Can gastric intramucosal pH measurement be useful in pediatric critical illness?
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Carbon Dioxide↗
Biomedical subjects
J A Carcillo
Publications and source records attributed to J A Carcillo.
Effect of the type IV phosphodiesterase inhibitor Ro 20-1724 on catecholamine-induced alterations in regional vascular resistance and regional blood flow.
Type IV phosphodiesterase inhibitors have been studied in multiple disease processes that commonly afflict patients who are treated with catecholamine infusions. To examine whether type IV phosphodiesterases alter catecholamine-induced changes in systemic and regional hemodynamic parameters, we examined the effects of Ro 20-1724 on rats during dobutamine, epinephrine, isoproterenol, and norepinephrine infusions. Twenty-six Sprague-Dawley rats received either Ro 20-1724 or vehicle. After central and regional hemodynamic monitoring was initiated, animals received increasing doses of two of the four catecholamines. In the absence of catecholamines, Ro 20-1724 infusion caused a significant increase in heart rate and a trend toward an increase in superior mesenteric artery blood flow. Ro 20-1724 attenuated the increase in blood pressure caused by epinephrine but had no effect on the dobutamine-, isoproterenol-, or norepinephrine-induced changes in blood pressure. Ro 20-1724 had no effect on catecholamine-induced changes in renal, carotid, and hindquarter vascular resistance but did attenuate the decrease in superior mesenteric artery vascular resistance caused by isoproterenol. Type IV phosphodiesterase inhibition in combination with catecholamines has no adverse effects on regional hemodynamics; however, it can inhibit the ability of epinephrine infusion to increase blood pressure.
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
Effects of type IV phosphodiesterase inhibition on cardiac function in the presence and absence of catecholamines.
Type IV phosphodiesterase (PDE4) inhibitors may be useful in several diseases in which catecholamine infusions are commonly used, including asthma, sepsis, and multiple organ failure. To determine whether type IV phosphodiesterase inhibitors alter baseline or catecholamine-induced changes in cardiac function or both, we examined the effects of Ro 20-1724 (PDE4 inhibitor) on several cardiac-performance parameters in the absence and presence of norepinephrine, epinephrine, isoproterenol, and dobutamine infusions (3, 1, 0.1, and 3 microg/kg/min, respectively). Male Sprague-Dawley rats received either Ro 20-1724 (10 microg/kg/min; n = 7) or vehicle (n = 6). After a left ventricular catheter was placed and connected to a heart-performance analyzer, each animal received each of the four catecholamines in randomized order (10 min per catecholamine with a 30-min washout period between infusions). In the absence of catecholamines, Ro 20-1724 significantly but mildly (i.e., <10%) increased heart rate but did not alter significantly any other measured cardiac parameter. In addition, Ro 20-1724 did not significantly alter norepinephrine-, epinephrine-, or dobutamine-induced changes in cardiac-performance parameters. There was, however, a significant attenuation of the isoproterenol-induced increase in a single measure of cardiac contractility (maximum dP/dt normalized to pressure). PDE4 inhibition does not cause significant cardiac toxicities in rats, both in the absence and presence of catecholamines. Our data suggest that PDE4 inhibitors may be safely used in critically ill patients receiving catecholamines. A clinical trial of this family of drugs in patients with critical illness is now being planned.
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
The compensatory anti-inflammatory cytokine interleukin 10 response in pediatric sepsis-induced multiple organ failure.
STUDY OBJECTIVES: To determine the circulating anti-inflammatory cytokine interleukin 10 (IL-10) response during the development of sepsis-induced multiple organ failure in children. DESIGN: Prospective study. SETTING: University pediatric ICU. PATIENTS: Fifty-three consecutive children with sepsis and 15 critically ill children without sepsis. INTERVENTIONS: Plasma IL-10, interleukin 6 (IL-6), and nitrite+nitrate (stable end products of nitric oxide) levels and an organ failure index (OFI indicating the number of failing organ systems) were determined in 53 children on days 1 to 3 of sepsis and in control children on day 1. The effect of exogenous human IL-10 or neutralizing IL-10 antibody on supernatant IL-6 levels in ex vivo whole blood culture from 17 children on day 1 of sepsis. MEASUREMENTS AND RESULTS: Children with three or more organ failures had higher plasma IL-10 levels than children with less than 3 organ failures (days 1 and 3; p<0.05). Children who developed sequential pulmonary/hepatic/renal failure had higher IL-10 levels (days 1 to 3; p<0.05). Nonsurvivors had higher IL-10 levels (day 3; p<0.05). IL-10 levels correlated with IL-6 levels (days 1 and 2) and nitrite+nitrate levels (days 1 and 3; p<0.05). Whole blood samples incubated ex vivo with exogenous recombinant human IL-10 had decreased supernatant IL-6 levels (p<0.05) and neutralizing IL-10 antibody showed no significant effect. CONCLUSION: A persistent compensatory anti-inflammatory cytokine response characterizes sepsis-induced multiple organ failure. Administration of exogenous IL-10 may inhibit the early proinflammatory response; however, identification of individual immune responsiveness and possibility of persistent infection could be important to rational use in the later stages of pediatric sepsis.
Adolescent↗
Hemodynamic support in fluid-refractory pediatric septic shock.
OBJECTIVE: Assess outcome in children treated with inotrope, vasopressor, and/or vasodilator therapy for reversal of fluid-refractory and persistent septic shock. DESIGN: Survey; case series. SETTING: Three pediatric hospitals. PATIENTS: Fifty consecutive patients with fluid-refractory septic shock with a pulmonary artery catheter within 6 hours of resuscitation. INTERVENTIONS: Patients were categorized according to hemodynamic state and use of inotrope, vasopressor, and/or vasodilator therapy to maintain cardiac index (CI) >3.3 L/min/m2 and systemic vascular resistance >800 dyne-sec/cm/m to reverse shock. OUTCOME MEASURES: Hemodynamic state, response to class of cardiovascular therapy, and mortality. RESULTS: After fluid resuscitation, 58% of the children had a low CI and responded to inotropic therapy with or without a vasodilator (group I), 20% had a high CI and low systemic vascular resistance and responded to vasopressor therapy alone (group II), and 22% had both vascular and cardiac dysfunction and responded to combined vasopressor and inotropic therapy (group III). Shock persisted in 36% of the children. Of the children in group I, 50% needed the addition of a vasodilator, and in group II, 50% of children needed the addition of an inotrope for evolving myocardial dysfunction. Four children showed a complete change in hemodynamic state and responded to a switch from inotrope to vasopressor therapy or vice versa. The overall 28-day survival rate was 80% (group I, 72%; group II, 90%; group III, 91%). CONCLUSIONS: Unlike adults, children with fluid-refractory shock are frequently hypodynamic and respond to inotrope and vasodilator therapy. Because hemodynamic states are heterogeneous and change with time, an incorrect cardiovascular therapeutic regimen should be suspected in any child with persistent shock. Outcome can be improved compared with historical literature.
Adolescent↗
Hypovolemic shock in pediatric patients.
Hypovolemic shock is a common disease treated in pediatric ICUs and emergency departments worldwide. A wide variety of etiologic factors may cause this disease, with the common net result of decreased intravascular volume leading to decreased venous return to the heart and decreased stroke volume. Inadequate perfusion results in impairment of delivery of nutrients and oxygen to vital end organs. With the advent of pediatric critical care and pediatric emergency medicine as specialties, deaths from hypovolemic shock have become increasingly rare in the United States. The physical signs of hypovolemic shock in children must be quickly recognized, and aggressive volume resuscitation must be administered before irreversible end-organ dysfunction occurs. This is best accomplished by large peripheral or central intravenous access, with intraosseous access an alternative option in the pediatric patient. The amount as well as the type of volume administered must be tailored for each individual patient, taking into account the amount of intravascular depletion and the disease state in which the shock has occurred. It is not uncommon for children to require large amounts of fluid for resuscitation, and close attention must be paid to children with fluid-refractory shock, who may require catecholamine and/or exogenous steroid support in combination with aggressive fluid resuscitation.
Adolescent↗
The cytochrome P450 suicide inhibitor, 1-aminobenzotriazole, sensitizes rats to zymosan-induced toxicity.
Reduction in whole body cytochrome P450 (CYP 450) activity is evident in humans who develop trauma and sepsis-induced multiple organ failure (MOF). It is not known whether this has any deleterious or protective effect. Intraperitoneal injection of zymosan, the cell wall of Saccharomycoses A, induces dose-dependent inflammation with concomitant MOF in rats. High dose intraperitoneal zymosan (100 mg/100 g body weight) causes mortality and organomegaly in rats; low dose zymosan (20 mg/100 g body weight) does not. To study a role for CYP 450 in zymosan-induced toxicity, we examined the effect of the non-specific CYP 450 suicide inhibitor 1-aminobenzotriazole (1-ABT)(80 mg/kg/d), on rats treated with low dose zymosan. The 90% reduction in CYP 450 content achieved by this dose of 1-ABT was associated with 58% mortality in rats treated with low dose zymosan, in contrast to no mortality in rats treated with low dose zymosan alone (p < 0.01). In survivors, liver and lung organomegaly (p < 0.01), and polymorphonuclear leukocyte accumulation in the liver (p < 0.01) were increased after zymosan administration in rats treated with 1-ABT compared to those without 1-ABT. There was no effect of treatment with 1-ABT on the increased urinary excretion of nitric oxide byproducts observed after zymosan administration. These observations are consistent with the hypothesis that the CYP 450 enzyme system is an endogenous protectant in this experimental model of inflammation-induced MOF.
Animals↗
Comparison of the interleukin-6 and interleukin-10 response in children after severe traumatic brain injury or septic shock.
Inflammation may play an important role in the evolution of damage after traumatic brain injury (TBI). IL-6 and IL-10 are markers of inflammation that are pro- and anti-inflammatory in nature, respectively. They have been used as an index of the degree of inflammation in diseases including sepsis and meningitis. We hypothesized that both IL-6 and IL-10 would be increased in the cerebrospinal fluid (CSF) of children after TBI. We measured ventricular CSF concentrations of these metabolites (ELISA) each of the first 3 days after TBI in 15 children. CSF IL-6 was increased on day 1 (p < 0.05 vs days 2 or 3). CSF IL-10 was similarly increased on day 1 (p < 0.05). CSF IL-6 after TBI is similar to serum IL-6 levels previously reported in children with septic shock. In contrast, the CSF IL-10 response was markedly attenuated following TBI compared to sepsis. These data suggest a unique balance between pro- and anti-inflammatory cytokines in brain after TBI.
Brain Injuries↗
The role of adenosine during the period of delayed cerebral swelling after severe traumatic brain injury in humans.
Cerebrovascular failure with an increase in cerebral blood volume or hyperemia contributes delayed cerebral swelling after severe traumatic brain injury (TBI) in humans. One mediator that could be involved in this process is adenosine, which stimulates a concurrent reduction in cerebral metabolic rate and an increase in cerebral blood flow (CBF). We hypothesized that during the delayed phase after TBI in humans: 1) CSF adenosine concentration is associated with uncoupling of CBF and CMRO2, and 2) adenosine formation is driven by mediator-stimulated cAMP production in injured brain. We serially measured CBF and AVDO2, and CSF adenosine, lactate and cAMP after severe TBI in 13 humans. After 6-18 h, global CBF was increased and AVDO2 was reduced vs all other time periods, defining the uncoupling phase as the period between 18 h and 5 days. CSF adenosine concentration was negatively associated with AVDO2 and strongly associated with death (both p < 0.05), CSF lactate peaked during the initial 18 h, but remained increased for 5 days. CSF cAMP concentration was not increased (vs normal). The association between CSF adenosine concentration and death, and the correlation between uncoupling of CBF and oxidative metabolism and CSF adenosine concentration support our first hypothesis. In contrast, the low levels of cAMP in CSF observed in these patients, but persistently increased CSF lactate, refute our second hypothesis. We speculate that hyperglycolysis or occult ischemic foci are possible sources of ATP breakdown and adenosine formation, and that adenosine is playing a neuroprotective role.
Adenosine↗
Septic shock.
Although our understanding of molecular events in septic shock is growing exponentially, bedside management has changed only incrementally over the last 20 years. In pediatric and adult patients alike, treatment continues to be largely supportive. Morbidity and mortality, though gradually improving, continue to be high. The major similarities, as well as the minor differences, between pediatric and adult septic shock are reviewed in this article, with an emphasis on current clinical practice and recent clinical investigations of novel therapies.
Adult↗
Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children.
Cytokines may play an important role in the pathophysiology of traumatic brain injury (TBI) in children. Interleukin-6 (IL-6) is a proinflammatory cyotkine that plays a role in regenerative processes within the central nervous system (CNS), whereas interleukin-10 (IL-10) is an antiinflammatory cytokine. Both have been measured in serum and cerebrospinal fluid (CSF) as an index of the degree of inflammation in diseases, including sepsis and meningitis. We hypothesized that both IL-6 and IL-10 would be increased in the CSF of children after severe TBI. Fifteen children who sustained severe TBI (Glascow Coma Score [GCS] < or = 7) were studied. Standard neurointensive care was provided. Ventricular CSF collected the first 3 days after TBI was analyzed for IL-6 and IL-10 concentrations by ELISA. Controls were 20 children who were evaluated for meningitis with diagnostic lumbar puncture subsequently found to have no CSF pleocytosis and negative cultures. IL-6 was increased in children after TBI versus controls on all days studied (day 1, 3158.2 +/- 621.8 pg/ml; day 2, 1111.6 +/- 337.0 pg/ml; day 3, 826.7 +/- 193.5 pg/ml vs. 20.6 +/- 5.8 pg/ml, p < 0.0001, Mann-Whitney Rank Sum). IL-10 was increased in children after TBI vs controls on all days studied (day 1, 47.2 +/- 12.9 pg/ml; day 2, 21.0 +/- 6.7 pg/ml; day 3, 15.5 +/- 5.9 pg/ml vs. 8.9 +/- 7.5 pg/ml, p < 0.01). Increased IL-10 concentrations were independently associated with age < 4 years and mortality (p = 0.004 and 0.04, respectively, multivariate linear model). This study demonstrates that IL-6 is increased after TBI in children to levels similar to those reported in adults and is the first to show that IL-10 is increased in CSF of humans after TBI. These data suggest that there may be an age-dependent production of IL-10 after TBI in children.
Adolescent↗
100% oxygen in the delivery room is just fine, for now.
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Animals↗
Phosphodiesterases in the rat renal vasculature.
The objective this investigation was to determine the relative importance of type I, III, and IV phosphodiesterases in the regulation of cyclic adenosine monophosphate (cAMP) in the renal circulation. In the first experimental series, four groups of isolated rat kidneys perfused with Tyrode's solution were stimulated with isoproterenol (3 microM) and then treated with increasing concentrations (from the approximately IC50 to 30 times the approximately IC50 in threefold increments) of one of four phosphodiesterase inhibitors: group 1, 3-isobutyl-1-methylxanthine, a "broad-spectrum" phosphodiesterase inhibitor (10-300 microM); group 2, Ro 20-1724, a selective type IV phosphodiesterase inhibitor (3-100 microM); group 3, 8-methoxymethyl-3-isobutyl-1-methylxanthine, a selective type I phosphodiesterase inhibitor (3-100 microM); and group 4, milrinone, a selective type III phosphodiesterase inhibitor (0.3-10 microM). In the second experimental series, five groups of cultured preglomerular (interlobular and afferent arteriolar) vascular smooth-muscle cells were stimulated with isoproterenol (1 microM) and treated with vehicle or supramaximal concentrations (30 times IC50) of either 3-isobutyl-1-methylxanthine (300 microM), Ro 20-1724 (100 microM), 8-methoxymethyl-3-isobutyl-1-methylxanthine (100 microM), or milrinone (10 microM). In perfused kidneys and cultured pre-glomerular vascular smooth-muscle cells, 3-isobutyl-1-methylxanthine and Ro 20-1724 similarly increased renal cAMP release and total cellular (extracellular + intracellular) cAMP levels, respectively. In contrast, neither 8-methoxymethyl-3-isobutyl-1-methylxanthine nor milrinone affected renal cAMP release or total cellular cAMP levels. These data indicate that in the renal circulation, type IV phosphodiesterase is the predominant phosphodiesterase isozyme.
1-Methyl-3-isobutylxanthine↗
Cerebrospinal fluid adenosine concentration and uncoupling of cerebral blood flow and oxidative metabolism after severe head injury in humans.
OBJECTIVE: Uncoupling of cerebral blood flow (CBF) and oxidative metabolism is observed after severe head injury in comatose patients; however, the mechanism(s) involved remain undefined. Adenosine can produce cerebral vasodilation and reduce neuronal activity and is a possible mediator of uncoupling. We hypothesized that cerebrospinal fluid (CSF) adenosine concentrations would be increased during uncoupling of CBF and oxidative metabolism, defined as a narrow arterio-jugular venous oxygen difference [D(a-v)O2 4 vol%] after head injury. METHODS: Adenosine concentrations were measured using fluorescent-based high-pressure liquid chromatography in 67 CSF samples obtained from 13 comatose (Glasgow Coma Scale score 7) adult patients who sustained a severe closed head injury. At the time each sample was obtained, CBF was measured by the xenon-133 method, and blood samples were obtained for determination of D(a-v)O2. RESULTS: CSF adenosine concentration was negatively associated with D(a-v)O2 (P < 0.05, generalized multivariate linear regression model). In addition, CSF adenosine concentration was increased when D(a-v)O2 was 4 versus > 4 vol% (38.5 [3.2-306.3] versus 14.0 [2.7-795.5] nmol/L, respectively, median [range]; P < 0.025) and in patients who died versus survivors (40.1 [6.9-306.3] versus 12.9 [2.7-795.5] nmol/L, respectively, median [range]; P < 0.001). CONCLUSION: The association between increased CSF adenosine concentration and a reduction in global cross-brain extraction of oxygen supports a regulatory role for adenosine in the complex balance between CBF and oxidative and nonoxidative metabolism severe head injury in humans.
Adenosine↗
Inflammatory cytokine and nitric oxide responses in pediatric sepsis and organ failure.
OBJECTIVE: To examine the relationship of circulating proinflammatory and anti-inflammatory cytokine concentrations to nitric oxide and organ failure in pediatric sepsis. DESIGN: Prospective study. SETTING: Pediatric intensive care unit (ICU), children's Hospital of Pittsburgh, University of Pittsburgh. PATIENTS: Nineteen patients with a diagnosis of sepsis admitted to the pediatric ICU. Twelve uninfected critically iII patients served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma interleukin (IL)-10, IL-6, and nitrite/nitrate concentrations were measured and compared with an index of organ failure daily for 3 days after presentation with the sepsis syndrome. Children with increased plasma IL-6 concentrations (n = 6) had increased plasma nitrite/nitrate concentrations (p < 0.01 on each day), increased organ failure scores (p < .05 on days 1 and 3), and the highest plasma IL-10 concentrations (p < .05 on days 1 and 3, p = .054 on day 2) when compared with children with sepsis and undetectable IL-6 concentrations. Children with sepsis and detectable IL-6 concentrations, and children with undetectable IL-6 concentrations, both had increased nitrite/nitrate concentrations (p < .005 on days 1 through 3) and increased IL-10 concentrations (p < .05 on days 1 and 2) compared with controls. Children with increased IL-6 concentrations had higher organ failure on each day (p < .01), and children with undetectable IL-6 concentrations had higher organ failure on days 1 and 2 only (p < .005) when compared with controls. Organ failure improved over time in the children with undetectable IL-6 concentrations (p < .005). CONCLUSIONS: Increased plasma nitrite/nitrates and increased organ failure scores occurred in the children with sepsis who had an exaggerated proinflammatory state, despite a pronounced anti-inflammatory response. When the anti-inflammatory response predominated and the proinflammatory state was dampened, organ failure status improved.
Adolescent↗
Nitric oxide production in critically ill patients.
OBJECTIVE: To measure serum nitrite and nitrate levels in critically ill children as indicators of endogenous nitric oxide (NO) production. HYPOTHESIS: Endogenous NO production is increased in children with conditions characterised by immune stimulation. DESIGN: Prospective descriptive study in a multidisciplinary paediatric intensive care unit. PATIENTS: 137 consecutive critically ill children with a variety of clinical conditions. INTERVENTIONS: Using a rapid microtitre plate technique, daily serum nitrite and nitrate levels were measured from serum samples that remained in the clinical laboratory after daily routine phlebotomy. Clinical and laboratory information was also gathered daily for each patient. RESULTS: The maximum serum nitrite plus nitrate levels (microM) reached by children with infection (41.8 (SD 18.1)), sepsis syndrome (85.1 (39.9)), shock without sepsis (36.4 (19.1)), transplantation alone (61.0 (43.4)), transplantation with sepsis (200.7 (150.5)), or rejection (161.7 (70.4)), were higher than in controls (18.1 (9.3)). In the absence of exogenous NO donors, levels greater than 80 microM were reached only in children with the sepsis syndrome, organ transplantation, or acute rejection. CONCLUSIONS: Increased endogenous NO production occurs in children with clinical conditions associated with immune stimulation. Further investigation is warranted to determine the value of this simple and rapid test as a clinically useful diagnostic tool and therapeutic monitor in the evaluation of children at risk for the sepsis syndrome or acute allograft rejection.
Child↗
Possible role of adenosine deaminase in vaso-occlusive diseases.
OBJECTIVE: To describe several emerging concepts regarding the biosynthesis, metabolism and biological roles of adenosine and to illustrate the possible significance of these ideas to vascular biology by proposing a hypothesis pertaining to the role of erythrocyte-derived adenosine deaminase in vaso-occlusive diseases associated with damaged erythrocytes. MULTIPLE PATHWAYS FOR ADENOSINE FORMATION: Three pathways of adenosine biosynthesis have been well established: the intracellular ATP pathway, the extracellular ATP pathway and the transmethylation pathway. A fourth pathway that has received relatively little attention, but could be particularly important in vascular smooth muscle, is the cyclic AMP-adenosine pathway. This pathway involves the extracellular or intracellular metabolism, or both, of cyclic AMP to AMP and hence to adenosine. Our recent experiments in cultured vascular smooth muscle cells, isolated vascular beds and intact animals support the existence of the cyclic AMP-adenosine pathway. Together these four pathways of adenosine formation should assure pharmacologically active levels of vascular adenosine. ANTIVASO-OCCLUSIVE ACTIONS OF ADENOSINE: The overall pharmacologic profile of adenosine suggests that this nucleoside functions to protect vascular beds from vaso-occlusive events. In this regard, some well known effects of adenosine include vasodilation, release of nitric oxide from vascular endothelial cells and inhibition of platelet aggregation, platelet adhesion, neutrophil-endothelial interactions, renin release and noradrenergic neurotransmission. Moreover, studies indicate that adenosine also releases nitric oxide from cultured vascular smooth muscle cells and inhibits vascular smooth muscle cell growth. Thus, any condition that reduces the levels of adenosine in the blood vessel wall or blood vessel-blood interface might predispose toward vaso-occlusive events. DAMAGE TO ERYTHROCYTES REDUCES ADENOSINE LEVELS: Adenosine deaminase rapidly metabolizes adenosine to inosine, which lacks antivaso-occlusive properties. Because erythrocytes are generously endowed with adenosine deaminase, any condition that damages erythrocytes will cause leakage of adenosine deaminase from erythrocytes directly onto the blood vessel wall, thus diminishing local vascular levels of adenosine. Experiments using dimethyl sulfoxide-induced hemolysis have confirmed the hypothesis that erythrocyte-derived adenosine deaminase can reduce adenosine levels in vivo. HYPOTHESIS: THE ROLE OF ERYTHROCYTE-DERIVED ADENOSINE DEAMINASE IN VASO-OCCLUSIVE DISEASES: Because multiple biosynthetic pathways maintain pharmacologically active levels of adenosine within the blood vessel wall and adenosine exerts a number of antivaso-occlusive effects, release of adenosine deaminase from erythrocytes may increase the risk for vaso-occlusive events.
Adenosine Deaminase↗
Inhibition of type IV phosphodiesterase by Ro 20-1724 attenuates endotoxin-induced acute renal failure.
We recently found that the type IV-specific phosphodiesterase inhibitor Ro 20-1724 increases isoproterenol-induced cAMP secretion in the isolated rat kidney, whereas type I- and type III-specific phosphodiesterase inhibitors do not. Because cAMP is a known vasodilator of renal microvessels, we examined whether Ro 20-1724 is protective against endotoxin-induced acute renal failure. Fifteen rats were anesthetized, instrumented and administered a constant rate intravenous infusion of either Ro 20-1724 (10 micrograms/kg/min; n = 6) or vehicle (n = 9). After 1 hr, a base-line renal clearance period was conducted. All rats then received intravenous endotoxin (20 mg/kg), and six additional renal clearance periods were performed. Urinary cAMP excretion in the Ro 20-1724 group was elevated 2- to 3-fold (P < .01) compared with the control group throughout the protocol. In the control group, endotoxin decreased renal blood flow, increased renal vascular resistance and decreased glomerular filtration rate. Ro 20-1724 markedly attenuated endotoxin-induced changes in renal blood flow (P = .0004), renal vascular resistance (P = .0001) and glomerular filtration rate (P < .0001). The type IV-specific phosphodiesterase inhibitors warrant further study as selective therapeutic agents in the treatment of endotoxin-induced renal failure.
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗