases in lung superoxide generation and MPO activity (index of neutrophil sequestration). Plasma and lung nitrite levels (breakdown product of nitric oxide) were also significantly increased in CLP rats. IFN-gamma antibody (1.2 mg/kg, i.v.) administered immediately after CLP significantly decreased lung superoxide levels to levels similar to the sham controls without affecting MPO activity, or lung or plasma nitrite levels. These results provide evidence that IFN-gamma may contribute to lung inflammation 5 h following CLP via increased production of superoxide.
Asunto(s)
Ciego , Interferón gamma/fisiología , Neumonía/fisiopatología , Animales , Constricción , Inmunohistoquímica , Mediadores de Inflamación/fisiología , Interleucina-1/fisiología , Interleucina-6/fisiología , Masculino , Nitritos/sangre , Nitritos/metabolismo , Neumonía/etiología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxidos/metabolismo , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
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.
Asunto(s)
Choque Hemorrágico/tratamiento farmacológico , Choque/tratamiento farmacológico , Hormona Liberadora de Tirotropina/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Proteínas Sanguíneas/metabolismo , Gatos , Masculino , Factor Depresor Miocardico/sangre , Pentobarbital/farmacología , Ratas , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Esplácnica/efectos de los fármacos , Hormona Liberadora de Tirotropina/farmacologíaRESUMEN
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.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Factor Depresor Miocardico/sangre , Nifedipino/análogos & derivados , Péptidos/sangre , Choque Hemorrágico/tratamiento farmacológico , Animales , Calcio/metabolismo , Catepsina D , Catepsinas/sangre , Gatos , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Arterias Mesentéricas/fisiología , Nifedipino/farmacología , Nitrendipino , Flujo Sanguíneo Regional/efectos de los fármacos , Choque Hemorrágico/fisiopatologíaRESUMEN
Thromboxane A2 (TxA2) has been implicated as a mediator of ischemic damage to the myocardium. A new, selective thromboxane receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg per h infusion) was studied for its effects on the extension of ischemic damage following acute myocardial ischemia (MI) in the rat. Administration of SQ-29,548 to sham MI rats had no significant effect on mean arterial blood pressure or heart rate over the 6 h experimental protocol. Ischemic damage was assessed by measurement of the depletion of creatine kinase (CK) activity and amino-nitrogen concentration from the myocardium. Six hours following ligation of the left main coronary artery, there was a significant loss of both CK (P less than 0.001) and amino-nitrogen (P less than 0.001) from the left ventricular free wall (LVFW). Administration of SQ-29,548 significantly blunted this loss of CK activity (P less than 0.01) and amino-nitrogen concentration (P less than 0.001) from the ischemic myocardium. Furthermore, the survival rate at 6 h following acute coronary artery ligation was 100% (7/7) for rats given SQ-29,548 and 58% (11/19) for rats given only the vehicle (P less than 0.05). These data indicate that SQ-29,548 significantly prevents the extension of ischemic damage in the myocardium and improves survival following acute coronary artery ligation, suggesting an important role for TxA2 in the pathophysiology of acute myocardial ischemia.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Hidrazinas/uso terapéutico , Receptores de Superficie Celular/fisiología , Receptores de Prostaglandina/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes , Enfermedad Coronaria/enzimología , Enfermedad Coronaria/fisiopatología , Vasos Coronarios/fisiología , Creatina Quinasa/metabolismo , Ácidos Grasos Insaturados , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Masculino , Miocardio/enzimología , Consumo de Oxígeno/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores de Prostaglandina/efectos de los fármacos , Receptores de TromboxanosRESUMEN
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.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Catepsinas/sangre , Factor Depresor Miocardico/sangre , Péptidos/sangre , Choque Hemorrágico/tratamiento farmacológico , Alcaloides Solanáceos/uso terapéutico , Vasodilatadores/uso terapéutico , Animales , Catepsina D , Gatos , Modelos Animales de Enfermedad , Técnicas In Vitro , Infusiones Parenterales , Masculino , Arterias Mesentéricas/fisiología , Páncreas/metabolismo , Flujo Sanguíneo Regional/efectos de los fármacos , Choque Hemorrágico/sangre , Choque Hemorrágico/fisiopatología , Alcaloides Solanáceos/farmacología , Vasodilatadores/farmacologíaRESUMEN
We investigated the respective contributions of the renin-angiotensin and alpha-adrenergic systems to nicotine-induced, canine, renal vasoconstriction by using saralasin (4 micrograms/kg/min) and phentolamine (25 micrograms/kg/min) blockade respectively. Nicotine infusion (0.024 mg/kg/min) increased mean arterial blood pressure (MABP) (114 +/- 3.0 to 219 +/- 8.0 mmHg) and decreased total renal blood flow (TRBF) (3.12 +/- 0.34 to 1.60 +/- 0.37 ml/min/g). Nicotine infusion produced a significantly lesser blood flow in outer cortex (OC), inner cortex (IC), and outer medulla (OM) compared to control dogs. The intrarenal-artery infusion of saralasin or phentolamine had no effect on the nicotine-induced MABP changes. Phentolamine infusion prior to nicotine resulted in a significantly greater TRBF (P less than 0.01), OC (p less than 0.001), IC (p less than 0.001) and OM (p less than 0.01) flow than in the group that received nicotine only. Saralasin pretreatment prior to nicotine resulted only in a significantly (p less than 0.01) greater OC flow than nicotine only. Our data suggest that while angiotensin II mediates a portion of the action of nicotine on the OC renal vasculature, the alpha adrenergic system predominates as the mediator of nicotine-induced renal vasoconstriction in the first 7 minutes of nicotine infusion.
Asunto(s)
Riñón/irrigación sanguínea , Nicotina/farmacología , Receptores Adrenérgicos alfa/fisiología , Sistema Renina-Angiotensina , Vasoconstricción/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Fentolamina/farmacología , Receptores Adrenérgicos alfa/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Sistema Renina-Angiotensina/efectos de los fármacos , Saralasina/farmacología , Radioisótopos de XenónRESUMEN
Acute physical stress in the form of immobilization resulted in a decrease in the concentration of immunoreactive beta-endorphin (IR-BE) in the anterior pituitary (AP) and an increase in the concentration of IR-BE in the neurointermediate lobe of the pituitary (NIL) and the plasma. Hypothalamic IR-BE was not influenced by immobilization. In response to chronic cardiovascular (physiological) stress resulting from constriction of the aorta (aortic banding) and subsequent pressure overload, the concentration of IR-BE in the AP was increased as was the concentration of IR-BE in the plasma. The concentration of IR-BE in the NIL and the hypothalamus was not affected. These findings suggest that physical stress and cardiovascular stress have the same affect on IR-BE levels in the plasma but differ in their respective effects on IR-BE in the AP and NIL and do not affect the concentration of IR-BE in the hypothalamus. The difference in the effects of each form of stress on the AP and the NIL respectively, may be attributed to either the type of stress employed (physical versus physiological), the duration of the stress (acute vs chronic), or both.
Asunto(s)
Cardiomegalia/metabolismo , Estrés Fisiológico/metabolismo , betaendorfina/análisis , Animales , Presión Sanguínea , Hipotálamo/química , Masculino , Hipófisis/química , Ratas , Ratas Sprague-Dawley , Restricción Física , betaendorfina/inmunologíaRESUMEN
Necrotizing enterocolitis has been attributed to the use of indomethacin (INDO) for medical closure of patent ductus arteriosus. To study the effect of INDO on cardiac output and mesenteric circulation, INDO was given by rectum (0.25 mg/kg, 0.5 mg/kg, 1.25 mg/kg--3 dogs in each group) and the control group received none. The cardiac output and organ blood flow were measured before and 1 hr after INDO with radioactive microspheres using 4 isotopes (Cr53, Ni95, Co57, Sn113). The blood flow to different parts of the GI tract was measured as percent of cardiac output using a gamma counter. Paired t test was used to calculate percent reduction in organ blood flow. During the experiment, there was no reduction in cardiac output in the entire group. Anesthesia had no effect on the control group. In the three INDO treated groups, percent reduction of mucosal blood flow of the stomach (63%, 32%, 68%, p less than 0.01), mid ileum (19%, 59%, 57%, p less than 0.05) and terminal ileum (57%, 35%, 54%, p less than 0.015) was significant. A strong trend in reduction of organ blood flow was noted in other regions. There was no significant change due to different dosages of INDO. The area of ischemia in this dog model corresponds to clinical pathology noted in necrotizing enterocolitis.
Asunto(s)
Indometacina/farmacología , Circulación Esplácnica/efectos de los fármacos , Animales , Gasto Cardíaco/efectos de los fármacos , Perros , Enterocolitis Seudomembranosa/inducido químicamenteRESUMEN
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.
Asunto(s)
Cardiotónicos/uso terapéutico , Pirimidinas/uso terapéutico , Choque Traumático/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Cardiotónicos/sangre , Catepsina D/metabolismo , Gatos , Técnicas In Vitro , Masculino , Contracción Miocárdica/efectos de los fármacos , Páncreas/enzimología , Pirimidinas/sangre , Ratas , Ratas Endogámicas , Choque Traumático/fisiopatología , Factores de TiempoRESUMEN
The angiotensin converting enzyme inhibitor, lisinopril, was studied in a cryo-injury model of chronic heart failure. This model is characterized by a progressive decrease in cardiac output starting six weeks after cryo-injury to a 30% decrease in cardiac output 10 weeks after injury. Although histological damage to the myocardial tissue, particularly in the epicardial area, was observed, no significant changes occurred in body weight, mean arterial blood pressure, heart rate or central venous pressure. Daily intraperitoneal injection of 3 mg/kg lisinopril was instituted starting four weeks after injury for a duration of six weeks. Lisinopril completely restored the cardiac output to normal values at the end of this six week period. Thus, converting enzyme inhibition appears to be an effective therapeutic agent in this model of chronic cardiac failure.
Asunto(s)
Enalapril/análogos & derivados , Cardiopatías/fisiopatología , Animales , Gasto Cardíaco/efectos de los fármacos , Criocirugía , Modelos Animales de Enfermedad , Enalapril/farmacología , Cardiopatías/etiología , Ventrículos Cardíacos , Hemodinámica/efectos de los fármacos , Lisinopril , Masculino , Ratas , Ratas EndogámicasRESUMEN
Evidence indicates that dietary lipids influence adrenocortical function. In the present study, weanling rats were fed isocaloric synthetic diets for 6 and 12 months that contained 10% of one of the selected fatty acids as the predominant lipid: butter fat (high saturated, low polyunsaturated fat); olive oil (monounsaturated); corn oil (polyunsaturated); omega-3 ethyl ester mixture (long-chain polyunsaturates); elevated eicosapentaenoic acid; elevated docosahexaenoic acid. Adrenocortical cells derived from individual rats were evaluated for corticosterone and aldosterone responses to adrenocorticotropic hormone (ACTH). All comparisons were to the butter fat diet. Adrenocortical cell sensitivity to ACTH was not affected by the diets. However, there were differences in basal and maximal ACTH-induced corticosteroid production. Compared to the butter fat diet, the other diets variably decreased cellular corticosteroid production. Corticosterone and aldosterone production were affected similarly. The greatest decrease was most often seen with the omega-3 mixture diet (about -67%). At 6 months, the docosahexaenoic acid-elevated diet had selective suppressive actions on adrenocortical function whereas at 12 months, both docosahexaenoic and eicosahexaenoic acid-elevated diets had similar suppressive efficacies. The data indicate that a diet rich in high saturated, low polyunsaturated fat augments adrenocortical function and increasing the representation of long-chain unsaturated fatty acids suppresses adrenocortical function.
Asunto(s)
Corteza Suprarrenal/citología , Corteza Suprarrenal/efectos de los fármacos , Grasas de la Dieta/farmacología , Pruebas de Función de la Corteza Suprarrenal , Hormona Adrenocorticotrópica/sangre , Animales , Dieta , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Ácidos Grasos/farmacología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Traumatic shock was induced in anesthetized rats using the Noble-Collip method. This resulted in an abrupt decline in mean arterial blood pressure (MABP) and heart rate. Plasma cathepsin D activity increased sixfold, plasma thromboxane B2 (TxB2) concentration increased 2.5-fold, plasma myocardial depressant factor (MDF) activity increased 3.5 fold, and the mean survival time was 1.4 +/- 0.2 hours. Administration of the selective thromboxane synthetase inhibitor 5-(3-pyridinylmethyl) benzofuran-2-carboxylate (U-63,557A) (4 mg/kg) resulted in a significant improvement in survival time, 3.3 +/- 0.5, p less than 0.01. Plasma cathepsin D activity was not affected by U-63,557A (7.4 +/- 0.8 vs. 8.5 +/- 1.1 U/ml). However, both plasma and peritoneal fluid TxB2 concentration were significantly reduced and accumulation of the toxic peptide, MDF, was significantly blunted (69 +/- 6 vs. 40 +/- 5 U/ml, p less than 0.01). Our data indicate that blockade of thromboxane A2 (TxA2) production by selective synthetase inhibition is beneficial in trauma and support a role for TxA2 in the pathogenesis of circulatory shock.
Asunto(s)
Benzofuranos/uso terapéutico , Oxidorreductasas/antagonistas & inhibidores , Choque Traumático/tratamiento farmacológico , Tromboxano-A Sintasa/antagonistas & inhibidores , Animales , Presión Sanguínea/efectos de los fármacos , Catepsina D/sangre , Relación Dosis-Respuesta a Droga , Lisosomas/efectos de los fármacos , Masculino , Factor Depresor Miocardico/sangre , Pronóstico , Ratas , Ratas Endogámicas , Tromboxano B2/sangreRESUMEN
We studied the effects of a selective antagonist of LTD4 (LY-171883, 2 and 4 mg/kg) in traumatic shock. Anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by a survival time of 1.7 +/- 0.3 h, a sixfold increase in plasma cathepsin D activity, and a fourfold increase in plasma myocardial depressant factor (MDF) activity. Administration of LY-171883 did not significantly inhibit the release of the lysosomal hydrolase cathepsin D during traumatic shock. However, LY-171883 (2 mg/kg) significantly attenuated the accumulation of MDF activity in the plasma (51 +/- 2 vs 37 +/- 3 U/ml), vehicle vs drug, respectively, and significantly (p less than 0.02) prolonged survival time to 2.7 +/- 0.2 h. Administration of the antagonist at a dose of 4 mg/kg further improved survival time (3.4 +/- 0.6 h, p less than 0.01) and additionally blunted circulating MDF activities compared to traumatized rats given only the vehicle. LY-171883 was found to antagonize the bronchoconstrictor effect of LTD4 given intravenously to anesthetized rats as well as the coronary vasoconstrictor actions of LTD4 in vitro. The beneficial effect of LTD4 antagonism in the present study is consistent with the concept that peptide leukotrienes are important mediators of the pathogenesis of traumatic shock.
Asunto(s)
Acetofenonas/uso terapéutico , Azoles/uso terapéutico , SRS-A/antagonistas & inhibidores , Choque Traumático/tratamiento farmacológico , Tetrazoles/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Catepsina C , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/sangre , Masculino , Factor Depresor Miocardico/sangre , Ratas , Ratas Endogámicas , Choque Traumático/sangreRESUMEN
Eglin C is a polypeptide inhibitor of the neutral proteases elastase and cathepsin G. We have investigated its action in traumatic shock in rats. Eglin C (2 mg/kg) given following trauma prolonged survival time from 2.3 +/- 0.5 h to 3.6 +/- 0.4 h (p less than 0.05) in traumatized rats. Although eglin C treatment had no significant effect on the increase in plasma cathepsin D activity, eglin C administration significantly blunted plasma myocardial depressant factor (MDF) accumulation, 54 +/- 3 vs 79 +/- 8 U/ml (p less than 0.02). Our findings indicate a potential role for neutral proteases in toxic factor formation.
Asunto(s)
Inhibidores de Proteasas/uso terapéutico , Proteínas/uso terapéutico , Serpinas , Choque Traumático/tratamiento farmacológico , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Catepsina D/sangre , Frecuencia Cardíaca/efectos de los fármacos , Lisosomas/enzimología , Masculino , Factor Depresor Miocardico/metabolismo , Ratas , Ratas Endogámicas , Choque Traumático/sangre , Choque Traumático/fisiopatología , Factores de TiempoRESUMEN
A new thromboxane synthetase inhibitor, CGS-12970, was evaluated for its ability to reduce the extension of myocardial infarct size in rats. CGS-12970 was given at either 4 or 8 mg/kg following acute coronary artery ligation. Both myocardial creatine kinase (CK) and amino-nitrogen loss from the left ventricular free wall (LVFW) were used as indices of ischemic damage at 48 hours. Rats given only the vehicle following coronary artery ligation lost 4.9 +/- 0.5 IU/mg protein (p less than 0.001) CK activity from the LVFW. This loss of CK activity was only slightly reduced by CGS-12970 at 4 mg/kg. However, at 8 mg/kg, the CK depletion from the LVFW was significantly reduced (p less than 0.05). This protective effect was confirmed by similar curtailment (p less than 0.05) of the loss of nitrogenous compounds from ischemic myocardium, at the high dose of CGS-12970. These findings represent a protective effect of CGS-12970 in reducing the extent of ischemic cardiac damage following experimental coronary artery ligation.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Piridinas/uso terapéutico , Tromboxano-A Sintasa/antagonistas & inhibidores , Animales , Enfermedad Coronaria/enzimología , Vasos Coronarios/fisiología , Creatina Quinasa/metabolismo , Masculino , Miocardio/enzimología , Ratas , Ratas EndogámicasRESUMEN
Hemorrhagic hypotension produces significantly increased plasma arginine vasopression (AVP) concentrations. We have utilized a specific antagonist (AVP-A) of the pressor effects of endogenous AVP to investigate the role of this neurohypophyseal hormone on the pathogenesis of hemorrhagic shock. Infusion of the AVP-A (2 micrograms/kg bolus + 2 micrograms X kg-1 X h-1 infusion) into sham-shocked animals produced no significant changes in any of the observed experimental variables. Cats subjected to hemorrhagic shock given AVP-A had final superior mesenteric artery flow (SMAF) values significantly (P less than 0.05) higher than shock cats given vehicle (7.7 +/- 1.1 vs. 4.5 +/- 0.8 ml X kg-1 X min-1, respectively). Increases in postreinfusion plasma cathepsin D activities were significantly blunted in hemorrhaged animals treated with AVP-A (10.4 +/- 2.0 vs. 24.8 +/- 5.5 U/mg protein; P less than 0.05). Plasma proteolysis as well as the plasma accumulation of myocardial depressant factor (MDF) were also significantly modulated by AVP-A treatment in hemorrhaged animals. MDF activities were 75 +/- 6 and 53 +/- 4 U/ml (P less than 0.02) for shock cats given vehicle or AVP-A, respectively. However, these beneficial actions were not reflected in any significant improvement in postreinfusion mean arterial blood pressure (MABP). These findings suggest that endogenous AVP functions not only as a potent splanchnic vasoconstrictor but also as a key humoral factor in the maintenance of postreinfusion MABP, a profile that is different from the role of angiotensin II, the other major splanchnic vasoconstrictor, in shock.