Prostaglandin e biosynthesis during cardiopulmonary bypass

Initiation of cardiopulmonary bypass (CPB) causes immediate drop in blood pressure and peripheral vascular resistance (PVR) with activation of complex neurohumoral reflex mechanisms and redistribution of systemic blood flow. Prostaglandin E (PGE) is a potent vasodilator released during ischemia and low flow states. This study was designed to determine if CPB provided stimulus for PGE biosynthesis and its effect on PVR.Fourteen dogs were placed on CPB for 60 min at 80 ml/kg/min. Plasma PGE concentration and PVR were determined prior to and immediately after the start of CPB and at 15-min intervals. There were eight control animals (Group I) and six (Group II) had PGE inhibited by indomethacin (2.5 mg/kg). With the initiation of CPB, PVR decreased to 18 ± 1 U in both groups. In Group I, PGE increased from 404 ± 88 to 619 ± 256 pg/ml. In Group II, PGE levels dropped from 363 ± 94 to 218 ± 96 pg/ml after indomethacin block and did not change in response to CPB. At 15 min, Group I PVR rose to 30 ± 3 U while Group II PVR was higher at 42 ± 2 U (P < 0.001). PGE concentrations at this time were 652 ± 106 in Group I and 260 ± 92 pg/ml in Group II (P < 0.01). After 15 min, PGE returned to control in Group I but remained significantly elevated over Group II at 30 and 45 min. PVR continued to increase in both groups for the duration of CPB and Group II PVR remained significantly elevated (P < 0.05) compared to Group I.These data show that PGE is released in response to the initiation of CPB and is one of several factors affecting PVR during CPB.     

Venous prostheses: improved patency with external stents

A uniformly successful prosthesis for replacement in the venous system has not been developed. This study assesses the effect of external stents on the patency of polytetrafluoroethylene (PTFE) grafts in the infrarenal vena cava. Under general anesthesia, 21 mongrel dogs underwent midline laparotomy. The infrarenal vena cava was resected and replaced by a standard segment (8 cm X 10 mm) of stented PTFE (12 dogs) and nonstented PTFE (9 dogs). Patency was assessed by contrast venography and the results compared between the two groups. The 7-, 30-, and 90-day patency was 12/12, 10/12, and 9/12, respectively, for stented PTFE and 6/9, 2/9, and 2/9, respectively, for nonstented PTFE. The patency of externally stented PTFE at 30 and 90 days was significantly better than grafts fashioned from PTFE alone (P less than 0.05 by chi-square analysis). These data demonstrate that external stenting improves the early patency of PTFE prostheses in the infrarenal vena cava. Consideration should be given to the clinical use of externally stented PTFE when prosthetic replacement in the venous system is required.     

Methionine sulfoximine prevents the accumulation of large neutral amino acids in brain of hyperammonemic rats

Accumulation of neutral amino acids in the brain due to altered transport across the blood-brain barrier appears to be a consequence of portal-systemic shunting and hyperammonemia. It has been suggested that high brain concentrations of glutamine, a product of cerebral ammonia detoxification, accelerates the transport of other neutral amino acids from blood to brain. To test this hypothesis, normal rats were infused with ammonium salts with or without pretreatment with L-methionine-dl-sulfoximine (MSO), an inhibitor of glutamine synthesis. Pretreatment with MSO prevented most ammonium salt-induced changes in the concentrations of the neutral amino acids in brain, suggesting that hyperammonemia alters the transport of neutral amino acids across the blood-brain barrier by causing the brain glutamine level to rise.     

Leupeptin's effect on organ weight,RNA, DNA,and protein content after long bone fracture in the rat

Long bone fracture in the rat is accompanied by enhanced urinary nitrogen loss reflecting changes in protein synthesis and breakdown. The effects of leupeptin, an inhibitor of lysosomal proteases, were assessed on organ weights, RNA, DNA, and protein content after injury in the rat. Two groups of 8-week-old rats were studied: The first group received left femoral fracture. Half of these received leupeptin (25 μmole ip/day), and the remainder received saline. The second group served as uninjured pair-fed controls, with half receiving leupeptin and half receiving saline. On Days 0, 1, 2, 4, and 7 after injury, animals were sacrificed and organs were removed for determination of weight, RNA, DNA, and protein content. All injured rats lost weight, with maximum loss occurring on Day 4. Food intake was also reduced. Pair-fed rats lost the same amount of weight as injured ones, and leupeptin could not prevent whole body weight loss. Expressed as percentage of total body weight, livers from leupeptin-treated injured rats weighed 10% greater than saline-treated ones on Days 2, 4, and 7 after injury (P < 0.05). No differences occurred in RNA, DNA, or protein contents. Diaphragms similarly weighed 10, 20, and 30% greater on Days 2, 4, and 7 after injury, respectively, in leupeptin-treated rats (P < 0.05). In addition, the RNA and DNA contents of diaphragms were 96 and 88% greater, respectively, in treated rats than in controls (P < 0.05) on Day 4. It is concluded that leupeptin causes a relative increase in the weights of livers and diaphragms after injury, and causes a marked increase in the RNA and DNA contents of diaphragms.     

Inhibition of murine neuroblastoma growth by dopamine antagonists

C-1300 murine neuroblastoma ( MNB ) contains the catecholamine biosynthetic pathway. This study investigated manipulation of this pathway for effects on cell growth and survival in tumor-bearing mice, and to correlate these findings with specific membrane-bound dopamine-binding activity. The dopamine antagonists domperidone, pimozide, and spiroperidol inhibited macromolecular synthesis in vitro as demonstrated by decreased [3H]TdR and [14C]leu incorporation in a dose-response fashion; 56, 49, and 43% inhibition was noted at 10(-6) M concentration of each drug, respectively, with no loss of cell viability. Dopamine agonists showed no significant inhibition. Scatchard analysis of dopamine binding was consistent with a single class of receptor sites with a mean concentration of 13.2 +/- 2.0 pmole/g wet weight of tissue and mean dissociation constant (Kd) = 0.69 +/- 0.38 nM, compared to a mean receptor concentration of 28.1 +/- 5.2 pmole/g wet weight of tissue and Kd = 0.38 +/- 0.09 nM in receptor-rich dog caudate nucleus, the normal control. A/J mice injected with 1 X 10(6) tumor cells and treated with daily pimozide or domperidone had a significant increase in disease-free survival when compared to controls (15 versus 8.5 days, P less than 0.001) as well as a significant increase in overall survival (35 versus 25 days, P less than 0.001). These data suggest that dopamine antagonists inhibit macromolecular synthesis in the C-1300 MNB . The inhibition of MNB tumor growth in vivo by dopamine antagonists suggests a specific chemotherapeutic approach to neuroblastoma, possibly mediated by dopamine receptors.     

Neutrophil dysfunction in sepsis. III. Degranulation as a mechanism for nonspecific deactivation

Prominent and global abnormalities in chemotactic, oxidative, and microbicidal activity have been identified in neutrophils from patients with severe sepsis. To evaluate the possible contribution of degranulation as the basis for the observed abnormalities, 12 patients with intrabdominal infection were serially studied and neutrophil chemotaxis, enzyme content, and receptors for FMLP were evaluated. There was a significant correlation between chemotactic response to both activated serum and FMLP with the granular enzymes beta-glucuronidase and lysozyme. For FMLP-directed migration, r = 0.73, P less than 0.001 for lysozyme, and r = 0.59, P less than 0.001 for beta-glucuronidase. There was a similarly significant correlation between loss of lysozyme and an increase in FMLP receptors, previously shown to be a marker for degranulation. These data support the concept that in vivo degranulation, possibly due to effects of circulating chemoattractants on adherent neutrophils, is responsible for the enzymatic and chemotactic loss seen in cells from septic patients. This hypothesis also provides a mechanism to explain the respiratory distress syndrome if degranulation were to occur in the pulmonary capillary bed.     

Phagocytosis in experimental burns

The variations of phagocytic activity have been measured during a 9-day period following experimental burns. The burns are of an intermediate type; necrosis develops within 2 to 4 days after thermal trauma and covers up to 10% of total body surface.Phagocytic activity has been measured in peripheral blood, spleen, and liver by measuring both clearance of bacteria and the bactericidal index of the macrophages.Shortly after burn trauma, a considerable inactivation of the bactericidal index has been noticed. The decrease of the phagocytic activity of macrophages in the liver and peripheral blood is important but transient; the decrease of the phagocytic activity of splenic macrophages is drastic and persists unimproved for at least 9 days following burn injury.     

Effect of long-term metronidazole (MTZ) therapy on experimental colon cancer in rats

Current reports suggest a beneficial effect of long-term metronidazole (MTZ) therapy in Crohn's disease. Since Crohn's disease is associated with a higher risk of bowel cancer and long-term MTZ has been shown to have a tumorigenic potential in rodents and a cocarcinogenic effect in experimental colon cancer, more studies are required to explore this area. Eighty-one rats were divided into four groups. Group A served as a control, groups B and C were given MTZ in their food (50 mg/kg/day). In groups C and D, a 3-cm colonic segment was isolated and brought out as a blind loop fistula. All animals received 20 weekly sc doses of 1,2-dimethylhydrazine (DMH) and were killed 25 weeks after the first injection. The mean number of colon tumors per animal (±SEM) in MTZ groups B (1.65 ± 0.29) and C (2.57 ± 0.38) were higher than A (1.44 ± 0.3) and D (1.18 ± 0.21), but the increase was only significant for group C over groups A and D (P < 0.05) and group B (P = 0.06). The mean number of tumors per animal in the isolated loop of group C (0.95 ± 0.28) was similar to group D (0.68 ± 0.16) P = 0.41, but the mean number of tumors in the functioning colon of group C (1.62 ± 0.25) was higher than group D (0.5 ± 0.12) P < 0.001. These findings suggest that (1) long-term MTZ increased the number of colon tumors per rat in the DMH model but a statistical significance (P < 0.05) was only noted in the MTZ and surgery group. (2) Surgery alone did not increase the number of tumors. (3) This effect of MTZ is dependent on the presence of the fecal stream, since there was no significant difference between the number of tumors in the empty loops of MTZ and non-MTZ groups.     

Effects of pretreatment with coenzyme Q10 on myocardial preservation during aortic cross clamping

A protective effect of coenzyme Q₁₀ on the ischemic and reperfused myocardium was investigated in the isolated working rat heart preparation. Rats were treated intraperitoneally with 30 mg/kg coenzyme Q₁₀, daily for 7 days. The controls were given the same dose of the vehicle. After 25 min of equilibration the hearts were made totally ischemic at 35.5°C for 30 min, arrested with high potassium cardioplegic solution immediately after aortic cross clamping. The recovery of cardiac power in the coenzyme Q₁₀ pretreated group was significantly (P < 0.05) better than that in vehicle pretreated group. Creatine phosphokinase (CPK) release during reperfusion was significantly (P < 0.05) reduced by the pretreatment of coenzyme Q₁₀. Tissue analysis for high energy phosphate compounds revealed no significant difference between the two groups. Tissue lactate content at 30 min of ischemia was significantly (P < 0.001) lower in the coenzyme Q₁₀ pretreated group. These results suggest that pretreatment with coenzyme Q₁₀ is effective for reducing ischemic injury caused by aortic cross clamping.     

Thyroglobulin in struma ovarii

The serum assay of thyroglobulin offers a means of detection of recurrent thyroid cancer. We present immunohistochemical studies suggesting that the presence of ovarian thyroid tissue containing and producing thyroglobulin may introduce a source of diagnostic confusion.     

Effect of disuse and thermal injury on protein turnover in skeletal muscle

Both muscle inactivity and direct thermal injury increase net proteolysis and amino acid release by muscle. To assess their relative contribution to the altered protein metabolism by thermally injured muscle, rats were scalded on one hindlimb and half of these rats were fitted with casts immobilizing the lower half of the body. Three days later, soleus muscles from the burned and unburned limbs of all burned rats and from controls (uninjured, without casts) were studied in vitro. Protein synthesis was estimated by [¹⁴C]tyrosine incorporation into muscle proteins and net proteolysis was measured by tyrosine release. Protein synthesis by uncasted unburned limb muscles did not differ from that by controls but that by burned limb muscles was enhanced 134% (P < 0.001). Protein synthesis by casted unburned and burned limb muscles was augmented 56 and 309% (P < 0.003), respectively, above control. Tyrosine release by uncasted unburned muscles of burned rats did not differ from that of controls while that of burned limb muscles was elevated 163% (P < 0.007). Tyrosine release by casted unburned and burned limb muscles was increased 70 and 203% (P < 0.002), respectively, above control. It is concluded that both inactivity of and thermal injury to muscle stimulate its protein turnover. The acceleration of protein turnover by muscle underlying the burn wound far exceeds that produced by mere inactivity, suggesting that disuse is only a minor contributor to enhanced protein turnover in thermally injured muscle.     

Systemic and renal effects of dopamine in the infant pig

Dopamine is commonly employed in the management of hypotensive patients. Although this medication increases cardiac index (CI) and renal artery (RA) flow in adults, its effect in infants has not been adequately studied. In 13 infant pigs (mean wt 3.05 ± 0.75 kg; age 3–4 weeks) CI, RA flow and systemic blood pressure (BP) were measured at varying renal artery perfusion pressures before and after the administration of dopamine. Pigs were anesthetized with ketamine, intubated, and maintained on a ventilator with succinylcholine. Jugular vein, pulmonary (Swan-Ganz), carotid, and femoral artery catheters were placed. Laparotomy was performed and RA flow was measured with an electromagnetic flow probe. A Blalock clamp was placed around the suprarenal aorta to obtain graded aortic occlusions to pressures of 80 and 50 mm Hg. Dopamine had no significant effect on the CI vs control at 5, 10, 15, 20, 25, or 50 μg/kg/min. BP increased 25 mm Hg on Dopamine (10 μg/kg/min) P > 0.05). RA flow remained stable (318 ± 74 vs 300 ± 68 ml/min) despite reduction in perfusion pressure to 80 mm Hg, suggesting an autoregulatory flow mechanism. At 50 mm Hg perfusion pressure however, RA flow decreased significantly to 220 ± 54 ml/min (P < 0.05) indicating a loss of autoregulation at lower perfusion pressures.Dopamine (10 μg/kg/min) did not change RA flow at control BP (335 ± 76 vs 318 ± 74 ml/min). At 80 mm Hg perfusion pressure however, RA flow fell from 335 ± 74 to 175 ± 50 ml/min (P < 0.001) demonstrating a suppression of renal autoregulation by dopamine. At 50 mm Hg, RA flow was markedly reduced to 22 ± 31 ml/min (P < 0.001). These data suggest: (1) dopamine has no significant effect on CI in infant pigs, (2) an RA flow mechanism is present in infant pigs which protects the kidney at reduced perfusion pressures, and (3) dopamine interferes with autoregulation and may be harmful to the infant kidney in hypotensive states.     

The effects of malnutrition on serum fibronectin and reticuloendothelial function

A rat model was used to investigate the effects of starvation and protein depletion on serum fibronectin levels and reticuloendothelial function. Serum fibronectin levels decreased significantly following both test diets. The uptake of opsonin-independent test agents was minimally affected by starvation and protein depletion. Clearance of gelatinized colloidal carbon, which is dependent on circulating opsonins, was significantly reduced in the malnourished animals. This clearance defect was corrected by incubation of colloidal carbon with normal serum. These data suggest that reticuloendothelial dysfunction secondary to malnutrition is primarily mediated by a deficiency of circulating opsonins.     

Pathophysiology of acute pancreatitis: Evaluation of the effects and mode of action of indomethacin in experimental pancreatitis in dogs

Prostaglandins are known to affect vascular flow and the inflammatory response. Since acute pancreatitis involves both of these phenomena, we undertook studies using anesthetized mongrel dogs to investigate changes in blood pressure, cardiac output and pancreatic arterial flow for 6 hr in both normal animals (10 dogs) and following induction of acute pancreatitis (15 dogs). Indomethacin (5 mg/kg), which inhibits synthesis of prostaglandins, was then injected intravenously, and the animals were subsequently monitored for 2 hr. Results showed: (1) A significant fall in pancreatic arterial flow, relative to cardiac output, over the first 6 hr of the disease in the acute pancreatitis animals (P < 0.001). (2) A further significant decrease in relative pancreatic arterial flow following indomethacin in these animals (P < 0.001). A similar reduction in pancreatic arterial flow was observed following indomethacin administration in the control animals (P < 0.001). Conclusions: (1) Relative pancreatic arterial flow falls during experimental acute pancreatitis. (2) Indomethacin reduces both basal and compromised pancreatic arterial flow in the anesthetized dog; this suggests that prostaglandins may participate in the maintainance of basal acid-compromised pancreatic blood flow in the anesthetized dog.     

Myocardial protection: heparin-induced free fatty acid elevation during cardiopulmonary bypass and its prevention

Elevated serum free fatty acids (FFA) adversely affect the hypoxic or ischemic myocardium by impairing cardiac function, decreasing contractility, and increasing arrhythmogenicity . Heparin, an anticoagulant used routinely in cardiac surgery, elevates circulating FFA. The purpose of this study was to determine the magnitude of FFA elevation in cardiac surgery patients and to establish, in dogs, a dose-response of FFA to heparin and to test whether glucose-insulin-potassium (GIK) solution could prevent heparin-induced rise in FFA. In 52 patients undergoing cardiopulmonary bypass (CPB), serial blood samples were obtained for FFA determination before and after heparin (300 IU/kg) administration. Then in seven normal dogs, heparin at a dose of 80 or 300 IU/kg was given. In another group of five dogs either GIK solution or NaCl were infused, while intravenous heparin (300 IU/Kg) injection was given. Each dog acted as its own control. It was found that there was a twofold increase in circulating serum FFA after heparin administration during cardiac surgery in patients, reaching the toxicity level of greater than 0.80 meq/liter. One-third of these patients had elevations of FFA level above the arrhythmogenic threshold of greater than 1.20 meq/liter. In the canine experiments low-dose heparin (80 IU/Kg) resulted in milder elevations of FFA for a shorter duration. Dogs given saline and high-dose heparin (300 IU/Kg) had responses similar to those seen in human patients undergoing cardiac surgery, while GIK abolished the elevation of serum FFA in response to high-dose heparin, eventually reducing FFA to below preheparin levels.     

The pulmonary effects of opiate blockade in septic shock

Sepsis remains the most common associated factor in acute respiratory failure (ARF). Endogenous opiates are known to have both respiratory and cardiovascular depressant effects. Because there is a high level of circulating endogenous opiates in sepsis, the possible role of opioids in the ARF syndrome seen in sepsis was studied. Sixteen piglets were infused with an LD100 dose (7.5 X 10(10) organisms/kg) of live Escherichia coli (Type 09-41). The pigs were hemodynamically monitored. Serial blood samples were taken for arterial blood gases and lactate. Serial lung biopsies were taken for determining wet/dry lung weight ratios and for histology. Group I (n = 8): septic shock controls without naloxone; group II (n = 8): naloxone treated, given as 2 mg/kg/hr intravenous boluses, starting within 1 min of E. coli infusion. All animals died of septic shock. Survivors at 150 min in group II had a higher blood pressure than group I (67.7 +/- 5.33 SEM vs 39.0 +/- 9.39) and cardiac output was also greater (1.07 +/- 0.23 vs 0.25 +/- 0.25). By 210 min, group I had no survivors (0/8) while 3/8 in group II survived. Pulmonary vascular resistance in group II at 90 and 120 min (870.8 +/- 274.1 and 942.5 +/- 12.9, respectively) was lower than in group I (2868.3 +/- 843.6 and 4156 +/- 1067). The PO2 was markedly better in group II and at 90 min; controls had a PO2 70.7 +/- 13.0, while group II had a PO2 111.4 +/- 8.4 (P less than 0.05). PCO2 levels showed a progressive rise in group I from 39.25 +/- 1.4 to 49.4 +/- 8.57.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heart-rate effects on canine left-ventricular end-diastolic compliance measured by two-dimensional ultrasound

Despite recent interest in left ventricular (LV) compliance during open-heart surgery, the effect of heart rate (HR) remains unclear due to technical limitations of previous studies. In the presence of Formalin-induced complete atrioventricular (AV) block, AV sequentially paced heart rate was varied between 100, 125, and 150 beats/min in eight dogs on cardiopulmonary bypass. The heart was cradled in an open pericardial well filled with ultrasound-conducting gel. LV end-diastolic pressure (LVEDP) was varied over 0-20 mm Hg by flow regulation in the bypass circuit. Left ventricular end-diastolic volume (LVEDV) was calculated from three orthogonal two-dimensional (2-D) echocardiographic sections using Simpson's rule. Exponential curves derived from the relation LVEDP = ke(bxLVEDV) demonstrated a small, but significant increase in the mean exponential constants (b = 0.034, 0.037, and 0.049 at HR 100, 125, and 150, respectively) reflecting progressive stiffening with increasing heart rate. However, mean overall pressure-volume relations were not significantly altered when analyzed in four separate intervals of LVEDP. It is concluded that although LV volume determinations with 2-D echocardiography demonstrate a steady trend toward decreased end-diastolic LV compliance with increasing rate, this change is so small as to make heart rate a minor determinant of observed intraoperative compliance changes.     

Beneficial effects of alkalotic reperfusion following ischemic cardiac arrest.

The results of the present study indicate that exposure of ischemic myocardium to a solution with a low hydrogen ion concentration (pH 7.70) during the immediate post-ischemic period provides for better myocardial functional recovery and less myocardial water accumulation than does exposure to solutions with a normal hydrogen ion concentration (pH 7.40). Furthermore, exposure of the postischemic myocardium to a solution with a high hydrogen ion concentration (pH 7.10) results in poor recovery of ventricular function and significant myocardial water accumulation following reperfusion. Neither the beneficial effect of alkalotic reperfusion nor the harmful effect of acidotic reperfusion is associated with alterations in intramyocardial pCO₂ concentrations.     

Prevention of the inhibitory effects of aspirin on sodium transport in canine gastric mucosa by prostaglandin. Correlation with mucosal morphology

Using an in vitro canine gastric mucosal preparation, this study evaluated the effects of 1 mM aspirin in a buffered Ringer solution (pH = 7.4), with and without concomitant prostaglandin (PG) treatment, on net sodium transport (mucosa to serosa) across gastric epithelium. Administration of aspirin to the mucosal bathing solution for 2 hr significantly decreased the potential difference (PD), short circuit current (Isc), and net sodium transport (net J-Na+) when compared with untreated control mucosa. In mucosa treated with 16,16-dimethyl PGE2 (8 X 10(-6) M) in the serosal bathing solution 40 min after aspirin exposure and for 80 min thereafter, the initial inhibitory effects on PD, Isc, and net J-Na+ induced by aspirin were completely reversed within 40 min of PG treatment, having returned to control values. Histologically, mucosa exposed to aspirin alone showed evidence of diffuse cellular injury involving 50-60% of the surface epithelium. In contrast, mucosa treated with prostaglandin in conjunction with aspirin exposure demonstrated damage involving only 20-30% of the epithelium. These findings suggest that stimulation of sodium transport by PG may play a role in mediating the cytoprotective effects of PGs against aspirin-induced gastric mucosal injury.