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Biomedical subjects

F Coceani

Publications and source records attributed to F Coceani.

At least 55 records · Page 3Linked to original sources
PubMed1992

Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1.

A method was developed for recording isometric tension from isolated small arteries (mean internal diameter, 169 microns) and veins (mean internal diameter, 273 microns) of the term fetal lung and was then applied to the study of the mechanisms controlling perinatal pulmonary hemodynamics. The specific purpose was to determine whether the activity of the prostaglandin synthetic system in vessels is conditioned by the oxygen tension and the mode of action of endothelin-1. Both preparations appeared structurally intact and, after normalizing their lumen diameter to either the transmural pressure in vivo (artery) or the contractile capacity of the vessel in vitro (vein), generated force to the activating solution (5 mM Ca2+ in K+ Krebs' solution) in excess of the expected performance under physiological conditions. Treatment with indomethacin (2.8 microM) had no effect on arteries preequilibrated at low PO2 (21 +/- 1 mm Hg); however, the same treatment contracted (approximately 45% of the response to activating solution) arteries at either an intermediate (40 +/- 0.8 mm Hg) or high (70 +/- 0.9 mm Hg) PO2. Endothelin-1 contracted both arteries and veins in a concentration-dependent manner, the threshold being lower with veins (1-10 versus 10-100 pM). Endothelin-1 constriction was also seen in arteries whose tone had been raised with a thromboxane A2 analogue, whereas in thromboxane-treated veins constriction was preceded by a modest relaxation over the range of 1-1,000 pM. The findings with indomethacin lead us to infer that small pulmonary arteries are endowed with a prostaglandin-relaxing mechanism that becomes functional on raising the PO2 from fetal to neonatal levels. Endothelin-1 is a constrictor regardless of the level of intrinsic tone, suggesting a possible role of the peptide in maintaining elevated pulmonary vascular tone in the fetus.

Animals↗
PubMed1991

Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.

Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E2 (PGE2) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE2 formation during fever and also increase PGE2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1 beta. When given intraventricularly to cats, IL-6 produced an increase in PGE2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1 beta; however, IL-6 from 0.15-15 micrograms/ml did not increase mononuclear cell PGE2 production in vitro whereas IL-1 beta induced 20-30-fold increases in PGE2 at 100 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Leukotrienes in brain: natural occurrence and induced changes.

Peptidoleukotrienes (SP-LTs) (both total product and individual LTC4 and LTE4 and LTB4 were measured by radioimmunoassay in cerebrospinal fluid (CSF) collected from the third ventricle of conscious cats. Total SP-LT was expressed as LTE4 after treating samples with crude gamma-glutamyltranspeptidase. Prostaglandin (PG) E2 and thromboxane (TX) B2, the stable metabolite of TXA2, were also assayed in part of the experiments. Under basal conditions, SP-LT and LTC4 were consistently measurable (respectively, 327 +/- 14 and 244 +/- 41 pg/ml), while native LTE4 was below the threshold of the assay (60-280 pg/ml) in most cases. LTB4 was barely detectable (30 +/- 2 pg/ml) or not detectable at all. PGE2 was normally less abundant than TXB2 (31 +/- 4 vs 281 +/- 47 pg/ml). Intracerebroventricular (i.c.v.) administration of arachidonic acid (40 microgram) caused a 4-fold increase in SP-LT levels which was relatively small and transient compared to PGE2 (76-fold) and TXB2 (23-fold), while there was no change in either native LTE4 or LTB4. A similar response was obtained with platelet-activating factor (PAF, 1 microgram i.c.v.), though SP-LT elevation (4-fold) was more persistent. A further rise in SP-LT (9-fold) was noted when PAF administration was preceded by indomethacin (500 microgram i.c.v.), whereas PAF effect was reversed by pretreatment with either the PAF antagonist, BN52021 (1 microgram i.c.v.), or the 5-lipoxygenase inhibitors, U-60,257 (75 micrograms i.c.v.) and L-651,392 (10 mg/kg p.o.). PAF was also effective in causing a 3-fold rise in LTC4. Unlike PAF, pyrogens (endotoxin i.c.v. or i.v.; interleukin-1 i.v.) at doses above threshold for fever had no effect on LT levels in CSF, both in the absence and presence of indomethacin pretreatment. We conclude that SP-LTs are a normal constituent of CSF, LTC4, being the major species. The response to PAF accords with a pathogenetic role of the compounds in inflammatory processes and the reactive changes to injury. No evidence was obtained for the involvement of SP-LTs in the central mechanism of fever.

Administration, Oral↗
PubMed1991

Endothelin-1 release from lamb ductus arteriosus: relevance to postnatal closure of the vessel.

Our previous investigations have shown that endothelin-1 (ET-1) is a singularly potent constrictor of the ductus arteriosus and that a cytochrome P-450 system located in the sarcolemma is crucial for the contractile response of the vessel to oxygen. We have now studied the release of ET-1 from isolated ductus arteriosus preparations of near-term fetal lambs. Preparations produced measurable amounts of ET-1 under basal conditions (about 0.04 pg/100 mg wet weight.min) both in the presence and absence of the endothelium. Anisomycin (10(-4) M) reduced this release by 50%, while thrombin (1 U/mL) doubled the release. Treatment with a CO mixture (CO/O2 ratio, 0.27) inhibited ET-1 release from intact and endothelium-denuded preparations. We propose that oxygen triggers closure of the ductus arteriosus at birth by causing a conformational change in a specific cytochrome P-450, which, in turn, provides the signal for the synthesis of the constrictor ET-1.

Animals↗
PubMed1991

Evidence against the involvement of a cytochrome P-450 mechanism in pulmonary hemodynamics in the newborn pig.

Control mechanisms operating through a cytochrome P-450 system have emerged lately as a possible important determinant of pulmonary hemodynamics. Their action may be expressed in the adjustment of vascular tone under both physiologic and pathophysiologic conditions. One such condition is the pulmonary constrictor response to hypoxia. The identity of the effector agent, or agents, is not known, though there are data implicating monooxygenase products of arachidonic acid. From this premise, we wanted to evaluate the effect of cytochrome P-450 inhibitors on basal pulmonary vascular tone during normoxia, and their effect upon hypoxic pulmonary vasoconstriction response. Experiments were performed in an isolated, perfused lung preparation from 1- and 7-day-old piglets, and the effects of two cytochrome P-450 inhibitors (metyrapone and ketoconazole) were tested on the perfusion pressure. At 10(-5) and 10(-4) M, metyrapone caused a modest, but significant, increase in pulmonary pressure (p less than 0.05) in 7-day-old preparations, while it was without effect in the 1-day-old preparation. Similarly, ketoconazole at concentrations from 10(-6) M upwards increased the perfusion pressure in the older animal (p less than 0.01). Responses to the inhibitors were not seen in preparations that had been pretreated with a cyclooxygenase inhibitor (indomethacin, 2.8 x 10(-6) M) or a dual cyclooxygenase-lipoxygenase inhibitor (BW755C, 10(-5) M). Hypoxic vasoconstriction was marginally enhanced by 10(-4) M metyrapone, while it was affected inconsistently by 10(-5) M ketoconazole. We conclude that vasoactive agents formed through cytochrome P-450 reactions have a minor role, or no role at all, in the control of pulmonary hemodynamics in the newborn pig.

Animals↗
PubMed1990

Pulmonary vascular effects of prostaglandin D2 in newborn pig.

In the lamb, prostaglandin (PG) D2 dilates the fetal and early neonatal pulmonary vasculature but becomes a constrictor in the older animal. Constriction could result from conversion of PGD2 to 9 alpha,11 beta-PGF2, stimulated formation of an endogenous vasoactive agent, or a change in PGD2 receptor function. An answer to the latter question was sought in the newborn pig using an isolated lung preparation (1, 3, 7 days of age) and the anesthetized, acutely instrumented animal (1 day old). In vitro, PGD2 increased pulmonary vascular resistance (PVR) in a dose- (2-340 ng/g dry lung) and age-dependent fashion under both normoxia (basal or raised tone) and hypoxia. At 1 and 7 days of age, indomethacin (3 X 10(-6) M) blunted the PGD2 constriction by 50%. Likewise, a thromboxane (Tx) A2 receptor antagonist (ONO 3708, 6 X 10(-8) M) curtailed the PGD2 response. In contrast, a TxA2 synthesis inhibitor (OKY 1581, 10(-6) M) was effective (approximately 70% inhibition) only in the 7-day-old animal. 9 alpha,11 beta-PGF2 and PGF2 alpha, also increased PVR in a dose- and age-related manner, although their action was weaker. Conversely, the 9-epoxy,11-methano endoperoxide analogue was the most potent pulmonary vasoconstrictor among the agents tested. In vivo, PGD2 (0.25-1 microgram/kg) constricted both pulmonary and systemic circulations. We conclude that the porcine pulmonary circulation, unlike the lamb circulation, is constricted by PGD2 throughout the neonatal period. This effect is mediated, in part, by a cyclooxygenase product. The increase in the PGD2 response with age cannot be ascribed to conversion to 9 alpha,11 beta-PGF2, since such occurrence would result in reduced effectiveness.

Animals↗
PubMed1990

Lamb ductus venosus: evidence of a cytochrome P-450 mechanism in its contractile tension.

We have recently shown that a cytochrome P-450-based mechanism is important for the generation of contractile tension by the ductus arteriosus and have now examined whether the same mechanism operates in the ductus venosus. Carbon monoxide (CO/O2 ratio, 0.27) and cytochrome P-450 inhibitors [metyrapone; 4-phenylimidazole; 14-isocyano, 15-(methoxymethyleneoxy)-5Z,8Z,11Z- eicosatrienoic acid; alpha-naphthoflavone] were tested in vitro on the ductus venosus sphincter from mature fetal lambs. Each preparation was precontracted with indomethacin (2.8 x 10(-6) M). Carbon monoxide completely relaxed the ductus, and its action was reversed by illumination with monochromatic light. Peak photocontraction occurred at 450 nm. With the exception of alpha-naphthoflavone, all cytochrome P-450 inhibitors were also relaxant agents. Alpha-naphthoflavone (the sole type I inhibitor tested) produced instead a modest contraction that was often transient. Relaxation brought about by both carbon monoxide and drugs was fully reversed by the thromboxane A2 analog 9,11-epithio-11,12-methano-thromboxane A2 and by excess potassium (55 mM). Carbon monoxide was equally effective in the intact ductus and the ductus denuded of endothelium, whereas cytochrome P-450 inhibitors were marginally less effective in the latter preparation. These findings indicate that the ductus venosus sphincter, like the ductus arteriosus, relies on an intramural cytochrome P-450 mechanism to develop its contractile tone. The actual constrictor remains to be characterized in both vessels.

Animals↗
PubMed1989

A fetal-instrumented model to study age-specific responses to leukotriene D4 and prostaglandin D2 in unsedated newborn lambs.

Sequential studies of the pulmonary vascular response to leukotriene D4 (LTD4) and prostaglandin D2 (PGD2) in the immediate newborn period were performed in lambs, instrumented in utero and delivered vaginally. Compounds were tested in fully conscious 1.5-day-old lambs and the study was repeated 1 week later. Bolus injections of PGD2 (0.05-2.0 micrograms/kg) or LTD4 (0.01-1.0 micrograms/kg) were made into the main pulmonary artery or aorta while pulmonary blood flow and aortic, pulmonary artery, and left and right atrial pressures were monitored continuously. PGD2 was a systemic constrictor regardless of age. In lambs 1.5 days of age, it decreased pulmonary vascular pressure and resistance by 6% (p less than 0.05) and 15% (p less than 0.05), respectively, while 1 week later it increased pulmonary vascular resistance by 18% (p less than 0.05). In contrast, LTD4 was a pulmonary and systemic vasoconstrictor in both the early and late newborn, the threshold dose being between 0.01 and 0.05 micrograms/kg at either age. The decrease in pulmonary blood flow and the increase in pressure and resistance were greater in older animals. In lambs 1.5 days of age, LTD4 (1 micrograms/kg) increased pulmonary vascular resistance by 66.1% (p less than 0.05) and 1 week later by 210% (p less than 0.001). These sequential observations in the same animal indicate that unlike PGD2, LTD4 is a pulmonary vasoconstrictor regardless of age, and its effectiveness increases significantly with age. These results support previous reports that PGD2 action in the pulmonary circulation changes shortly after birth from dilation to constriction.

Aging↗
PubMed1989

Endothelin is a potent constrictor of the lamb ductus arteriosus.

Endothelin was tested on isolated ductus arteriosus preparations from mature fetal lambs. At low PO2 (18-24 Torr; 1 Torr = 133.3 Pa), the compound constricted the vessel dose-dependently over the range from about 10(-10) to 10(-7) M. The contraction was sustained and did not subside even after an extended period of washing. Endothelin was also effective on tissues (PO2,217-231 Torr; indomethacin, 2.8 X 10(-6) M) that had been completely relaxed with CO (CO/O2 ratio, 0.28). CO treatment interferes with a cytochrome P-450 mechanism, which is considered crucial for the contractile response of the vessel to oxygen. These findings are consistent with a role of endothelin in the closure of the ductus arteriosus at birth.

Animals↗
PubMed1989

Ductus arteriosus: involvement of a sarcolemmal cytochrome P-450 in O2 constriction?

Our previous studies implicate a cytochrome P-450-based mechanism in the constrictor response of the ductus arteriosus to oxygen. The present experiments were conducted on saponin-skinned strips of ductal muscle from mature fetal lambs to determine the location, sarcolemmal versus intracellular, of this cytochrome and to obtain a better insight into the sequence of events underlying the action of oxygen. Skinned preparations contracted to free Ca2+ over the range between 0.1 and 5-10 microM (pCa 7 to 5). In contrast, oxygen (PO2, 608-690 Torr; 1 Torr = 133.3 Pa) had no significant effect, both in the absence and presence of 10 microM calcium. Carbon monoxide, tested as pure CO or a CO-O2 mixture (ratio 0.28), did not relax preparations maximally contracted with calcium. These findings indicate that oxygen exerts its effect on the plasma membrane of ductus muscle cells and that a membrane-bound cytochrome P-450 mechanism likely functions as the signal transducer for oxygen in the formation of a constrictor agent.

Animals↗
PubMed1989

Prostaglandin formation in the hypothalamus in vivo: effect of pyrogens.

Conscious cats were used to study the local release of prostaglandin (PG) E2 and thromboxane (Tx) B2 (the stable TxA2 by-product) from the preoptic-anterior hypothalamus (AH-POA) and the tuberal-posterior hypothalamus (PH-Tu) using a modified "push-pull" perfusion procedure. In the absence of fever, PGE2 release was steady from the 2nd h of perfusion onward, its rate at either site ranging between 0.08 and 0.12 pg/min. Local treatment with probenecid (1 mM) increased PGE2 release about threefold. Compared with PGE2, basal release of TxB2 was greater (0.15-0.43 pg/min) and, occasionally, tended to fall with time. Both compounds were found in higher amounts (2- to 10-fold increase) after locally injecting endotoxin, and the effect was greater in AH-POA than PH-Tu. Conversely, intravenous endotoxin (bolus) or interleukin 1 (IL-1) (bolus plus infusion) at doses causing a sustained fever selectively stimulated the formation of PGE2, but the response itself did not differ between AH-POA and PH-Tu. In either region, the degree of enhancement in PGE2 release correlated with the magnitude of the fever. Intravenous indomethacin (2 mg/kg) reversed both the fever and PGE2 elevation. These findings support an intermediary role for PGE2 in the central action of pyrogens and the ensuing fever. Blood-borne pyrogens may act at multiple sites in brain, which are tentatively identified with the circumventricular organs.

Animals↗
PubMed1989

Prostaglandin E receptors in cardiac sarcolemma. Identification and coupling to adenylate cyclase.

Purified cardiac sarcolemmal membrane vesicles were used to determine if specific prostaglandin (PG) receptors are present on the myocyte. Two binding sites for PGE2 were identified in isolated bovine sarcolemmal membranes: a high-affinity site with a dissociation constant (Kd) of 0.32 nM and a maximum binding (Bmax) of 376 fmol/mg of protein and a lower-affinity site with a Kd of 3.41 nM and a Bmax of 2,112 fmol/mg of protein. In competition experiments, unlabeled PGE1 displaced [3H]PGE2 from its membrane receptor at concentrations similar to those of unlabeled PGE2. Both PGF2 alpha and PGD2 displaced [3H]PGE2 from the membrane, but only at high concentrations (greater than 10(-6) M and greater than 10(-5)M, respectively). Digestion of sarcolemmal membrane with trypsin resulted in a threefold decrease in specific [3H]PGE2 binding. Phosphorylation of the membrane with protein kinase A also decreased specific [3H]PGE2 binding. At concentrations of PGE2 that occupy the high-affinity site, sarcolemmal adenylate cyclase activity was inhibited in the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. We conclude that the isolated cardiac sarcolemmal membrane contains a high-affinity binding site for PGE2 that is functionally coupled to adenylate cyclase. The binding site is stereospecific and probably recognizes the 9-keto,11-hydroxyl portion of the ring structure of these prostaglandins.

Adenylyl Cyclases↗
PubMed1989

Oxygen-related prostaglandin synthesis in ductus arteriosus and other vascular cells.

We compared oxygen-related prostaglandin synthesis in fetal lamb ductus arteriosus (DA) pulmonary artery (PA) and aorta endothelial and smooth muscle cells. We measured basal synthesis of 6-keto-PGF1 alpha and PGE2, the response to calcium ionophore (A23187), a nonspecific stimulus of prostaglandin production, as well as the response to oxygen, a perinatal stimulus, monitoring both the effects of hyperoxia (95% O2) and hypoxia (2% O2). In addition, we established whether differences observed in fetal lamb PA cells related to oxygen tension were also observed in newborn central and microvessel PA cells. Our results indicate that DA endothelial cells increase 6-keto-PGF1 alpha in response to ionophore (p less than 0.05). With hyperoxia, DA endothelial cells increase PGE2 synthesis and DA smooth muscle cells increase 6-keto-PGF1 alpha (p less than 0.05 and 0.02, respectively). Aorta smooth muscle cells increase 6-keto-PGF1 alpha in response to ionophore and hyperoxia (p less than 0.003 and 0.05, respectively). PA endothelial and smooth muscle cells have higher levels of basal prostaglandin synthesis when compared with DA and aorta. In response to ionophore, increased 6-keto-PGF1 alpha is observed in both PA endothelial and smooth muscle cells (p less than 0.02 and 0.0004, respectively), and PGE2 is increased in PA smooth muscle cells (p less than 0.003). Hypoxia, however, decreases PA smooth muscle production of both 6-keto-PGF1 alpha and PGE2 (p less than 0.02 and 0.01, respectively). Similar observations were made in newborn lamb central and microvessel PA cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Occurrence of interleukin-1 in cerebrospinal fluid of the conscious cat.

Interleukin-1 (IL-1) is synthesized and released in response to various pathogens, including bacterial endotoxin, and is assigned an intermediary function in the genesis of fever. Its site of action in the central nervous system (CNS), however, is uncertain because the polypeptide is seemingly unable to cross the blood-brain barrier. Since several cell types, including astroglial, microglial, and vascular cells, can generate IL-1 upon appropriate stimulation, we examined whether IL-1 is formed in the CNS and may therefore serve as a messenger for systemic noxae. Experiments were conducted in the conscious cat and IL-1 was assayed in cerebrospinal fluid (CSF) from the third ventricle using a highly sensitive murine helper T cell line, D10.G4.1. In general, IL-1 levels were barely detectable in the absence of fever and did not increase at any stage of the sustained fever following intravenous injection of endotoxin (bolus) or crude monocyte supernate containing IL-1 (bolus plus infusion). In contrast, intracerebroventricular injection of a pyrogenic dose of endotoxin led to the appearance of IL-1 in the CSF. IL-1 levels reached maximal elevation during the uprise phase of the fever and declined thereafter. By the same route, natural or recombinant human IL-1 had no effect on CSF-IL-1 levels, though both preparations were as effective as endotoxin in eliciting fever. These findings confirm earlier data with radiolabelled pyrogens and indicate that the blood-brain barrier is impermeable to IL-1. We conclude that blood-borne IL-1 is likely to act at a discrete site outside the blood-brain barrier, possibly the organum vasculosum laminae terminalis. Centrally formed IL-1 may instead act diffusely in promoting fever and fever-related events (e.g. sleep).

Animals↗
PubMed1988

The effect of leukotriene D4 on pulmonary and systemic circulation in conscious newborn piglets.

In a conscious newborn piglet model, exogenous leukotriene D4 was found to be a potent pulmonary and systemic vasoconstrictor with significant left ventricular depressant effect. The pulmonary pressor effect was seen only in the arterioles and not the veins. In hypoxia the pulmonary response was less. The findings were similar to that in lambs. The role of leukotrienes in hypoxic pulmonary vasoconstriction and the foetal pulmonary circulation needs further elucidation.

Animals↗
PubMed1988

Modulation of human marrow haematopoiesis by leucotrienes in vitro.

The influence of products derived from the arachidonic acid 5-lipoxygenase (5-LO) pathway on normal human marrow haematopoiesis was studied using clonogenic assays. The leucotrienes (LT) B4 and C4 caused a reduction in granulocyte-macrophage (CFU-GM) as well as erythroid (CFU-E and BFU-E) colony numbers in a dose-dependent manner. Conversely, nordihydroguaiaretic acid (NDGA), a LT synthesis inhibitor, promoted proliferation of these colonies. The inhibitory effect of LTC4 but not that of LTB4 was abolished by FPL-55712, a LT antagonist; the enhanced colony growth induced by NDGA was reversed by both LTB4 and LTC4. LTD4 had no significant effect on colony growth despite its structural similarity to LTC4, which implies that the haematopoietic suppression by LTB4 and LTC4 is specific for these compounds. Depletion of marrow T-cells or removal of adherent cells, or both, did not alter the response to LTB4 and LTC4, suggesting that LT action is exerted directly on progenitor cells and probably is not mediated by other cell populations. Our studies show that the 5-LO pathway is functional in these culture systems and yields products with inhibitory properties. The 5-LO pathway may have an important regulatory function in normal marrow haematopoiesis.

Adult↗