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The purpose of this study was to examine the effect of angiotensin-converting enzyme inhibition with captopril upon renal function, renal vein renins and renography using 99m T-diethylenetriaminepentaacetic acid and 131 I-orthoiodohypurate in a canine model of two-kidney two-clip hypertension

Anabolic steroids are frequently taken by athletes and bodybuilders together with recombinant human GH (rhGH), though there is some scientific evidence that the use of anabolic steroids reverses the rhGH-induced effects. Recently, we have shown that treatment with rhGH (0.2 IU/kg s.c., daily × 12 days) in the dog markedly reduced the canine GH (cGH) responses stimulated by EP51216, a GH secretagogue (GHS), evaluated after 3 and 5 daily rhGH injections, and that the inhibition was still present a few days after rhGH discontinuation. The aim of the present study was to evaluate in the dog the GH response to EP51216 (125 µg/kg i.v.) in a condition of enhanced androgenic function (i.e. acute injection or 15-day treatment with testosterone at the dose of 2 mg/kg i.m. on alternate days), and in the hypophysectomized rat the hypothalamic and hippocampal expression of ghrelin, the receptor of GHSs (GHS-R), GH-releasing hormone (GHRH) and somatostatin (SS) after specific hormonal replacement therapies (testosterone, 1 mg/kg/day s.c.; hydrocortisone, 500 µg/kg/day s.c.; rhGH, 400 µg/kg/day s.c.; 0.9% saline 0.1 ml/kg/day s.c.; ×11 days). In the dog experiments, under baseline conditions, a single injection of EP51216 elicited an abrupt rise of plasma cGH. Twenty-four hours from the acute bolus injection of testosterone, Cmax and AUC0–90 of the GHS-stimulated cGH response were significantly lower than baseline cGH response; 5 days later, there was still a significant decrease of either parameter versus the original values. Short-term treatment with testosterone markedly reduced the GHS-stimulated cGH responses evaluated during (5th bolus) and at the end (8th bolus) of testosterone treatment. Four and 8 days after testosterone withdrawal, the EP51216-stimulated cGH response was still significantly reduced when compared with that under baseline conditions. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were stable until the 5th bolus of testosterone and decreased progressively in the remaining time of the testosterone treatment; 4 and 8 days from treatment withdrawal, IGF-1 levels were still suppressed. In rat studies, hypothalamic mRNA levels of GHS-R were significantly reduced by treatments with testosterone and hydrocortisone, whereas hippocampal expressions of ghrelin, GHRH and SS were reduced by rhGH replacement therapy. In conclusion, these studies show that a single administration of testosterone can abrogate the cGH response ensuing acute stimulation by a GHS; the inhibitory effect of testosterone on the cGH response to GHS is present during and even 8 days after termination of a short-lived treatment with testosterone; these events occur via a downregulation of hypothalamic GHS-R.

Background: We have reported that canine mastocytoma-derived CM-MC cells are activated via canine IgG and express a high-affinity IgG receptor (canine FcγRI). The predicted amino acid sequence of the canine FcγRI α subunit was found to be 72% similar to that of humans. These results suggest that canine FcγRI have binding activity with human IgG and led us to investigate CM-MC activation via canine FcγRI and human IgG. Methods: The binding of human IgG to canine FcγRI was examined by flow cytometry using FITC-conjugated human IgG. [Ca2+]i increase or histamine release via canine FcγRI and the four human IgG subclasses was measured following aggregation of IgG-bound FcγRIs by anti-human IgG. To determine the binding activity of canine FcγRI with human IgG1 or IgG3, the displacement of 125I-labeled canine IgG from canine FcγRI was examined by unlabeled human IgG1 or IgG3. Results: The fluorescence intensity of CM-MC cells was markedly (about 50 times) elevated by incubation with FITC-human IgG compared with the fluorescence of the control cells. A significant (p < 0.01) calcium response and histamine release were observed following aggregation of canine FcγRIs bound with human IgG1 or IgG4. 125I-labeled canine IgG was displaced from canine FcγRI by preincubation with unlabeled total human IgG or human IgG1 dose-dependently, whereas no displacement was detected by preincubation with human IgG3. Conclusions: Canine FcγRI possesses a significant binding activity with human IgG1 or IgG4, while IgG2 or IgG3 did not significantly react with canine FcγRI on CM-MC cells.

Purpose: The aim of this study was to determine whether omental transposition at the time of focal cerebral ischemia can decrease ischemic brain damage produced in dogs, in a new ischemia model, which had been described by us. Methods: In group 1 (n = 5), the left internal carotid artery and arterial circle of the brain (posterior communicating artery in humans) were occluded permanently. In group 2 (n = 5), additionally to this ischemia model, omental transposition was performed simultaneously. In the postoperative early period (first 24 h), single photon emission computed tomography (SPECT) and in the late period (72–96 h) SPECT and magnetic resonance imaging (MRI) of the brain were performed. Mann-Whitney U, paired t and Wilcoxon signed rank tests were used for statistical analyses, and p < 0.05 was considered significant. Results: The dogs had a neurological score (NS) of 3.6 ± 0.5 and 3.4 ±0.5 in groups 1 and 2, respectively, in the early period (p > 0.05). In the late period, the dogs had an NS of 4.4 ± 0.5 and 5.6 ± 0.5 in groups 1 and 2, respectively (p < 0.05). The NS of each group differed significantly between the early and late period (p < 0.05). Early SPECT imaging showed 50 ± 7.0% and 52 ± 8.4% hypoperfusion corresponding to the left middle cerebral artery territory in groups 1 and 2, respectively (p > 0.05). In the late period, the degree of hypoperfusion decreased to 34 ± 5.5% and 12 ± 4.8% in groups 1 and 2, respectively (p < 0.05). The degree of hypoperfusion in both groups changed significantly between the early and late period (p < 0.05). In T1- and T2-weighted MRI images, the volume of the lesion in group 1 was significantly greater than in group 2 (p < 0.001). Conclusion: In our new ischemia model, simultaneous omental transposition is helpful in reversing the neurologic deficit and cerebral ischemic damage.

Samples taken from 30 dogs with spontaneously acute trauma were investigated with two different resonance thrombographs (instrument 2: 28 dogs), a global method for examination of the haemostatic system. Reaction time of the resonance thrombogram (RTG-r), fibrin generation time (RTG-f), fibrin amplitude (RTG-F) and parameters of platelet function [amplitude of the platelet leg (RTG-P) and descending time of the platelet leg (RTG-p)] were evaluated statistically and compared with a normal control as well as with the results of individual components of the haemostatic system and other screening tests. Comparison of the results of the RTG of dogs suffering from trauma with the normal control revealed differences only for RTG-r, which was longer when measured with instrument 1 and lower RTG-F values measured with both instruments. Depending on the RTG parameter and instrument, only 1–6 samples showed values outside the reference ranges. Only 4 out of 26 cases (resonance thrombograph 2: 2 out of 24 cases) with mild to moderate deficiency in individual coagulation factor activity showed a prolongation of RTG-r which was significantly less sensitive than activated partial thromboplastin time (p < 0.001). Of the 26 samples having mainly mildly to moderately increased fibrin(ogen) degradation product (FDP) levels (median: 39 µg/ml, range: 2–90 µg/ml, reference values

After auxiliary partial orthotopic liver transplantation for inborn errors of metabolism, finding a balance in portal blood flow distribution between native liver and graft is complicated. We investigated the correction of hypoallantoinuria in the Dalmatian dog with a reduced-size Beagle orthotopic auxiliary liver graft, depending on intra-operative intervention in the portal flow. There were three groups: a ligation group, where the host portal vein was tied off, a free-flow group with random flow to both livers and a banding group, where the host portal vein was banded with an adjustable strapband. Metabolic correction was initially seen in all groups, but ligation led to portal hypertension and early mortality. In the free-flow group, correction was lost after 7 days, while banding preserved correction until 6 weeks. We conclude that acute ligation can lead to portal hypertension and free-flow leads to hypoperfusion and early loss of metabolic correction. Banding divided the portal blood flow between host liver and graft and prolonged metabolic correction.

Background: The source of glutamine for renal ammonium production is ultimately dietary protein in the fed state and body proteins in fasting. Objective: Our objective was to determine if less NH+4 would be excreted by fasted dogs with chronic metabolic acidosis resulting in conservation of lean body mass. Methods: Acid-loaded fed and fasted dogs were given 10 mmol NH4Cl/kg for 5 days; the fasted group had food withheld on days 4 and 5. Results: The renal production of NH+4 was not significantly different in both acid-loaded groups, yet the rate of NH+4 excretion was significantly lower in the fasted dogs (8 vs. 21 mmol NH+4/mmol creatinine). The urine pH was significantly higher (6.0 versus 5.5) while titratable acid and the urine flow rate were significantly lower in these fasted dogs. Despite nearly equal urine flow rates and Na+ excretion rates after an infusion of saline, the fasted dogs failed to increase the rate of excretion of NH+4 to rates seen in the fed group. Conclusions: The lower rate of excretion of NH+4 in fasted, acidotic dogs appeared to be due to a lower distal H+ secretion. This may help preserve lean body mass during fasting.

Ischemia-reperfusion injury is an important cause of primary nonfunction of transplanted organs, and neutrophil elastase has been implicated in the pathophysiology of ischemia-reperfusion injury. We assessed the kinetics of intracellular neutrophil elastase (INE) activity in canine liver transplantation. Mongrel dogs underwent orthotopic whole-liver transplantation. The animals in group I (n = 6) received fresh liver grafts, and all of the dogs survived longer than 24 h. The animals in group II (n = 5) received liver grafts injured by 30 min of warm ischemia. Only 1 animal survived longer than 24 h after reperfusion. A significant increase in the serum ALT and LDH levels was observed in group II after reperfusion of the graft. Isolated peripheral neutrophils were homogenized, and the neutrophil elastase activity in the supernatant was determined by using a spectrophotometric assay. The INE activity was expressed as the neutrophil elastase value per 1 × 1010 peripheral neutrophils. In group I, the INE activity 10 min and 2 h after reperfusion was 7.6 ± 2.6 and 6.1 ± 2.4 U, respectively. In group II, this activity was 25.9 ± 7.4 and 44.3 ± 23.7 U, respectively. There was a significant correlation between serum LDH levels and INE activity 10 min after reperfusion (γ = 0.70, p < 0.02). In conclusion, the INE activity increased more sharply after the reperfusion of ischemically injured liver grafts. The INE activity correlates with serum LDH levels immediately after reperfusion, suggesting that the increase in the INE activity depends on the severity of ischemic damage.

Background: Endothelin-1 (ET-1) is involved in some diseases, including renal disease. Recently, the role of ET-1 in postrenal transplantation has been demonstrated in experimental and clinical studies. A new endothelin receptor antagonist, TAK-044, blocks both, ETA and ETB receptors, and was useful in treating acute renal failure in rats. In this study, we evaluated the effect of TAK-044 on autotransplanted kidneys with 18 h of perfusion. Materials and Methods: TAK-044 was injected subcutaneously at 15 mg/kg/day for 2 weeks in one group of dogs, and blood analysis and renal function, were evaluated. A control group was given saline in the same manner as that used for the TAK-044 group. Histopathological examination and immunohistochemistry for ET-1 were performed in the two groups. Results: In the control group, 5 of the 7 dogs died of renal failure within 2 weeks after autotransplantation of the kidney. In the TAK-044 group, 5 of the 7 dogs survived and 2 died of renal failure within the same period. Although the histological changes in the tubules in both groups were severe due to the 18 h of perfusion, TAK-044 ameliorated these changes. Immunohistochemical staining for ET-1 was seen in tubules in the control group. Conclusion: These findings suggest that TAK-044 effectively reduces damage in autotransplanted perfused kidneys in dogs, and may be useful in limiting damage to the kidney by acute tubular necrosis after renal transplantation in humans.

We determined the utility of single-point measurements of circulating cardiac troponin T (cTnT) for the noninvasive estimation of infarct size in 16 beagle dogs after left anterior descending artery (LAD) ligation. Pathoanatomical infarct sizes were determined by the triphenyltetrazolium chloride method and correlated with serum concentration changes of cTnT. Peak cTnT levels (14.10 ± 4.71 μg/l) were reached after 110 ± 21 h. A significant correlation was found between peak cTnT levels (p = 0.0001, r = 0.83) or cumulative cTnT levels and relative infarct size (p = 0.0010, r = 0.72). A single cTnT measurement 96 h after LAD ligation was equally predictive of infarct size (p = 0.0010, r = 0.74) as peak or cumulative cTnT levels derived from serial sampling. cTnT levels at 96 h may thus be useful for practical and cost-effective estimation of infarct size.

Nonischemic end-systolic performance decreases during ischemia. These changes in performance are likely to be dependent on the size and site of the ischemic zone, as well as the prevailing loading conditions. This study was designed to examine the effect of regional and generalized changes in inotropy on nonischemic end-systolic performance, independent of the ischemic zone size. Twenty dogs were instrumented with sonomicrometers and micromanometer pressure gauges. End-systolic pressure-thickness relationship data were obained during vena-caval balloon inflation. Measurements were obtained before and 90 s after left circumflex (LC) artery occlusion. Then, simultaneous with the occlusion of the LC artery, isoproterenol (0.04 μg/ml) was infused into the left anterior descending artery. After recovery, the same protocol was repeated before and after propranolol (0.5 mg/kg). In a separate set of animals, the same measurements were made following 2.5 and 5 μg/kg/min dobutamine. The effect of ischemia on the nonischemic end-systolic pressure-thickness relationship was expressed as the extent to which the relationship is shifted to the left. Infusion of intracoronary isoproterenol into the perfusion bed of the nonischemic zone produced a significant increase in the slope of the end-systolic pressure-thickness relationship. During ischemia, however, the extent of leftward shift of this relationship was less than that following β-blockade. Intravenous dobutamine resulted in a dose-dependent increase in the slope of the nonischemic end-systolic pressure thickness relationship, but the extent of leftward displacement of the relationship in response to regional ischemia was less than that following the control occlusion. The nonischemic segment is coupled with the nonfunctioning ischemic zone in such a way that it is required of the nonischemic segment to operate at decreased end-systolic thickness for any end-systolic pressure, the extent of which is to be determined, in part, by the size of the ischemic zone and the contractile state of the nonischemic myocardium. The lower the contractile state prior to coronary occlusion the greater extent of leftward shift of the pressure-thickness relationship.

Objectives: Our aims were to investigate the systemic hemodynamic effects of constitutive endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) inhibitors in hyperdynamic endotoxemia. Patients and Methods: Group 1 comprised sham-operated controls, while in group 2, 3 and 4, a hyperdynamic circulatory reaction was elicited by a 2-hour infusion of Escherichia coli endotoxin (ETX) in a dose of 5.3 μg/kg. The animals in group 3 were treated with 12.5 mg/kg nonselective NOS inhibitor N-ω-nitro-L-arginine methyl ester (L-NAME), and those in group 4 with 2 mg/kg of the specific iNOS inhibitor S-methyl-isothiourea (SMT). Mean arterial pressure (MAP), cardiac output (CO) and myocardial contractility (MC) were measured, and total peripheral resistance (TPR) was calculated. The eNOS and iNOS activities were determined in myocardial biopsy samples taken after 8 h of endotoxemia. Results: ETX induced significant decreases in TPR and MAP, a transient myocardial depression, and increased the myocardial eNOS and iNOS activities. L-NAME decreased the activities of both isoenzymes, increased MC but induced a fall in CO. SMT inhibited iNOS by 60%, without influencing the eNOS activity, increased MAP and contractility in the early phase of endotoxemia, and induced only a slight decrease in CO. Conclusions: Nonselective NOS inhibition restores the arterial pressure and exerts a positive inotropic effect, but decreases CO. SMT selectively decreases the iNOS activation without disturbing the vasoregulatory function of the eNOS-derived nitric oxide in hyperdynamic endotoxemia in the dog.

Purpose: Magnetic stimulation (MS) produces its effect, according to Faraday’s law, by creating an electric field which can stimulate the neuromuscular tissues. The current study investigates, to our knowledge for the first time, the effect of MS on rectal pressure and evacuation with a view on its possible application in emptying the inertic or neuropathic rectum. Methods: The rectal, rectal neck and vesical pressures as well as the EMG activity of the two rectus abdominis muscles were recorded during sacral MS with a magnetic coil while the rectum was empty and while filled. Stimulation parameters were set at 70% intensity, 20 Hz freqency and 1- to 5-second burst length. Results: Sacral MS of both the filled and empty rectum effected a significant increase in rectal (p < 0.01) and vesical (p < 0.01) pressures and a decrease in rectal neck pressure (p < 0.01). Rectal evacuation of the filled rectum using intermittent stimulation was achieved in all animals. Conclusion: Sacral MS resulted in a rectal evacuation. It is a simple, easy and noninvasive method that might prove applicable in the treatment of inertic constipation and neuropathic rectum.

Recent studies suggest that nitric oxide (NO) may play an important role in the pathophysiology of pulmonary hypertension. Nitroglycerin is metabolized to NO, which is a potent vascular smooth muscle relaxant. The aim of the present study was to compare the effects of inhaled and infused nitroglycerin on pulmonary hemodynamics and gas exchange in anesthetized, artificially ventilated dogs. Nitroglycerin was administrated either by inhalation or by infusion. Systemic blood pressure (SBP), pulmonary arterial pressure (PAP), and pulmonary capillary wedge pressure (PCWP) were measured, and cardiac output was estimated by an electromagnetic flowmeter. Blood gas measurements were performed during hypoxic gas exposure (FiO2; 0.1) with a continuous inhalation or infusion of nitroglycerin (1, 2.5 µg/kg/min). Inhaled (n = 4) and infused (n = 4) nitroglycerin (1 µg/kg/min) did not produce any detectable effects on the hemodynamics. Inhaled nitroglycerin (2.5 µg/kg/min) reduced SBP, PAP and calculated pulmonary vascular resistance (PVR) in all dogs. Cardiac output did not change. In addition, inhaled nitroglycerin increased PaO2. In contrast, the continuous infusion of nitroglycerin (2.5 µg/kg/min) did not change in PAP, whereas infused nitroglycerin decreased the mean SBP. Infused nitroglycerin did not alter cardiac output and calculated PVR. A decreased PaO2 was noted in 2 dogs on nitroglycerin infusion. These findings indicate that inhaled nitroglycerin effects the pulmonary circulation relatively more than infused nitroglycerin, which tends to have more of a general effect on the systemic circulation. The effects of inhaled nitroglycerin may thus be comparable to the effects of NO inhalation.

Endotoxemia is accompanied by gastrointestinal motor disturbances while administration of oxygen free radical scavengers following endotoxemia ameliorates these motor disturbances. We hypothesized that the motor disturbance produced by endotoxemia may be associated with a change in the activity or production of superoxide dismutase (SOD). Strain gauge transducers were placed on the stomach and small bowel of dogs to determine fasting gastrointestinal motility. Manganese and copper/zinc SOD enzyme activities in gut smooth muscle were measured and protein expression was analyzed by Western blotting. Following completion of the baseline studies, dogs were given a single dose of Escherichia coli lipopolysaccharide, 200 µg/kg i.v., and the studies repeated for the next 3 days. Following endotoxin bolus, the migrating motor complex (MMC) was delayed for 2 days while gastric and jejunal smooth muscle levels of Cu/Zn SOD activity were decreased for 1 day in the stomach and for 2 days in the jejunum. Western blotting indicated that endotoxin did not change the amount of SOD enzyme produced. We conclude that endotoxemia results in a temporary prolongation of the MMC and a decrease in Cu/Zn SOD activity. Expression of Cu/Zn SOD and Mn SOD does not seem suppressed by endotoxin as measured by Western blotting. However, the impairment of Cu/Zn SOD activity may contribute to ileus associated with sepsis by altering oxygen-free metabolism in both the stomach and jejunum.

To compare the effects of laser light with those of radiofrequency (RF) current on ventricular myocardium, a total of 36 lesions (endocardial approach n = 10 each and epicardial approach n = 8 each) were produced by either transcatheter laser (Nd:YAG, 1,064 nm, 30 W, 30 s) or RF (70 degrees C, 30 s) catheter applications in the beating hearts of 4 dogs. Volumes of coagulated myocardium in endo-/epicardial approaches were 996 +/- 73/1,075 +/- 82 (laser) and 111 +/- 38/44 +/- 5 mm3 (RF). RF lesions showed intramural bleeding, rupture and dissociation of myocardial fibers, tissue vaporization with crater and thrombus formation. Transcatheter application of laser light produced significantly larger and better reproducible lesions than RF current, without undesirable effects on the ventricular walls.

The dose response and time course of micronucleated polychromatic erythrocytes (mPCE) in cat peripheral blood induced by various doses (150-250 mg/m2) of carboplatin in vivo was determined. The data indicate that carboplatin produced a significant (p < 0.05) dose-dependent increase in the number of mPCE over baseline values; however, the times following carboplatin administration when mPCE were first observed differed significantly (p < 0.05) between the three carboplatin dose groups. mPCE were present in significantly greater numbers (p < 0.05) on smears at an earlier time interval following a single carboplatin dose of 150 mg/m2 than for a dose of either 200 or 250 mg/m2. The peak number of mPCE occurred on days 7, 14 and 17.5 following administration of a carboplatin dose of 150, 200 and 250 mg/m2, respectively. The pattern of time course delay following carboplatin administration suggests that the block of erythropoietic stem cells in G2 is dose dependent. Indeed, the administration of carboplatin arrested the cell cycle in the G2 phase and, at higher doses, diminished the number of cycling erythroid precursor cells. mPCE were apparent in blood smears only after recovery from this arrest and resumption of replication. This observation has implications for the scheduling of carboplatin administration when used in combination with other anticancer drugs.

The aim of the present study was to evaluate superoxide dismutase (Cu, Zn-SOD) activity in the principal layers of polyester grafts implanted into the abdominal aorta of dogs. The grafts were examined 7 days and 1, 4 and 12 months after the operation. It was found that SOD activity occurred in all polyester graft layers during the whole experiment. The neointima activity ws 1.5-fold lower during the 1st month; with the passage of time, it became 2-fold lower than in the normal aorta (p < 0.01). SOD activity in the medial and outer graft layers behaved similarly: it was lowest after 7 days, increased after 1 month and significantly decreased after 4 and 12 months (p < 0.01). Our study shows that the activity of SOD is low in polyester grafts and it can thus be inferred that protection against the superoxide anion is inadequate.

Maldistribution of multidose blood cardioplegia (BCP) continues to be a problem causing perioperative subendocardial damage. However, it is not known whether alpha-adrenergic stimulation contributes to the maldistribution of multidose BCP. We have evaluated the effects of phenoxybenzamine (POB) on multidose BCP distribution, with a right heart bypass model in 14 dogs. Although gradual increases in coronary vascular resistance (CVR) were noted in the control group (CP-1: 0.53 +/- 0.08, CP-2: 0.57 +/- 0.07, CP-3: 0.78 +/- 0.10 mm Hg/ml/min/100 g), there was no significant rise in CVR in the POB group (CP-1: 0.36 +/- 0.03, CP-2: 0.37 +/- 0.04, CP-3: 0.42 +/- 0.04 mm Hg/ml/min/100 g). Improved delivery of BCP was observed in the POB group during CP-3 (endo/epicardial flow ratio 1.72 +/- 0.07 vs. 1.21 +/- 0.18 in the control group; p < 0.05). These data indicate that improved delivery of BCP can be obtained by alpha-adrenergic blockade, if multiple injections of BCP are used for cardiac surgery.

Platelet aggregation and plasma serotonin were studied during ischemia-reperfusion of the small intestine in dogs. Blood was withdrawn from the superior mesenteric vein before and 1 h after ischemia, then 5, 30 and 60 min after reperfusion. Dipyridamole (5 mg/kg body weight) and coenzyme Q10 (CoQ10; 10mg/kg body weight) were administered intravenously 5 min before reperfusion, following 1 h ischemia, in order to investigate their effects on platelet function and free serotonin. Ischemia-reperfusion resulted in an increased local free serotonin concentration together with an enhanced platelet response to ADP, collagen and arachidonic acid. Administration of dipyridamole and CoQ10 prior to reperfusion prevented, at least in part, augmented platelet activation and serotonin release. It appeared that dipyridamole was more potent than CoQ10. Our results may indicate a possible protective effect of dipyridamole on enhanced platelet activation during ischemia-reperfusion in dogs.

The present study evaluated the mechanisms by which upper airway (UAW)-dilating muscle contraction, elicited by hypoglossus nerve (HGN) stimulation, improved UAW patency. Pressure-flow (P-V) relationships of the isolated UAW as well as the negative intraluminal pressures required to cause UAW collapse were assessed before and during electrical stimulation of the HGN in 8 anesthetized, ventilated dogs. Sectioning of the HGN shifted the P-V relationship to the left, while electrical stimulation resulted in a substantial shift of the curve to the right, indicating UAW dilatation. UAW resistance decreased from 9.0 +/- 1.5 to 0.3 +/- 0.1 cm H2O.1(-1).s during HGn stimulation (p0.01). The magnitude of negative intraluminal pressure at which UAW collapse occurred (the critical pressure) increased from -2.7 +/- 0.7 to -13.2 +/- 2.1 cm H2O (p0.002). The increase in UAW conductance and stability raised the maximal flow which could be sustained without collapse from 0.28 +/- 0.07 to 2.07 +/- 0.35 l/s during HGN stimulation (p0.001). These findings indicate that in the anesthetized dog, UAW muscle contraction improves UAW patency both by dilating the UAW and by stiffening its walls.

We report the cross-reactivities and comparative molecular masses of the IgE epsilon chains in humans, rats, mice, and dogs. Monoclonal human, rat, and mouse IgE, and our purified polyclonal dog IgE were used in the study. IgE of the 4 species, separated by SDS-PAGE, were analyzed by immunoblotting with polyclonal and monoclonal antihuman IgE, polyclonal and monoclonal antimouse IgE, monoclonal antirat IgE, and polyclonal antidog IgE antibodies. The polyclonal antihuman and polyclonal antimouse IgE cross-reacted with the IgE of the other 3 species, while their monoclonal forms cross-reacted with dog IgE only. Polyclonal antidog IgE cross-reacted with human and mouse IgE, while the monoclonal antirat IgE did not cross-react with any other species. "Reverse' passive cutaneous anaphylaxis in ragweed-sensitized dogs revealed that polyclonal antihuman and polyclonal antimouse IgE were able to elicit positive skin responses, and monoclonal antihuman, antirat, and antimouse IgE antibodies were not. The molecular masses of the epsilon chains were 77 kDa for mice, 75 kDa for rats and dogs, and 70 kDa for humans.

Anterior gastric stapling with posterior truncal vagotomy has previously been investigated for its effect on canine gastric acid reduction and motility. Posterior truncal vagotomy could, however, induce reduced pancreatic function, which has been observed after total abdominal vagotomy. In this study, pancreatic secretion has been investigated after anterior gastric stapling with posterior truncal vagotomy in a series of canine experiments by means of a stimulation test. On the long term, no significant postoperative reduction of exocrine pancreatic secretion was observed.

The protective effect of a novel prostacyclin (PGI2) analog, OP-2507, on mesenteric circulation was investigated in a canine warm ischemia model. In 20 mongrel dogs, the entire portion of the intestine supplied by the superior mesenteric artery (SMA) and drained by the superior mesenteric vein (SMV) was completely isolated, maintaining the blood and lymph vessels intact. Sixty or 120 min of complete warm ischemia (WI) of the intestine was induced by clamping SMA and SMV, followed by reperfusion for 120 min. Animals were divided into five groups (each n = 4): group 1, sham operation; group 2, 60 min WI; group 3, 120 min WI; group 4, 60 min WI with PGI2 analog administration; group 5, 120 min WI with PGI2 analog administration. The analog was administered at a rate of 6 micrograms.kg-1.h-1 immediately after laparotomy until the end of the observation period. Mean arterial pressure, SMA blood flow (SMABF), SMV pressure were monitored and total mesenteric vascular resistance (TMVR) was calculated. To evaluate the endothelial activation, endothelin, which is secreted from the endothelium under hypoxic stress, was assayed from blood samples of SMV. None of the animals showed significant changes in mean arterial pressure. In groups 2 and 3, SMABF decreased significantly to less than 60% of preoperative value (15 ml.kg-1.min-1) and TMVR significantly increased from 8.1 and 7.3 mm Hg.ml-1.kg.min before WI to 14.0 and 16.4 mm Hg.ml-1.kg.min after 120 min reperfusion, respectively, resulting in delayed hypoperfusion. In contrast, in groups 4 and 5, SMABF increased to over 100% of preoperative level, while TMVR declined from 7.8 and 8.4 mm Hg.ml-1.kg.min before WI to 6.2 and 6.3 mm Hg.ml-1.kg.min after 120 min reperfusion. After 60 min reperfusion, SMABF and TMVR showed a significant difference between the treated and nontreated groups. Only in group 3, high endothelin concentrations (over 20 pg/ml) were observed even after 120 min reperfusion. It was concluded that the PGI2 analog was able to suppress the endothelial activation and the disturbance of mesenteric circulation caused by WI and reperfusion.

This study was performed to examine if the cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) or tumor necrosis factor (TNF) are released from the gastric mucosa during acute mucosal damage, and if the generation of these cytokines is affected by indomethacin. Cat stomachs were exposed to 2 M NaCl for 10 min followed by luminal perfusion at pH 1. Gastric mucosal blood flow was determined by radioactive microspheres, portal vein blood flow by transit-time flowmetry, and H+ back diffusion/secretion by pH-stat titration. Concentrations of active cytokines and of histamine in aortic and portal vein blood were measured by bioassay and RIA, respectively. Active IL-6, but not IL-1 and TNF, is released from the gastric mucosa during acute mucosal damage by 2 M NaCl and acid back diffusion. Indomethacin increased mucosal injury and enhanced the TNF generation but reduced the release of IL-6 from the gastric mucosa. We conclude that IL-1 and TNF probably do not play an important modulating role during acute gastric mucosal damage. The generation of IL-6 may, however, contribute to mucosal protection.

One to four months after implantation of a gastric fistula, a circadian rhythm in gastric acidity could be demonstrated by use of the intragastric 24-hour pH-metry in dogs with the gastric fistula protruding on the left side of the upper abdomen. This circadian rhythm was found to be fully developed within 3 years, and it remained unchanged up to 5 years after implantation. It is characterized by a daytime intragastric median pH of about 2 and a nocturnal intragastric median pH of about 7. In contrast, a circadian rhythm did not develop within 5 months after instrumentation of the dogs with a gastric fistula protruding on the right side of the upper abdomen. Only 2 years after implantation of the fistula, an intragastric daytime median pH of about 2 and a nocturnal median pH of about 4 appeared. Four years after implantation, the circadian rhythm had evolved. The results show a delayed postoperative restoration of circadian rhythm in canine gastric acidity if a gastropexy occurs at an untolerated position. This may lead to unphysiological distensions in the gastric wall with subsequent continuous stimulation of acid secretion.

To determine the effect of relative timing of atrial and ventricular activation on hemodynamic indices, we evaluated pressure-volume loops during pacing at 160 beats/min with various atrioventricular intervals in dogs. End-systolic pressure, end-diastolic volume, and stroke volume were reduced during pacing at atrioventricular intervals of 0 ms, compared with 80 ms. These changes were more significant during pacing at atrioventricular intervals of -50 and -100 ms than at 0 ms. During tachycardia, the abnormal timing of atrial contraction leads to unfavorable hemodynamic change and the degree of the changes are determined by the ventriculoatrial activation interval.

Hemodynamic changes at the distal femoral epiphysis measured by recording intraosseous pressure (IOP) were investigated in mature and juvenile dogs after changes in knee-joint position and intracapsular infusion of 3 ml isotonic saline solution. Juvenile and mature animals responded to infusion test with a similar 5-fold increase in intracapsular pressure. A 2-fold increase in IOP was found when knee-joint flexion passed from 30 degrees to complete flexion. In juvenile dogs, IOP values were lower than in adults both in complete knee flexion and during infusion test. The similar response to joint hyperpressure tests observed in adult and juvenile dogs suggests that the barrier effect of the growth plate for epiphyseal venous drainage has no major influence in the hemodynamics of the distal femoral epiphysis.

We previously reported that N-acetyl-L-cysteine (NAC), an oxygen free-radical scavenger, can increase the oxygen extraction capabilities during endotoxic shock when blood flow is progressively reduced. In the present study, we investigated whether the protective effects of NAC are related to an improvement in regional blood flow following endotoxemia. Fourteen anesthetized, saline-infused and ventilated dogs were divided into two groups: 7 dogs received NAC (150 mg/kg, followed by a 20 mg/kg.h infusion), and the other 7 dogs served as a control time-matching group. Thirty minutes later all the dogs received Escherichia coli endotoxin (2 mg/kg) i.v. A saline infusion was started 30 min after endotoxin challenge to restore pulmonary artery occlusion pressure to baseline and maintain it constant. Regional blood flow was measured by ultrasonic volume flowmeter. In the control group, arterial pressure, left ventricular stroke work index and systemic vascular resistance remained lower than baseline. Mesenteric, renal and femoral arterial blood flow increased but only femoral blood flow returned to baseline levels. In the NAC group, cardiac index and left ventricular stroke work index remained higher and systemic and pulmonary vascular resistance were lower than in the control group. Blood flow in mesenteric, renal and especially femoral arteries was higher than in the control group. Fractional blood flow increased only in the femoral artery. PaO2 and PvO2 had similar courses in the two groups. A higher venous admixture was associated with a higher cardiac index and a lower pulmonary vascular resistance in the NAC group. Oxygen delivery and oxygen-uptake were higher in the NAC-treated than in the control animals throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

The reported increase of gastric secretion after small bowel (SB) resection is controversial. To determine the effect of SB resection on gastric acid secretion we studied basal and dose step pentagastrin-stimulated gastric acid secretion as well as basal serum gastrin, secretin, neurotensin and postprandial gastrin levels in 12 dogs, before and after resection of 60% of the intestine representing both proximal (n = 6) and distal (n = 6) SB. Rat bioassay was also performed to rule out the presence of unknown gastric secretagogues in the blood. Proximal SB resection produced a significant increase in basal and low dose (100 ng/kg/h) pentagastrin-stimulated gastric acid secretion (ED50 = 1,110 vs. 720 ng/kg/h after resection). However, no significant changes in gastric secretion were observed after distal SB resections. Neither proximal nor distal SB resection altered basal or postprandial serum gastrin levels. Proximal SB resection reduced serum secretin levels (229 +/- 38 vs. 134 +/- 16 pg/ml, p0.05) but did not alter neurotensin levels. Rat bioassay failed to reveal a circulating secretagogue after SB resections. We conclude that proximal but not distal SB resection increases basal and submaximally stimulated gastric acid secretion. Such an effect may be due to the observed decrease in circulating secretin levels.

Absorbable, nonwoven patches made from polyhydroxybutyrate (PHB) were implanted as transannular patches into the right ventricular outflow tract and pulmonary artery in 13 weanling sheep, the test group. Six sheep, in which a transannular Dacron patch was implanted, served as control group. The test and the control patches were harvested 3-24 months later. The results were documented macroscopically, by histological examination, and by scanning electron microscopy. The 6-keto-PGF1 alpha activity was measured in the regenerated tissue and compared with that in the native pulmonary artery. No aneurysms were noted. Regeneration of a neointima and a neomedia, comparable to native arterial tissue, was observed in the test group. In the control group, a neointimal layer was present but no neomedia comparable to native arterial tissue. Scanning electron microscopy disclosed differences in the endothelial structure between the test and control groups. 6-keto-PGF1 alpha activity was present in both the test and control groups. It is concluded that absorbable, nonwoven patches of PHB can be used as a scaffold for tissue regeneration in low-pressure systems. The regenerated vessel had structural and biochemical qualities in common with the native pulmonary artery.

Excessive stimulation of glutamate receptors and elevation of intracellular calcium levels initiate the neurodegenerative process resulting from cerebral ischemia. However, the subsequent cascade of molecular changes which are of pathogenic significance is less well understood. Breakdown of the cytoskeleton may be involved in the progression from compromise of neuronal viability to irreversible damage. Alteration of the microtubule-associated protein tau, as reflected by increased Alz-50 immunoreactivity, was induced by permanent focal cerebral ischemia in vivo but only in a proportion of neurones. Alz-50 immunoreactive neurones did not exhibit the characteristics of irreversible ischemic cell damage. Increased immunoreactivity to the stress response protein ubiquitin was also induced by ischemia in a proportion of neurones. Both proteins are components of neurofibrillary tangles in Alzheimer''s disease. Alterations of the microtubule-associated protein tau may be a feature of the early stages of the ischemia-induced degeneration and the ubiquitin response may be an attempt by compromised neurones to deal with the presence of abnormal proteins.

Hyaluronan is a structural component of the interstitial matrix in skin and is catabolized locally in skin as well as by lymphatic removal and subsequent degradation in lymph nodes and liver. The present experiments were designed to evaluate the role of interstitial fluid flux in turnover of hyaluronan in skin by measuring the maximal lymphatic flux of hyaluronan. Lymph flow, total protein concentration, hyaluronan concentration, and flux were measured every 15 min in prenodal lymph from the hind paw in 12 pentobarbital-anesthetized mongrel dogs at normal and increased interstitial fluid flux. An intravenous saline load (15% of body weight during the course of 30 min) was followed by a one-step increase in local venous pressure 30 min later (to a maximum of 50 mm Hg) and maintained at this level for the next 240 min. Lymph flow and hyaluronan concentration during the control period averaged 25.6 +/- (SD) 23.2 (range 4.7-61.9) microliters/min and 8.6 +/- 2.8 (range 2.0-11.6) micrograms/ml, respectively. The hyaluronan concentration fell by 30% during the experimental period, while the lymph flow increased up to ten times above control. Total tissue water increased from 1.73 +/- 0.11 ml/g dry weight during the control period to 1.91 +/- 0.12 ml/g dry weight at the end of the experiment (p0.01). The corresponding tissue contents of hyaluronan averaged 3.5 +/- 0.9 and 3.6 +/- 0.6 mg/g dry weight, respectively (p0.05). The average lymphatic hyaluronan flux was 8.4 +/- 5.4 micrograms/h during the control period, peaked at about 60 micrograms/h, and averaged 33.6 +/- 13.9 micrograms/h during the last hour of the experimental period.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between portal hemodynamics and the energy metabolism of the liver with acute hepatic venous occlusion (HVO) was investigated by assessing the changes in the hepatic blood flow, arterial blood ketone body ratio (AKBR) and adenylate energy charge potential (ECP) of the liver tissue in canine model. Acute HVO was induced by the ligation of both the supra- and infrahepatic inferior vena cava (IVC) over the protruding ends of a heparin-coated polyethylene cannula inserted into the IVC. All dogs with only HVO (n = 5) died within 30 min. HVO dogs with additional mesocaval (MC) shunt (n = 10) survived longer than 7 days, during which time their AKBR were maintained in the normal range (over 1.0). ECP was also maintained above the normal level (over 0.850) during the 28-day period. Along with increasing portal pressure caused by the narrowing of the shunt anastomosis, the hepatic blood flow decrease gradually, resulting in a sudden decrease in AKBR and ECP when the portal pressure increased over 11 mm Hg. It is suggested that the normalization of portal pressure is one of the most important factors for maintaining the hepatic energy metabolism and that MC shunt is an effective therapy for maintaining the function of the liver with HVO, as long as portal pressure can be kept within normal range.

In order to study the segmental difference in the density of autonomic receptors of the vas deferens, we measured the amount of adrenergic alpha 1-, alpha 2- and beta-receptors and muscarinic cholinergic receptors in the three portions (prostatic, intermediate and epididymal) of dog vas deferens using radioligand binding techniques. Saturation experiments with 3H-prazosin, 3H-yohimbine, 3H-dihydroxyalprenolol and 3H-quinuclidinyl benzilate demonstrated that three were significant amounts of adrenergic alpha 1-, alpha 2- and beta-receptors and muscarinic cholinergic receptors in the three portions of dog vas deferens. Of the three portions examined, the prostatic portion was found to have a larger amount of alpha 1-, alpha 2-receptors and muscarinic receptors, while the intermediate portion was found to have a larger amount of beta-receptors. The epididymal portion was found to have a smaller amount of autonomic receptors. These data suggest that the prostatic portion plays a more important role in the function of the dog vas deferens. It is thought that the different segments of the vas deferens have a different functional role according to the distribution of autonomic receptors.

Microcirculatory nonperfusion of the intestinal mucosa may result in a subsequent prolongation of tissue ischemia, even after restoration of the mesenteric blood flow. It was hypothesized that there is a relationship between mucosal no-reflow and the amount of previously ischemic tissues during intestinal ischemia reperfusion. Accordingly, an examination was made of the changes in intestinal and gastric intramucosal pH (pHi) in dogs after a 120-min complete occlusion of the superior mesenteric artery (SMA) and those observed following ischemia of an ileal segment only. pHi, as an indicator of the adequacy of mucosal microcirculatory perfusion, was calculated by the tonometer technique. Baseline values of intestinal pHi (mean 7.25 +/- 0.12) and gastric pHi (mean 7.23 +/- 0.27) were determined in sham-operated animals. The 120-min intestinal ischemia caused a progressive fall in intestinal pHi to a mean value of approximately 6.8. Reperfusion resulted in a slow return to nearly normal pHi levels in the ileal segment, but essentially no intestinal pHi elevation was observed during the 90-min period following occlusion of the SMA. The gastric pHi remained at the control level during segmental intestinal ischemia reperfusion, but declined below the normal range following release of the occlusion of the SMA. It is proposed that continuing microcirculatory nonperfusion could explain the failure to demonstrate a postreperfusion elevation of pHi following complete occlusion of the SMA.

Ten beagle dogs were given omeprazole orally at a dose of 0.17 mg/kg (0.5 mumol/kg) daily for 7 years. Six dogs served as controls. Regularly evaluated criteria were clinical signs, body weight, food consumption, rectal temperature, electrocardiography, hematology, blood chemistry, urinalysis, ophthalmoscopy, gastroscopic examination including gastric mucosal biopsy sampling for histological evaluation, pharmacokinetics of omeprazole, and plasma gastrin levels. After approximately 5 years, a quantitative gastric acid secretion test was performed. No treatment-related adverse clinical signs or effects were observed in the dogs, and all animals survived to term. The annual gastroscopy with histological examinations of gastric mucosa did not show any treatment-related changes. At all investigations and in all dogs, the parietal cells were morphologically normal, and there were no changes of pattern or any increase in the number of argyrophil enterochromaffin-like cells compared to the control animals. In the plasma samples collected 24 h after dosing, there were no significant differences in either basal or meal-stimulated gastrin levels between the controls and the omeprazole-treated animals. Peak plasma concentration of omeprazole occurred within 2 h of dosing. The area under the concentration curve (AUC) was not affected by dosing over 7 years and was in good agreement with the AUC in humans given a dose of 20 mg omeprazole daily. Acid secretion tests after 5 years of treatment showed that the mean inhibition of acid secretion by omeprazole 4-7 h after dosing was as expected--about 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to evaluate the effectiveness of 15-deoxyspergualin (DSG) administration against acute rejection of canine pancreatic allografts. Subsequent to partial pancreatic allotransplantation and total extirpation of the pancreas, 20 adult mongrel dogs were divided into four groups and treated with saline (group 1, controls, n = 5), DSG at 1.0 mg/kg/day (group 2, n = 5), DSG at 3.0 mg/kg/day (group 3, n = 5), or DSG at 5.0 mg/kg/day (group 4, n = 5) on postoperative days 4-7. The graft survival, defined by a fasting serum glucose level < 150 mg/dl, was significantly prolonged from 6.2 +/- 1.2 days in group 1 to 12.4 +/- 2.7 days in group 3 (p < 0.05) and to 16.8 +/- 3.2 days in group 4 (p < 0.05). Graft survival was not significantly prolonged in group 2, however. Two normoglycemic dogs in group 4 died due to gastrointestinal toxicity, one of the most serious side effects of DSG. The observation that the serum insulin levels increased in dogs treated with DSG was compatible with dose-dependent graft survival and suggested that DSG had no toxic effects on pancreatic endocrine function. In group 1 significantly increased thromboxane B2 (TXB2) levels and TXB2/6-keto-prostaglandin F1 alpha (PGF1 alpha) ratios were observed on postoperative days 3-5 which was thought to reflect acute rejection. Following administration of DSG, both TXB2 levels and TXB2/PGF1 alpha ratios were decreased on the 5th postoperative day in groups 2-4.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitric oxide (NO), an endothelium-derived relaxing factor (EDRF), is released by different types of cells under the influence of endotoxin and various cytokines: a causative role of endothelium-derived NO in the endotoxin-induced hypotension has thus been suggested. To test the hypothesis that NO may be involved in the acute hypotension following endotoxin challenge, we administered a competitive inhibitor of NO synthase, L-N-monomethylarginine (L-NMMA) to anesthetized dogs in the presence and absence of endotoxin. Dogs were randomly allocated to three groups. Group 1 (n = 3) was given Escherichia coli endotoxin (3 mg/kg, i.v.), group 2 (n = 3) was given L-NMMA (5 mg/kg, i.v. bolus) 15 min after endotoxin and group 3 (n = 3) was given L-NMMA only. One additional dog was given L-arginine (100 mg/kg, i.v. bolus) after L-NMMA and endotoxin to reverse the inhibition of NO synthase. In each animal, saline was infused intravenously throughout the experiment to restore and maintain pulmonary artery occluded pressure at baseline level. After L-NMMA, the increases in mean arterial pressure were similar in group 2 (from 55 +/- 18 to 75 +/- 15 mm Hg, p < 0.01) and in group 3 (from 107 +/- 27 to 128 +/- 24 mm Hg, p < 0.01). Systemic vascular resistance increased from 2,994 +/- 72 to 3,658 +/- 673 dyn.s.cm-5 (p < 0.01) in group 3. Group 1 had lower plasma lactate levels than group 2 (3.5 +/- 2.3 +/- vs. 2.0 +/- 1.6 mEq/l, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Three types of colonic sphincter substitutes were placed at an abdominal colostomy in dogs. Simple valve construction (8) was based on orthograde intussusception of the colon over 3.5 cm. In calibrated valves (6) the intraluminal pressure was increased by reducing the diameter of the overlying muscle coat. Reverse smooth muscle plasties (5) and simple colostomies (5) served as controls. Immediately after construction highest pressure (50 +/- 8.9 mm Hg) was obtained in calibrated valves. After 1 month the pressure dropped to 20 mm Hg, but remained stable thereafter. Although valvular constructions cannot maintain high pressure, they may be useful as substitutes for the internal anal sphincter by filling up the lumen so that the action of a surrounding striated muscle ring becomes more effective.

The effects of the intra-arterial infusion of ATP, ADP and AMP into the internal maxillary artery (IMA), which provides the blood supply to the nasal and forehead regions of the dog, were analyzed. Total blood flow and perfusion pressure measurements in the IMA after administration of each adenyl compound indicated dose-dependent and active vasodilatory responses that were restricted to the ipsilateral vessels. The rank order of potency was ADP > or = ATP > AMP. In order to determine the microcirculatory effects caused by ADP, the tracer microsphere technique combined with absolute blood flow measurement was used. Intra-arterial infusion of ADP in the range 1-200 nmol/min produced elevations in the IMA flow on the stimulated side that ranged between 11 and 74%. The responses to low doses of ADP were mainly confined to the capillaries (CAP), whereas the arteriovenous anastomoses too were sensitive to high doses. The relative contributions of the anatomically and functionally different compartments of the forehead and nose to ADP-produced relaxations of the CAP were dependent upon their location. The CAP flows in the tissues which play a crucial role in conditioning the inspired air increased significantly, while the compartments of the furred surfaces were less sensitive to ADP. The results suggest that, since ATP, ADP and AMP are effective vasodilatory agents in all the regions examined, purines could have a regulatory or modulatory role in the complex vascular regulation of the nasal and forehead regions.

The pulmonary vascular and systemic effects of PGE1 were studied in a canine model of pulmonary hypertension. Systemic arterial, central venous and pulmonary arterial pressures were monitor

The ability of retrograde cardioplegia to protect the right ventricle has been questioned. Canine myocardial circulation was assessed by infusing colored microspheres through the coronary sinus. The relative flow index (RFI), a normalized measure of tissue blood flow, was determined for 76 sections of myocardium. Three distinct flow regions were evident from these measurements. A paucity of blood flow through some basal sections of the right ventricle (RFI = 0.23 +/- 0.19) was found to be significantly different (p0.005) from regions of the heart with normal flow (RFI = 1.12 +/- 0.06). Sections from the right ventricular apex demonstrated augmented flow (RFI = 3.72 +/- 1.18). These data indicate that retrograde coronary perfusion provides nonuniform flow and under some conditions may provide inadequate perfusion to portions of the right ventricle.

Autologous hepatocellular transplantation using reflux into the spleen via the venous tributaries was compared in 65% hepatectomized dogs to direct injection into the splenic pulp. Transplantation into the spleen via the inferior terminal polar splenic vein led to a better survival rate (50 vs. 0%). Hepatocytes embolization to the intrahepatic portal vein system was observed. Although hepatocyte transplantation into the spleen can be accomplished either by direct punction of the spleen or by retrograde injection into a splenic vein, the second method decreases the frequency of cell embolization.

To determine if late asthmatic response (LAR) is associated with hyperresponsiveness of airway smooth muscle itself, we performed antigen challenge in dogs treated with Metopirone. We studied the contractile response to acetylcholine (ACh) in isolated bronchial and bronchiolar segments 8 h after either saline inhalation (the control group) or antigen challenge in dogs demonstrating immediate asthmatic response (IAR) alone and in dogs demonstrating both IAR and LAR. Airway responses to Ascaris suum antigen were assessed by changes in respiratory resistance measured with the forced oscillation technique at 3 Hz. Concentration-response curves of bronchial preparations to ACh did not differ significantly among three groups consisting of the control, IAR and LAR. However, the contractile response of bronchiolar preparations to ACh was significantly greater in the LAR group when compared to the control and IAR groups at the concentrations of ACh ranging from 10(-6) to 3 x 10(-4) M (p0.01). SQ 29548, a receptor antagonist of thromboxane A2 and prostaglandin D2 (PGD2), inhibited LAR-induced hyperresponsiveness to ACh in a concentration-dependent fashion. The bronchiolar preparations obtained from dogs showing LAR contained a significantly higher amount of PGD2 than those obtained from dogs showing IAR alone (p0.01, n = 6). These results suggest that LAR is associated with hyperresponsiveness of peripheral airway smooth muscle to ACh, and this augmented response to ACh mediates via PGD2 released during LAR.

We have studied in old dogs the effects of short-term administration of growth hormone (GH)-releasing hormone (GHRH) alone or co-administered with clonidine (CLO), an alpha 2-adrenergic agonist, on the GH secretory pattern (cluster analysis), and GH responsiveness to an acute GHRH or GHRH + CLO challenge and plasma somatomedin C (SMC) levels. Dogs were given either GHRH alone twice daily for 10 days (treatment 1) or combined GHRH + CLO both given twice daily (treatment 2) or GHRH + CLO given once daily (treatment 3). Animals were sampled from 09.00 to 15.00 h, at 10-min intervals, both before and 14 h after treatments. At the end of the 6-hour sampling period, dogs were challenged with simultaneous administration of GHRH and CLO, while they were tested with GHRH alone on the morning of the following day. In dogs undergoing treatment 1, acute administration of GHRH or GHRH + CLO elicited mean GH peak responses higher than before treatment, but none of the GH secretory indices were modified during the 6-hour sampling period, except for the increase in mean GH peak amplitude. In dogs undergoing treatment 2, acute administration of GHRH elicited a mean GH peak response higher than that before treatment, whereas administration of GHRH + CLO induced a mean GH peak response not different from that elicited by GHRH + CLO before treatment or by GHRH alone after treatment. However, this treatment significantly augmented the frequency of spontaneous bursts of GH secretion, the mean GH peak amplitude and the total peak area.(ABSTRACT TRUNCATED AT 250 WORDS)

RWJ 22108 (N-benzyl-N-methylaminoethyl 9-(2-chloro-6-fluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1, 1-dioxothiacyclohepteno-[3,2-b]pyridine-8-carboxylate) is a new bronchoselective calcium entry blocker with potential use as an antiasthmatic agent. Previous studies have shown that RWJ 22108 is a potent calcium entry blocker in vitro and demonstrates tissue selectivity for airway smooth muscle over vascular smooth muscle. The current study demonstrates the in vivo activity of RWJ 22108 in several different models of airway obstruction and asthma. RWJ 22108 relaxes preconstricted airways in dogs with little effect on blood pressure when administered by aerosol. In addition, it inhibits airway obstruction induced by antigen, histamine and exogenous leukotriene D4 in guinea pigs. In a conscious sheep model of allergic asthma, aerosol RWJ 22108 inhibits antigen-induced early and late phase airway obstruction and also the cellular infiltration associated with late phase. Total leukotrienes production is decreased in the guinea pig model probably as a result of fewer inflammatory cells infiltrating the lungs as shown in the sheep model of late phase. These data suggest that RWJ 22108 may have pharmacological potential in the clinical management of asthma.