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Biomedical subjects

N D Smith

Publications and source records attributed to N D Smith.

At least 19 recordsLinked to original sources
PubMed2005

Hyperthyroidism impairs pancreatic beta cell adaptations to late pregnancy and maternal liporegulation in the rat.

AIMS/HYPOTHESIS: Hyperthyroidism modifies lipid dynamics (increased oxidation), impairs insulin action and can suppress insulin secretion. We therefore examined the impact of hyperthyroidism on the relationship between glucose-stimulated insulin secretion (GSIS) and insulin action, using late pregnancy as a model of physiological insulin resistance that is associated with compensatory insulin hypersecretion to maintain glucose tolerance. Our aim was to examine whether hyperthyroidism compromises the regulation of insulin secretion and the ability of insulin to modulate circulating lipid concentrations in late pregnancy. MATERIALS AND METHODS: Hyperthyroidism was induced by tri-iodothyronine (T(3)) administration from day 17 to 19 of pregnancy. GSIS was assessed during an IVGTT and during hyperglycaemic clamps in vivo and in vitro, using step-up and -down islet perifusions. RESULTS: Hyperthyroidism in pregnancy elevated the glucose threshold for GSIS and impaired GSIS at low and high glucose concentrations in islet perifusions. In the intact animal, insulin secretion (after bolus glucose) was more rapidly curtailed following removal of the glucose stimulus to secretion. In contrast, GSIS was maintained during protracted hyperglycaemia (hyperglycaemic clamps) in the hyperthyroid pregnant state in vivo. CONCLUSIONS/INTERPRETATION: Hyperthyroidism in vivo during late pregnancy blunts GSIS in subsequently isolated and perifused islets at low and high glucose concentrations. It also adversely affects GSIS under conditions of an acute glucose challenge in vivo. In contrast, GSIS is maintained during sustained hyperglycaemia in vivo, suggesting that in vivo factors can rescue GSIS. The ability of insulin to suppress systemic lipid levels during hyperglycaemic clamps was impaired. We therefore suggest that higher circulating lipids may preserve GSIS under conditions of sustained hyperglycaemia in the hyperthyroid pregnancy.

Adaptation, Physiological↗
PubMed2005

Interactive influences of peroxisome proliferator-activated receptor alpha activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat.

AIMS/HYPOTHESIS: We sought to elucidate whether excess glucocorticoids and increased dietary lipids act synergistically to impair glucose tolerance and, if so, whether activation of peroxisome proliferator-activated receptor alpha (PPARalpha) has an adverse or beneficial effect on glucose tolerance. METHODS: Dexamethasone (100 microg kg(-1) body weight day(-1); 5 days) was administered to insulin-resistant rats fed a high-saturated-fat (HF) diet for 4 weeks. The PPARalpha agonist WY14643 was administered (50 mg kg(-1) body weight intraperitoneally) 24 h before sampling. Glucose-stimulated insulin secretion (GSIS) was assessed in vivo after an acute glucose bolus injection, and in vitro using step-up and step-down islet perifusions. RESULTS: Although neither PPARalpha activation nor dexamethasone alone affected fasting glycaemia in the HF group, dexamethasone in combination with PPARalpha activation elicited marked postabsorptive hyperglycaemia. Dexamethasone treatment of HF rats had little effect on GSIS after an acute glucose challenge in vivo, but induced glucose intolerance. PPARalpha activation augmented GSIS in dexamethasone-treated HF rats in vivo, restoring glucose tolerance. Contrasting with data obtained in vivo, greatly enhanced peak rates of GSIS were observed ex vivo in perifusions of islets from dexamethasone-treated HF rats compared with those from untreated HF rats, an effect attenuated by antecedent PPARalpha activation. CONCLUSIONS/INTERPRETATION: The study demonstrates that glucocorticoid excess precipitates the development of glucose intolerance in rats maintained on a high-saturated-fat diet. It does this by interrupting the negative feedback loop between insulin sensitivity and secretion in vivo, such that further enhancement of compensatory insulin secretion is not possible. PPARalpha activation restores the coupling between insulin secretion and action.

Animals↗
PubMed2004

Renal tumors in young adults.

PURPOSE: The clinical and pathological features of solid or complex cystic renal masses in young adults have not been defined. We present our experience with patients 17 to 45 years old with such renal masses to define the incidence of malignant vs benign lesions, familial tendencies and clinical outcomes. MATERIALS AND METHODS: The medical records of all patients 17 to 45 years old who presented with a solid or suspicious complex cystic renal mass at 2 tertiary care hospitals between 1988 and 2002 were retrospectively reviewed. Pertinent clinical information was compiled, including age, gender, mode of presentation, renal function, year and type of surgery, pathological analysis and survival data. RESULTS: There were 114 evaluable patients who underwent a total of 119 nephrectomies. Mean patient age was 37.1 years and males comprised 56.1% of the population. Twelve patients had familial renal cell carcinoma (RCC), the von Hippel-Lindau syndrome. Mode of presentation for patients with sporadic disease was symptomatic (55.9%), incidental (35.3%) or unknown (8.8%). Radical nephrectomy, partial nephrectomy and nephroureterectomy were performed in 80 kidneys (67.2%), 37 (31.1%) and 2 (1.7%), respectively. Malignant lesions comprised 79.8% of all masses and 95.8% of these were renal cell carcinoma. Of the RCCs 75.8% were grade 1 or 2 and 89% were organ confined. Young women were much more likely than men to have a benign lesion (36.0% vs 9.5%, p <0.01) and the diversity of histologies was impressive (of the 24 total benign masses 9 were different tumor types). With an average followup of 38.3 months overall survival is 90.2%. Among patients with RCC 84.9% are alive and cancer-free, 11.6% are dead from disease and 3.5% are alive with recurrent disease. CONCLUSIONS: We report the largest known series of solid or suspicious complex renal masses in young adults. As expected, familial tumors are more common in this population. While RCC is the most common tumor, a wide variety of potential pathological outcomes are possible, particularly in women, who were much more likely to have a benign lesion. RCC in this patient population appears to have a favorable prognosis, despite symptomatic presentation in the majority of cases.

Adolescent↗
PubMed2003

Acute (24 h) activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) reverses high-fat feeding-induced insulin hypersecretion in vivo and in perifused pancreatic islets.

Abnormal depletion or accumulation of islet lipid may be important for the development of pancreatic beta cell failure. Long-term lipid sensing by beta cells may be co-ordinated via peroxisome proliferator-activated receptors (PPARs). We investigated whether PPARalpha activation in vivo for 24 h affects basal and glucose-stimulated insulin secretion in vivo after intravenous glucose administration and ex vivo in isolated perifused islets. Insulin secretion after intravenous glucose challenge was greatly increased by high-fat feeding (4 weeks) but glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-fat feeding to enhance glucose-stimulated insulin secretion was retained in perifused islets demonstrating a stable, long-term effect of high-fat feeding to potentiate islet glucose stimulus-secretion coupling. Treatment of high-fat-fed rats with WY14,643 for 24 h reversed insulin hypersecretion in vivo without impairing glucose tolerance, suggesting improved insulin action, and ex vivo in perfused islets. PPARalpha activation only affected hypersecretion of insulin since glucose-stimulated insulin secretion was unaffected by WY14,643 treatment in vivo in control rats or in perifused islets from control rats. Our data demonstrate that activation of PPARalpha for 24 h can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function. PPARalpha could, therefore, participate in ameliorating abnormal glucose homeostasis and hyperinsulinaemia in dietary insulin resistance via modulation of islet function, extending the established requirement for PPARalpha for normal islet lipid homeostasis.

Animals↗
PubMed2001

Excessive glucocorticoid exposure during late intrauterine development modulates the expression of cardiac uncoupling proteins in adult hypertensive male offspring.

We investigated the impact of intrauterine growth retardation and fetal programming of hypertension by maternal dexamethasone treatment on cardiac uncoupling protein (UCP) expression during development and in adulthood in the rat. Dexamethasone administered via an indwelling osmotic pump (100 micrograms/kg body mass per day from day 15 of gestation) decreased fetal body mass at day 21 of gestation (by 13%; P < 0.05), elicited significant (+24%, P < 0.01) systolic hypertension and elevated corticosterone levels (+15%; P < 0.05) in adult (24-week-old) male offspring. Cardiac UCP-2 and UCP-3 protein expression was significantly upregulated during early postnatal development, reaching 1.7-fold and 2.7-fold the respective fetal day-21 levels by postnatal day 7 and reaching plateaus at postnatal days 15-21 (2.5-fold and 3.5-fold of respective fetal levels). Cardiac UCP protein expression at fetal day 21 and the ontogeny of cardiac UCP expression during early postnatal life were unaffected by prenatal dexamethasone treatment. Prenatal dexamethasone treatment did not abrogate the postnatal surge in corticosterone levels or modify plasma non-esterified fatty acid (NEFA) levels over this period. However, UCP-2 and UCP-3 protein expression was significantly downregulated in the hearts of adult hypertensive male offspring of dexamethasone-treated mothers (to 27% and 65% of control values respectively). We propose that changes in cardiac UCP protein expression are linked with changes in cardiac metabolic fuel selection (from glucose-->fatty acids at birth and from fatty acids-->glucose during hypertension).

Animals↗
PubMed2001

The role of hypoxia and p53 in the regulation of angiogenesis in bladder cancer.

PURPOSE: Our previous studies defined thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF) as the primary mediators of angiogenesis in the bladder and the loss of inhibitory TSP-1 as a key event in the transition to an angiogenic phenotype during bladder cancer development. We evaluated the role of p53, which is commonly inactivated in bladder cancer, and hypoxia in the regulation of angiogenesis in the bladder. MATERIALS AND METHODS: The p53 status was modulated in normal urothelial and bladder cancer cells, and conditioned media was collected under normal oxygen or hypoxic (0.5% O2) conditions. Angiogenic activity was evaluated with the endothelial cell migration assay, and the levels of secreted TSP-1 and VEGF were determined by Western blot analysis and enzyme-linked immunosorbent assay, respectively. RESULTS: Retroviral mediated expression of the E6 oncoprotein reduced wild-type p53 levels in normal urothelial cells by greater than 90% but did not significantly alter TSP-1 or VEGF levels, while total inductive and inhibitory activities remained unchanged. Adenoviral mediated expression of wild-type p53 was confirmed in 4 bladder cancer cell lines by Western blot analysis for p53 and its downstream effector protein p21 (2.5 to 5.0-fold increase). TSP-1 levels remained unchanged but the levels of secreted VEGF in the high grade UMUC-3 and 253J cell lines were significantly decreased 5 to 50-fold and a corresponding decrease in net angiogenic activity was observed. However, (increased expression) of p53 had no effect on the angiogenic activity of the low grade RT4 or high grade HT1376 bladder cancer cells. Hypoxia converted normal urothelial cell derived conditioned media from anti-angiogenic to angiogenic and increased the angiogenic activity of bladder cancer cell derived conditioned media. This change was due to 2.5 to 6-fold hypoxic up-regulation of VEGF because the expression of inhibitory TSP-1 was not significantly altered. CONCLUSIONS: Our results suggest that p53 does not regulate angiogenesis in the bladder in the setting of an otherwise normal genome and gene therapy with wild-type p53, which is currently being studied for this cancer, may have only limited effects on angiogenesis. In contrast, hypoxia regulates angiogenesis in this system, primarily through its effects on VEGF.

Blotting, Western↗
PubMed2000

The efficacy and safety of synchronous bilateral extracorporeal shock wave lithotripsy.

PURPOSE: Bilateral renal calculi have traditionally been managed by staged extracorporeal shock wave lithotripsy (ESWLdagger) due to concern about bilateral obstruction. We evaluated the safety and efficacy of synchronous bilateral ESWL in a large series of patients treated at our institution to determine the safety and efficacy of this controversial technique in what is to our knowledge the largest series to date. MATERIALS AND METHODS: We retrospectively evaluated the records of 120 patients with a mean age of 48 years who underwent bilateral synchronous ESWL between 1987 and 1996. Of the patients 71 (59%) were male. Average followup was 21 months. ESWL was performed using a Dornier HM3 lithotriptor in all cases. Intraoperative technique and postoperative factors were analyzed using the Pearson product moment correlation, the 2-tailed t test and multiple regression analysis. RESULTS: Mean stone size was 13 and 15 mm. on the left and right sides, respectively. There was an average of 1.7 stones per renal unit. After 1 treatment 72 of the 120 patients (60%) were stone-free bilaterally, while 72% and 73% of left and right renal units, respectively, were also stone-free. Mean creatinine was similar preoperatively and postoperatively (1.46 and 1.41 mg./dl., respectively, p = 0.73). There was 1 or more complications in 18 cases. The majority of complications were minor with no long-term morbidity or death and there was no case of bilateral obstruction or renal failure. Additional procedures were required in 19 patients (16%) due to significant residual stone disease or obstruction during followup. Multiple regression analysis revealed that only patient age, a right ureteral stent and the number of shocks correlated with the complication rate. Stone size and number independently increased the probability of treatment failure and a repeat procedure (p <0.05). Patients with stones 20 mm. or greater were at particularly high risk for treatment failure and additional procedures. A total of 27 of the 35 patients (77%) with residual calculi and 13 of the 19 (68%) requiring additional procedures were in this high risk subgroup. CONCLUSIONS: Bilateral synchronous ESWL is safe and effective monotherapy for bilateral urolithiasis. No patient had bilateral obstruction or renal failure and no deterioration of renal function was detected at followup. Knowing which patient populations are at higher risk for failure or complications may guide decision making.

Adult↗
PubMed1999

Combined osteolathyric effects of beta-aminopropionitrile and penicillamine on Xenopus embryos: statistical comparison with dose-addition and independence.

The combined osteolathyric effects of beta-aminopropionitrile (beta APN) and penicillamine (PNC) on developing Xenopus embryos were determined and compared with theoretical effects for the dose-addition and independence models. The testing protocol utilized a 1.2-factor matrix design that generated two single chemical and seven mixture concentration-response curves within 36 treatments. Testing was for 96-h with daily solution removal and replacement. The chi 2 goodness-of-fit test was used to compare experimental responses with theoretical responses. Response curve analyses indicated, in general, a combined effect between that expected for dose-addition and that for independence, which is a combined effect typical of chemicals acting dissimilarly.

Aminopropionitrile↗
PubMed1998

Total protein and acid phosphatase concentrations in prostatic fluid from patients with BPH compared to carcinoma.

OBJECTIVE: To obtain evidence of metabolic changes in the human prostate associated with prostate pathology, in particular carcinoma of the prostate, by identifying and evaluating associated changes in prostatic secretory products. METHODS: Expressed prostatic fluid (EPF) from 36 patients with carcinoma, 128 with BPH histologically confirmed, and 148 with clinical BPH was subjected to determination of protein (Lowry; UV 280 nm absorption), enzymatic (DMA modified Row procedure) acid phosphatase (AcP), and immunologically identified (Tandem-PAP immunoenzymatic assay) prostatic acid phosphatase (PAP) concentration. RESULTS: The important EPF findings are the following: (1) Protein concentrations (Lowry and UV determinations) are significantly increased in carcinoma as compared to histologic BPH, (2) AcP and PAP secretions remain stable in carcinoma versus BPH, and (3) AcP and PAP/Lowry protein ratios are significantly lower with carcinoma. CONCLUSIONS: These findings of increased protein and the decreased relative secretions of AcP and PAP to total protein (ratio) in EPF from patients with carcinoma compared to BPH support and help to characterize the diffuse metabolic alteration in the prostate associated with prostate carcinoma. EPF observations identify potential metabolic changes occurring in prostate carcinoma that may have potential clinical and investigative relevance.

Acid Phosphatase↗
PubMed1997

Transcatheter embolization of a ruptured superior gluteal artery aneurysm: case report and review of the literature.

PURPOSE: To report the successful coil embolization of a true gluteal artery aneurysm and review therapeutic options for this rare condition. METHODS AND RESULTS: A ruptured superior gluteal artery aneurysm in a symptomatic 80-year-old man was successfully thrombosed by embolization using a combination of Gianturco coils and helical platinum microcoils. Six-month computed tomography demonstrated persistent thrombosis of the aneurysm and resolution of the perivascular blood. CONCLUSIONS: This report offers support for the use of catheter-based techniques as an alternative to standard surgical repair of gluteal artery aneurysms.

Aged↗
PubMed1997

Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate.

PURPOSE: We sought to determine the efficacy of radical retropubic prostatectomy in men with high grade adenocarcinoma of the prostate in a population that had not been screened for prostate specific antigen (PSA). MATERIALS AND METHODS: An inception cohort of 116 men surgically treated for prostate cancer between 1980 and 1991 was created in April 1992 and prospectively followed thereafter. Median followup was 7 years (range 2.2 to 14.6). RESULTS: The major cause of death in this group of men was prostate cancer, not competing causes. Ten-year disease specific survival was 96% for organ confined (stage pT2c or less) and 78% for unconfined (stage pT3a or greater) disease. Five and 10-year PSA progression-free survival by pathological stage was 83 and 53% for organ confined disease, and 34 and 22% for unconfined disease with negative pelvic lymph node dissection (p = 0.001). Five and 10-year metastasis-free survival was 96% for organ confined disease, and 81 and 62% for unconfined disease (p = 0.011). Men with pelvic lymph node metastasis had 70 and 30% 5 and 10-year metastasis-free survival, and 75 and 55% disease specific survival, respectively. PSA progression-free survival was 33% at 5 years. A significantly decreased risk of PSA progression was observed in men with unconfined carcinoma who received adjuvant external beam radiotherapy. CONCLUSIONS: In men with high grade prostate cancer the major cause of death was prostate cancer, not competing causes. Pathologically confined carcinoma had a significantly decreased rate of metastatic progression. These observations support the bias that early detection in these men at high risk for cause specific death may favorably impact survival.

Actuarial Analysis↗
PubMed1995

Prostate specific antigen in the expressed prostatic fluid of men with benign prostatic hyperplasia and prostate carcinoma.

PURPOSE: We tested the hypothesis that the histochemically demonstrated prostate specific antigen (PSA) content of prostate carcinoma cells does not necessarily reflect PSA production and secretion by evaluating expressed prostatic fluid. MATERIALS AND METHODS: Expressed prostatic fluid and serum from 152 men with clinical benign prostatic hypertrophy (BPH), 132 with histologically proved BPH and 46 with prostate carcinoma were analyzed with the Hybritech PSA assay. RESULTS: Expressed prostatic fluid PSA levels from carcinoma patients (median 1.70 mg./ml., mean 2.25) were significantly higher than in the histologically proved BPH group (median 1.28 mg./ml., mean 1.42, p < 0.05). CONCLUSIONS: PSA concentration is increased in the expressed prostatic fluid of prostates of men with carcinoma compared to those with histological BPH. This finding may be a functional manifestation of a field change or paracrine effects within the prostate.

Aged↗
PubMed1989

Protein kinase C agonists inhibit bile secretion independently of effects on the microcirculation in the isolated perfused rat liver.

The role of hormones in the regulation of bile secretion is not known; however vasoactive agents, which act via the phosphoinositide signal transduction pathway, may mediate changes in bile flow by altering the hepatic microvasculature. We therefore examined the effects of phorbol esters and diacylglycerol, agonists of the protein kinase C branch of the phosphoinositide cascade, on perfusion pressure and bile flow in a single-pass, hemoglobin-free, isolated perfused rat liver system with constant perfusate flow. The active phorbol ester, 12,13-phorbol dibutyrate, produced a dose-dependent (maximal effect at 10(-6) M), sustained and reversible decrease in bile flow from 1.09 +/- 0.18 to 0.61 +/- 0.09 microliters per min per gm liver (37.2 +/- 5.9%) while simultaneously increasing perfusion pressure from 12.3 +/- 0.7 to 21.5 +/- 2.5 cm H2O (74.0 +/- 4.3%). Both effects were inhibited by the synthetic protein kinase C antagonist H-7. 1,2-Dioctanoyl-sn-glycerol, a diacylglycerol, produced changes in bile flow and perfusion pressure that were similar to, but more marked than, those caused by 12,13-phorbol dibutyrate, whereas the inactive phorbol ester 4 alpha-phorbol didecanoate and the vehicle dimethyl sulfoxide had no effects on either parameter. 12,13-Phorbol dibutyrate infusion resulted in reversible decreases in oxygen consumption (23.3%) and a reversible vascular redistribution of trypan blue dye but did not alter hepatic venous effluent concentrations of K+.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Bicarbonate-dependent and -independent intracellular pH regulatory mechanisms in rat hepatocytes. Evidence for Na+-HCO3- cotransport.

Using the pH-sensitive dye 2,7-bis(carboxyethyl)-5(6)-carboxy-fluorescein and a continuously perfused subconfluent hepatocyte monolayer cell culture system, we studied rat hepatocyte intracellular pH (pHi) regulation in the presence (+HCO3-) and absence (-HCO3-) of bicarbonate. Baseline pHi was higher (7.28 +/- 09) in +HCO3- than in -HCO3- (7.16 +/- 0.14). Blocking Na+/H+ exchange with amiloride had no effect on pHi in +HCO3- but caused reversible 0.1-0.2-U acidification in -HCO3- or in +HCO3- after preincubation in the anion transport inhibitor 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS). Acute Na+ replacement in +HCO3- alos caused acidification which was amiloride independent but DIDS inhibitible. The recovery of pHi from an intracellular acid load (maximum H+ efflux rate) was 50% higher in +HCO3- than in -HCO3-. Amiloride inhibited H+ effluxmax by 75% in -HCO3- but by only 27% in +HCO3-. The amiloride-independent pHi recovery in +HCO3- was inhibited 50-63% by DIDS and 79% by Na+ replacement but was unaffected by depletion of intracellular Cl-, suggesting that Cl-/HCO3- exchange is not involved. Depolarization of hepatocytes (raising external K+ from 5 to 25 mM) caused reversible 0.05-0.1-U alkalinization, which, however, was neither Na+ nor HCO3- dependent, nor DIDS inhibitible, findings consistent with electroneutral HCO3- transport. We conclude that Na+-HCO3- cotransport, in addition to Na+/H+ exchange, is an important regulator of pHi in rat hepatocytes.

Amiloride↗
PubMed1985

Monitoring urinary bladder temperature.

We evaluated bladder, rectal, and esophageal temperatures compared with nasopharyngeal temperatures in 12 patients who underwent cardiac surgery that required CPB. Changes in bladder temperature lagged behind those of esophageal and nasopharyngeal temperature during rapid cooling and rewarming. Changes in rectal temperature were the slowest. Bladder and rectal temperatures were similar after surgery. Monitoring bladder temperature represents the core temperature in a steady state.

Adult↗
PubMed1984

Directional variability in the R wave response during serial exercise testing in patients with coronary artery disease.

The reproducibility of the direction of R wave amplitude response to exercise was analyzed in patients with coronary artery disease. Forty-three serial exercise tests were performed by 10 patients with exertional angina pectoris and documented coronary artery disease (CAD). Seventeen tests (37%) resulted in no change or an increase in R wave amplitude (abnormal response). Twenty-six tests (63%) resulted in a decrease in R wave amplitude. The direction of the R wave amplitude response was variable in at least one exercise test in 7 of 10 patients with CAD, all of whom had reproducible ischemic ST segment responses during serial testing. The inconsistent R wave response in these patients was unrelated to heart rate, workload, or duration of exercise. Because of the variability in the directional R wave response during serial exercise testing in CAD patients, we conclude that the R wave response during exercise is unreliable for the detection of CAD or ischemia-related myocardial dysfunction.

Adult↗
PubMed1984

Pneumococcal-induced pulmonary leukostasis and hemodynamic changes: role of complement and granulocytes.

In the present study we investigated the cardiopulmonary dysfunction caused by systemic pneumococcal (PNC) disease. We studied the hemodynamic and hematologic effects of intravascular challenge with nonviable PNC in normal, granulocyte-depleted, and genetically C3-deficient dogs. In normal dogs PNC administration caused a decrease in cardiac output (CO) of 58% (p less than 0.001), an increase in pulmonary vascular resistance (PVR) of 151% (p less than 0.02), and an increase in systemic vascular resistance (SVR) of 72% (p less than 0.02). The PNC challenge also caused significant decreases in both circulating granulocytes (-73%; p less than 0.02) and platelets (-58%; p less than 0.02). Histologic examination revealed granulocyte plugging within small pulmonary vessels. PNC challenge in granulocyte-depleted and C3-deficient dogs resulted in hemodynamic and hematologic changes that were not significantly different from those seen in normal PNC-challenged animals. Infusion of PNC-activated plasma resulted in hematologic changes that were not significantly different from those seen in PNC-challenged animals. Infusion of plasma treated with ethylenediamenetetraacetic acid (EDTA) prior to PNC incubation induced the same hematologic alterations but the hemodynamic response was less pronounced. To control for PNC constituents not removed by centrifugation and filtration, saline was incubated with PNC. After the PNC was removed, infusion of the saline induced no significant hemodynamic changes, although profound granulocytopenia occurred. We conclude that an intact complement system, but not normal numbers of circulating granulocytes, is essential to PNC-induced hemodynamic changes. PNC generates a plasma factor in vitro that does not require an intact complement system or cellular machinery to induce granulocytopenia without hemodynamic effect.

Animals↗