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Biomedical subjects

F Coceani

Publications and source records attributed to F Coceani.

At least 73 records · Page 4Linked to original sources
PubMed1988

The control of cardiovascular shunts in the fetal and perinatal period.

The fetal circulation has two major vascular shunts, the ductus arteriosus and the ductus venosus. The ductus arteriosus connects the pulmonary artery with the descending portion of the aortic arch, hence shunting most of the right ventricular output away from the unexpanded lungs. The ductus venosus connects instead the portal sinus with the inferior vena cava and allows well-oxygenated umbilical vein blood to bypass the liver and reach the central circulation rapidly. Both blood vessels cease their function after birth and undergo permanent closure. It is now well established that prenatal patency of the ductus arteriosus is an active state sustained by a prostaglandin. A similar mechanism has been recently recognized in the fetal ductus venosus. Evidence is presented indicating that prostaglandin E2 and prostaglandin I2 are natural relaxants, respectively, for the ductus arteriosus and the ductus venosus. In addition, both vascular shunts share the dependence on an endogenous cytochrome P-450 mechanism to develop their contractile tone. This mechanism may be important in the normal process of shunt closure at birth. While broadening the knowledge of fetal cardiovascular homeostasis, advances in this field have important implications for the prevention and management of certain pathological conditions affecting the newborn.

Animals↗
PubMed1988

Further evidence implicating prostaglandin E2 in the genesis of pyrogen fever.

Conscious cats were used to study the effects of endotoxin and interleukin 1 (IL 1) on levels of prostaglandin (PG) E2 and thromboxane (TX) B2 (the stable TXA2 byproduct) in cerebrospinal fluid (CSF) from the third ventricle. Pyrogens were given intravenously or intraventricularly and prostanoids were measured by radioimmunoassay. PGE2 was normally less abundant than TXB2 (mean, 37 vs. 528 pg/ml), and its level increased severalfold during the sustained fever following intravenous endotoxin (bolus) or IL 1 (bolus plus infusion). PGE2 elevation preceded the fever and was maintained thereafter. Likewise, intraventricular pyrogens promoted PGE2 formation, and their effect was also manifest during the latent period of the fever. The PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, was not measurable in CSF from either afebrile or febrile animals. Basal content of PGE2, on the other hand, was higher in animals pretreated with probenecid (30 mg/kg ip or iv; 50 or 100 micrograms ivt), confirming the importance of transport processes in removing prostanoids from brain. Unlike PGE2, TXB2 levels did not change during the fever to intravenous endotoxin. TXB2 rose instead in response to intraventricular endotoxin, although the elevation did not extend beyond fever uprise. Furthermore, a TXA2 analog (ONO-11113;2 or 4 micrograms ivt) had inconsistent effects on body temperature, while a TXA2 antagonist (ONO-11120;2 micrograms ivt) did not interfere with endotoxin fever. These findings strongly support a causative role for PGE2 in the onset and progression of pyrogen fever. No evidence of a similar role was obtained for TXA2.

Animals↗
PubMed1988

Further evidence implicating a cytochrome P-450-mediated reaction in the contractile tension of the lamb ductus arteriosus.

The authors have recently provided evidence implicating the cytochrome P-450 system in the generation of contractile tension of the ductus arteriosus. To confirm this possibility, carbon monoxide (CO/O2 ratio, 0.27) and cytochrome P-450 inhibitors [4-phenylimidazole; 14-isocyano,15-(methoxymethyleneoxy)-5Z,8Z,11 Z-eicosatrienoic acid; 9-hydroxyellipticine; alpha-naphthoflavone] were tested on the isolated ductus arteriosus from mature fetal lambs equilibrated at low (4-26 mm Hg) or high (229-694 mm Hg) O2 partial pressure (PO2). Carbon monoxide completely relaxed intact vessel wall preparations and preparations consisting of only the muscle. Carbon monoxide relaxation was reversed by illumination with monochromatic light and the peak for the photoactivated contraction occurred at 450 nm. 4-Phenylimidazole (100 and 1,000 microM) was also a relaxant agent, and its action was manifest at both low and high PO2. Unlike 4-phenylimidazole, the isonitrile compound (5 microM) and 9-hydroxyellipticine (10 and 100 microM) were relaxant only at low PO2 and were also less potent. At the same PO2, alpha-naphthoflavone (10 microM) barely reduced ductal tension. Treatment of the ductus with either a combination of superoxide dismutase (60 or 150 U/ml) and catalase (40 or 1,000 U/ml) or mannitol alone (80 mM) failed to alter the steady-state tone at low PO2 and the contractile response to O2. Arachidonic acid was tested on tissues pretreated with the dual cyclooxygenase and lipoxygenase inhibitor, BW755C (10 microM), and produced a weak relaxation at a concentration of 1 microM or higher. 5,6-Epoxytrienoic acid relaxed the untreated tissue, and its action was abolished by indomethacin (2.8 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

A method to study pulmonary vascular response in the conscious newborn piglet.

New methods for chronic instrumentation of the newborn piglet are described, which allow continuous monitoring of not only pressures in the pulmonary artery and aorta but also in the left and right atria, pulmonary vein, as well as main branch pulmonary artery flows. Changes in pulmonary vascular tone to short-acting vasoactive agents can be recognized by redistribution of flow between lungs and localized to the precapillary vessels or pulmonary veins. Furthermore, vasoactive response in small pulmonary veins may be investigated as well as selective metabolic studies across the right lung. Methods are also described for the chronic cannulation of the neck vessels permitting repeated introduction of catheters on separate study days in the conscious piglet. The pulmonary circulation of the piglet constricts briskly to moderate hypoxemia (PaO2 = 39.2 +/- 2 Torr, 1 Torr = 133.32 Pa) with little change in cardiac output or systemic resistance. The piglet demonstrated responses to dilator and constrictor prostaglandins generally similar to the lambs and other species. None of these agents significantly affect pulmonary venous tone.

Animals↗
PubMed1987

Prostaglandin formation in feline cerebral microvessels: effect of endotoxin and interleukin-1.

The pathogenesis of fever involves the appearance of interleukin-1 in the circulation in response to appropriate noxae (e.g., endotoxin) and subsequent generation of prostaglandin E2 in the CNS. The present study was undertaken to determine whether the cerebral microvasculature may function as a source of the fever-producing prostaglandin E2. Microvessels, consisting predominantly of capillaries, were isolated from the cat forebrain by selective sieving and glass bead elutriation. Preparations contained enzymes for the synthesis of 6-keto-prostaglandin F1 alpha (hence prostaglandin I2), prostaglandin E2, and possibly prostaglandin F2 alpha. No prostaglandin D2 was detected, nor was evidence obtained for the formation of 6-keto-prostaglandin E1. Intact microvessels released prostaglandin E2 and 6-keto-prostaglandin F1 alpha under basal conditions, the latter compound exceeding the former by about sevenfold. Endotoxin stimulated prostaglandin E2 release without significantly altering 6-keto-prostaglandin F1 alpha release. In contrast, monocyte-derived interleukin-1 reduced the release of both compounds, while recombinant interleukin-1 was ineffective. Endotoxin stimulation is likely directed on the cleavage of substrate arachidonic acid from precursor lipids, while inhibition from monocyte-derived interleukin-1 is ascribed to the presence of an interfering substance. This substance, like endotoxin, is thought to act prior to the cyclooxygenase cascade and its identity remains to be ascertained. We conclude that the cerebral microvasculature does not lend itself to an active role in the genesis of fever by being the site at which blood-borne interleukin-1 promotes prostaglandin E2 synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Lipid mediators in the control of the ductus arteriosus.

The ductus arteriosus (DA) is kept open during fetal development by the continuous relaxant effects of prostaglandins (PG), primarily E2. Although this PGE2 is probably intramurally produced. a subsidiary role for blood-borne PGE2 and PGI2 is not excluded. PGE2 synthetic activity develops early in the developing ductus and is greater in immature than in mature tissues. Ductus sensitivity to PGE2 is greatly diminished after exposure to oxygen. Arachidonic acid (the precursor of PGE2) may inactivates cytochrome P-450, completely reverses the contractile tension of the DA at both low (4 to 12 torr) and high (511 to 712 torr) oxygen tension and is equally effective in the presence and absence of indomethacin. Carbon monoxide-induced relaxation occurs with a PCO/PO2 ratio of 0.27 and is reversed by white light and by monochromatic light with maximal reversal seen at 450 nm wavelength. Both these findings favor involvement of a cytochrome P-450. Metyrapone and phenylimidazole, chemical inhibitors of cytochrome P-450, also relax the ductus. These findings suggest that ductus tone is controlled through the opposing activities of cyclooxygenase and monooxygenase products of AA. The former predominate in the fetus, and the latter at birth when they induce closure/

Animals↗
PubMed1987

Bipyridine derivatives lower arteriolar resistance and improve left ventricular function in newborn lambs.

Milrinone may be used in the treatment of pulmonary hypertensive diseases of the newborn. We have studied its effects in chronically instrumented newborn lambs over a dose range from 1-100 micrograms/kg. These actions have been compared with those of amrinone. We have also tested the effect of milrinone on hypoxia and leukotriene D4-induced pulmonary vasoconstriction. Injected into the right pulmonary artery, both amrinone and milrinone cause a dose-related fall in pulmonary arteriolar resistance with milrinone being approximately 20 times more potent than amrinone and possessing an ED50 of about 10 micrograms/kg. Both agents increase left ventricular dp/dt significantly and tend to increase cardiac output. Systemic vascular resistance falls with both drugs but the change is significant only with milrinone. While milrinone attenuates the increase in pulmonary arteriolar resistance induced by leukotriene D4 and hypoxia, this is probably an indirect effect. Milrinone does not modify either the increases in left atrial, aortic pressure, and systemic vascular resistance or the decreases in cardiac output and left ventricular dp/dt induced by leukotriene D4. These findings suggest that milrinone deserves clinical trial in newborn infants with pulmonary hypertension in whom myocardial depression often coexists.

Amrinone↗
PubMed1986

Involvement of intramural prostaglandin E2 in prenatal patency of the lamb ductus arteriosus.

Release of prostaglandin E2 (PGE2) was studied in isolated ductus arteriosus preparations from immature (103 or 104 days gestation; term, 147 days) and near-term fetal lambs. Mature preparations produced measurable amounts of the compound in most cases and the release rate was 19 +/- 2 pg/(100 mg wet weight X min) at a PO2 of 3-8 Torr (1 Torr = 133.3 Pa). PGE2 release increased with the PO2 of the medium, peak values (about 125 pg/(100 mg X min)) being attained at 106-276 Torr when the oxygen-induced contraction was still submaximal. Experiments in which tissues were either contracted with excess potassium or relaxed with CO proved that PGE2 formation is independent from the contractile state. PGE2 was also released from ductus preparations lacking the adventitia, the intima, or both; however, release values were maximal when the adventitia was preserved. The magnitude of the intrinsic tone in these stripped preparations was inversely related to the rate of PGE2 formation. Reduced glutathione increased PGE2 release from the mature ductus, whole or stripped, and also relaxed hypoxic preparations; both effects were reversed by concomitant treatment with indomethacin. PGE2 synthesis tended to be greater in the immature than the mature ductus, maximal values (115 +/- 27 pg/(100 mg X min)) being observed at 6-8 Torr. We conclude that the ductus arteriosus is endowed with an enzyme system for the synthesis of PGE2 whose function accords with an effector role of the compound in the regulation of tone. These findings, together with the potent relaxation exerted by PGE2 at low PO2, indicate that the locally generated prostaglandin is well suited for keeping the ductus patent in the fetus.

Animals↗
PubMed1986

The circulatory effects of nifedipine in the conscious newborn lamb.

The cardiac, pulmonary vascular, and systemic vascular effects of bolus injections (2.5, 25, 50 micrograms/kg) and 5-min infusions of 50 micrograms/kg/min of Nifedipine were tested in conscious, chronically instrumented newborn lambs. While breathing room air, bolus injections of 50 micrograms/kg into the pulmonary artery caused the cardiac index and left ventricular dp/dt to fall as did systemic arterial pressure and calculated resistance (all changes significant p less than 0.05). Pulmonary artery, pulmonary vein, and left atrial pressure all tended to increase and there was a shift in flow away from the injected lung (14 +/- 0.05%). Pulmonary arteriolar resistance in the injected lung increased significantly (p less than 0.05). Nifedipine failed to prevent hypoxia-induced pulmonary vasoconstriction, and when given during hypoxia, caused a further rise in pulmonary artery pressure with a marked fall in left ventricular dp/dt and systemic vascular resistance. These acute effects peaked 30 s to 2 min after injection and all hemodynamic variables returned to baseline by 10 min. Five-min infusions caused similar effects which completely reversed 20 min after the infusion was stopped. Nifedipine causes significant cardiac depression combined with systemic vasodilatation and pulmonary arteriolar constriction in conscious newborn lambs. Assuming similar actions in humans, it seems quite unsuitable for the therapy of pulmonary hypertensive problems of newborn infants.

Animals↗
PubMed1985

Evidence for a role of prostaglandin I2 and thromboxane A2 in the ductus venosus of the lamb.

The prostaglandin (PG) endoperoxide, PGH2, and the thromboxane (TX) A2 analog, 9,11-epithio-11,12-methano-TXA2, were tested in vitro on the ductus venosus sphincter from fetal (premature and mature) and neonatal (1-day-old) lambs. PGH2 relaxed the indomethacin-contracted fetal ductus in a dose-dependent manner and its action was reduced after treatment with 15-hydroperoxyarachidonic acid. In contrast, reduced glutathione did not affect the PGH2 relaxation in the indomethacin-treated ductus, nor did it modify the response of the untreated ductus to constrictor stimuli. Unlike PGH2, the stable 9 alpha,11 alpha-epoxymethano-PGH2 analog contracted the vessel. Similarly, the TXA2 analog was a contractile agent, its action exceeding that of the PGH2 analog in potency and efficacy. The TXA2 analog was active on preparations from both premature (minimum 117 days gestation) and mature lambs, but a maximal effect was attained during the perinatal period. These results confirm the existence of a PG-mediated relaxing mechanism in the ductus venosus and suggest that the active compound is PGI2. This mechanism is likely responsible for keeping the ductus patent in the fetus. TXA2, formed within the liver parenchyma, is well suited for playing a role in postnatal closure of the vessel.

Animals↗
PubMed1985

Prostaglandins and fetal cardiac output distribution in the lamb.

With the use of a triple thermodilution technique in 17 fetal lambs, combined with microsphere estimations in 7, the effects of indomethacin prostaglandin (PG) I2 and PGE2 on cardiac output and its distribution were measured. Indomethacin (0.2 mg/kg) induced a main pulmonary artery-to-aorta pressure gradient, which peaked within 45-60 min and persisted for 2-3 h. PGE2 abolished this gradient (threshold 50 ng X kg-1 X min-1), while PGI2 in doses up to 100 ng X kg-1 X min-1 increased it. Indomethacin did not change total cardiac output but altered its distribution (right ventricular output, left ventricular output) and increased the percentage of right ventricular output flowing to the lungs. Ductal flow decreased concomitantly. After indomethacin, PGI2 further decreased ductal flow, increased pulmonary flow, and decreased pulmonary vascular resistance. PGE2 restored the original right ventricular-to-total cardiac output ratio, although ductus flow did not return to base-line levels. Pulmonary resistance increased slightly, reflecting decreased pulmonary flow, associated with decreased right ventricular output. Thus PGE2 was more effective on the ductus than on the pulmonary circulation. PGI2 did not relax the ductus but was a potent pulmonary vasodilator. Neither PGI2 nor PGE2 nor indomethacin changed total cardiac output but all altered its distribution.

Animals↗
PubMed1984

Action of PGI2 analogs on the pulmonary and systemic circulations in the conscious newborn lamb.

Previous work (Lock et al., J. Pharm . Exp. Ther. 215:156, 1980) has shown that conventional screening procedures for vasoactive PGI2 analogs were little value in predicting pulmonary vasodilator activity in the newborn lamb. To gain a better insight into the structural requirements for pulmonary vasoactivity and possibly identify useful compounds for the management of neonatal pulmonary hypertensive disorders, we have tested the following PGI2 analogs in normoxic and hypoxic newborn lambs: 15(S)-9-deoxy-15-methyl-9 alpha,6- nitrilo -PGF1 (analog I); 9-deoxy-9 alpha,5- nitrilo -PGF1 (analog II); (6S, 15S)-15-methyl-PGI2 (analog III); and ( 6R , 15S)-15-methyl-PGI1 (analog IV). A prostaglandin analog mimicking PGI2 (compound BW245C ; (+/-)-5-(6- carboxyhexyl )-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin ) was tested as well. Compounds were injected into a branch pulmonary artery and any local pulmonary effect could be assessed from the change in the ratio of blood flow to the injected lung over total flow. None of the analogs tested proved to be a selective pulmonary dilator. BW245C was a potent peripheral vasodilator (threshold around 0.5 microgram/kg) and indirectly lowered pulmonary vascular resistance through its systemic effects. Analog I also dilated the systemic circulation, but only at the highest dose tested (100 micrograms/kg). The latter finding is surprising because it was previously shown that the parent, non-methylated compound is a fairly potent and selective pulmonary vasodilator. Analog II and IV were inactive at a dose up to, respectively, 30 and 20 micrograms/kg. Analog III, on the other hand, weakly constricted the systemic circulation at a dose of 10 micrograms/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The influence of lipoxygenase inhibitors on the in vitro production of human leukocytic pyrogen and lymphocyte activating factor (interleukin-1).

Leukocytic pyrogen (LP), the endogenous mediator of fever, is synthesized and released from mononuclear phagocytes following activation by several microbial and immunologically-derived substances. Purified fractions of LP also stimulate thymocyte proliferation and LP seems to be indistinguishable from lymphocyte activating factor (LAF) otherwise known as interleukin-1 (IL-1). In the present investigation, we have examined the effect on IL-1 production of drugs inhibiting both cyclooxygenase- and lipoxygenase-mediated transformations of arachidonic acid (ETYA, 5,8,11,14-eicosatetraynoic acid and compound BW755C, 3-amino-1-3-trifluoromethylphenyl-2-pyrazoline). Ibuprofen inhibited the production of PGE2 from stimulated human monocytes but had no effect on LP and LAF release. ETYA prevented LP production from human monocytes when added to the incubation fluid prior to activation by Staphylococcus albus. When added after cell activation, ETYA was ineffective. Similar results were obtained using BW755C. Prostaglandin E2 (PGE2) levels in cell supernates were markedly decreased in the presence of either drug when compared to supernates from untreated, stimulated cells. Low PGE2 levels were also demonstrated in supernates of cells in which either ETYA or BW755C were added 1 hour after stimulation. Pretreatment with BW755C also resulted in decreased LAF activity in the supernates of mononuclear cells stimulated with staphylococci, endotoxin, or muramyl dipeptide. Other experiments demonstrated that crude or purified human LP retains its activity following treatment with soybean lipoxidase. These findings indicate that a product of arachidonate lipoxygenase is important in the sequence of events underlying cell activation for the production of human LP/LAF/IL-1. The possibility that LP might be an eicosanoid-peptide conjugate structurally resembling the leukotrienes was ruled out.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Surgical management of critical pulmonary stenosis in the neonate.

Experience with 36 consecutive neonates less than 1 month of age with critical pulmonary stenosis (PS) with intact ventricular septum was analyzed to define the role of pulmonary valvotomy and of a concomitant systemic-pulmonary shunt as well as the impact of prostaglandin E1 (PGE1) therapy in the management of this disorder. Operative procedures included pulmonary valvotomy as an isolated procedure (Group 1, N = 22), pulmonary valvotomy plus a systemic-pulmonary shunt (Group 2, N = 8), pulmonary valvotomy with PGE1 therapy (Group 3, N = 5), and one miscellaneous procedure. The hospital mortality (+/- 70% confidence limits [CL]) by treatment group was as follows: Group 1, 54% (CL, 41-67%) (12/22); Group 2, 25% (CL, 9-50%) (2/8); and Group 3, 0 (CL, 0-32%); Group 1 versus Group 2 plus Group 3 (p less than or equal to 0.05). Patients managed with a shunt or perioperative administration of PGE1 experienced a significant improvement in early survival. Late postoperative angiography demonstrated exemplary right ventricular growth in the majority of patients, although important residual abnormalities of the outflow tract necessitating operative repair were frequently present (5-year and 10-year actuarial freedom from reoperation, 73 +/- 10% and 42 +/- 16%, respectively [+/- standard error of the mean]). This review illustrates the limitations of pulmonary valvotomy as an isolated therapeutic method in neonates with critical PS. Provision of a systemic extracardiac source of pulmonary blood flow, accomplished by a systemic-pulmonary shunt or PGE1 infusion continued postoperatively, is the most important determinant of early survival in this disorder.

Alprostadil↗
PubMed1984

Placental drug transfer in near-term ewes: acetylsalicylic and salicylic acid.

Radiolabelled acetylsalicylic acid (ASA) and salicylic acid (SA) were given intravenously to four near-term ewes and their occurrence in both maternal and fetal plasma was ascertained using a specific thin-layer chromatographic analysis procedure. Findings proved that ASA and SA cross the placental barrier and reach distribution equilibrium about 40 min after salicylate administration. The equilibrium plasma fetal/maternal ratio for both salicylates averaged 0.4. Plasma concentrations of the two compounds in the mother and the fetus accorded with a two-compartment model having unusually large mean estimates (54 and 39 L) for the tissue distribution space of ASA and SA, respectively. Furthermore, the mean SA clearance in the ewe (358 mL X min-1) was much greater than that reported in man, while the mean ASA clearance (764 mL X min-1) was similar. Since ASA is an irreversible inhibitor of arachidonate cyclooxygenase, our findings reassert the need for caution in the use of the drug during pregnancy.

Animals↗