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Biomedical subjects

F Coceani

Publications and source records attributed to F Coceani.

At least 91 records · Page 5Linked to original sources
PubMed1984

Cytochrome P 450-linked monooxygenase: involvement in the lamb ductus arteriosus.

CO and metyrapone were tested on isolated ductus arteriosus preparations from mature fetal lambs equilibrated at low (4-12 Torr) and high (511-712 Torr) O2 partial pressure (PO2). CO completely reversed the contractile tension of the ductus at either PO2 value and was equally effective in the absence and presence of indomethacin. CO relaxation still occurred when the tissue was exposed to a gas mixture having a CO-to-O2 ratio of 0.27. The inhibitory effect of CO on the O2-contracted ductus was variably reversed by light. Metyrapone was also a relaxant agent, and its action was greater at low than at high PO2. Unlike the lamb ductus, the O2-constricted guinea pig ductus did not respond to CO (maximum CO-to-O2 ratio around 1), whereas it was relaxed by metyrapone. These findings implicate a cytochrome P450-catalyzed enzymic process in the maintenance of muscle tone of the lamb ductus arteriosus and in the contractile response of the vessel to O2.

Animals↗
PubMed1984

Autonomic mechanisms in the ductus venosus of the lamb.

Morphological and pharmacological studies were performed in the ductus venosus from near-term fetal and neonatal (1 day of age) lambs. Light and electron microscopic analysis demonstrated a concentration of circularly oriented muscle fibers at the junction of the ductus with the portal sinus (the sphincter region). With the use of histochemical methods, adrenergic and cholinergic fibers were visualized in both the sphincter and extrasphincter regions of the ductus. At either site, nerve fibers were confined to the adventitial layer and never formed a plexus. Norepinephrine and transmural electrical stimulation contracted the ductus sphincter in vitro, and their action was abolished by dibenzyline. In contrast, atropine had no effect on the transmural response. Moreover, acetylcholine contracted the vessel inconsistently. In the fetus, both the norepinephrine-induced and the electrically induced contractions increased on raising the O2 tension of the bathing fluid from 17-31 to 520-705 mmHg. In addition, the transmural response increased with advancing gestation. Norepinephrine and transmural stimulation relaxed dibenzyline-treated preparations in which the tone had been raised with indomethacin. Norepinephrine relaxation was antagonized by propranolol. We conclude that the ductus venosus sphincter contains functional adrenergic nerves, causing contraction and relaxation via, respectively, alpha- and beta-adrenoceptors. The alpha-adrenoceptor-mediated contraction may have a role in postnatal closure of the vessel.

Acetylcholine↗
PubMed1984

Mechanisms of fever induced by recombinant human interferon.

Since the early trials using human interferon (hIFN) derived from blood leukocytes or cell lines, fever has been a prominent component of IFN therapy. Human protein impurities might account for the fever to cell-derived hIFN, but recombinant hIFN, free of extraneous human proteins, has produced fever in nearly all recipients during clinical trials. Our present studies were carried out to determine the mechanisms of fever due to recombinant hIFN currently being used in humans. Because recombinant hIFN is produced in Escherichia coli, in these experiments we considered contaminating endotoxin as the cause of fever. Polymyxin B, which blocks endotoxin, had no effect on the pyrogenicity of hIFN in rabbits. In addition, hIFN injected into an endotoxin-resistant strain of mice produced fever. The pyrogenicity of hIFN does not appear to involve production of leukocytic pyrogen (LP), since no circulating LP was detected in rabbits during IFN fever. Furthermore, human mononuclear cells incubated with hIFN in vitro at 10(4)-10(6) U/ml did not release LP. However, hIFN stimulated prostaglandin E2 (PGE2) release from rabbit hypothalamic tissue in vitro. Intracerebroventricular injection of hIFN into the awake cat also produced fever and a rise in PGE2 levels in the cerebrospinal fluid; both effects were reversed by treatment with indomethacin. We conclude that the fever of recombinant hIFN is not due to endotoxin but that hIFN is intrinsically pyrogenic by inducing PGE2 in the hypothalamus.

Animals↗
PubMed1983

Prostaglandin E2 and thromboxane B2 in cerebrospinal fluid of afebrile and febrile cat.

Levels of prostaglandin (PG) E2 and thromboxane (TX) B2, the stable metabolite of TXA2, were measured by radioimmunoassay in cerebrospinal fluid (CSF) collected from the third ventricle and the cisterna magna of conscious cats. In the absence of fever, PGE2 was usually below the threshold of the assay (0.05-0.37 ng/ml), while TXB2 was measurable in the majority of cases and its concentration was greater in the third ventricle (about 0.7 ng/ml) than in the cisterna magna (about 0.2 ng/ml). At either site, TXB2 content rose if any manipulation was required for the collection of samples. PGE2 levels increased to measurable values (max 1.1-1.4 ng/ml) during fever produced by intrathecal or intravenous administration of leucocytic pyrogen. In contrast, TXB2 concentration rose to an average of 2.2-4 ng/ml only when pyrogen (bacterial or leukocytic) was given intrathecally. Moreover, TXB2 elevation, unlike PGE2 elevation, was limited to the uprise phase of the fever. Imidazole, given either intraperitoneally (50 mg/kg) or intrathecally (3 mg), attenuated the pyrogen fever and suppressed any rise in TXB2 levels. At the same time, the drug tended to increase the PGE2 content of the CSF. Evidence was also obtained suggesting that a fraction of PGE2 is bound to CSF protein, and this event may be important to the inactivation of the compound. These findings are consistent with the concept that PGE2 is involved in the sequence of events underlying pyrogen fever. A role for thromboxane A2 in this process remains to be established.

Animals↗
PubMed1982

Evidence against a role for lipoxygenase-derived products of arachidonic acid in the lamb ductus arteriosus.

The effects of leukotrienes, the leukotriene antagonist FPL55712 (sodium 7-(3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate), and inhibitors of arachidonate lipoxygenase and cyclo-oxygenase (compound BW755C, 3-amino-1-(m-(trifluoromethyl)-phenyl)-2-pyrazoline; ETYA, 5,8,11,14-eicosatetraynoic acid) were studied in an isolated preparation of ductus arteriosus from mature foetal lambs. Leukotrienes (LT) C4 and D4 produced a modest relaxation of the ductus but only at the highest concentrations tested (10(-7) to 10(-6) M) and under hypoxic conditions (PO2, 6--9 Torr (1 Torr = 133.322 Pa)). LTB4 had no effect at any concentration tested. BW755C (10(-6) to 10(-5) M) and FPL55712 (10(-5) M) contracted the hypoxic ductus; however, their action was abolished by pretreatment of the tissue with the cyclooxygenase inhibitor indomethacin (2.8 x 10(-6) M). Indomethacin-treated preparations were also unresponsive to ETYA 3 x 10(-5) M. The contraction of hypoxic tissues to either BW755C or FPL55712 increased further upon raising the oxygen tension of the medium (PO2 591--691 Torr). These findings indicate that leukotrienes and allied compounds formed from lipoxygenase-catalysed reactions do not contribute to prenatal patency of the ductus and are unlikely to have a role in its closure at birth. It is also confirmed that prostaglandin E2 is essential for keeping the vessel patent in the foetus.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1981

Transformations of prostaglandin H2 in the cat brain.

Transformations of prostaglandin H2 were studied in the whole homogenate and subcellular fractions (microsomes, high-speed supernatant) of the cat brain. Prostaglandin H2 was converted enzymatically to prostaglandin E2, 6-ketoprostaglandin F 1 alpha, and thromboxane B2. While prostaglandin E2 and thromboxane B2 predominated, respectively, in the whole homogenate and the microsomes, 6-ketoprostaglandin F1 alpha was formed in both tissue preparations. Pretreatment of the microsomes with reduced glutathione stimulated the formation of prostaglandin E2 at the expense of 6-ketoprostaglandin F1 alpha and thromboxane B2. Imidazole and 15-hydroperoxyarachidonic acid interfered with the microsome-induced transformations of prostaglandin H2 to thromboxane B2 and 6-ketoprostaglandin F1 alpha, respectively. No prostaglandin D2 was detected even after treatment of the tissue with reduced glutathione. Prostaglandin H2, on the other hand, was converted to prostaglandin F2 alpha, but the yield of this compound in native tissue was equal to, or lower than, that in boiled tissue. We conclude that the feline brain is endowed with several enzymes (prostaglandin E2 isomerase, thromboxane A2 and prostaglandin I2 synthetases) competing for the added endoperoxide. All enzymes were located in the microsomes. No evidence was obtained indicating enzymic reduction of prostaglandin H2 to prostaglandin F2 alpha.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Prostaglandins and the ductus arteriosus.

Fetal patency of the ductus arteriosus is an active state maintained by the relaxant action of a prostaglandin, most probably prostaglandin E2. This PG mechanism is most active in the immature ductus and decreases toward term. The ductus closes when this prostaglandin effect if withdrawn. Indomethacin may induce closure of the patent ductus arteriosus of prematurity. It is most likely to be successful if given intravenously and early in postnatal life. Prostaglandin E1, to maintain patency of the ductus, is now established in the emergency management of several congenital heart defects causing problems in the newborn.

Animals↗
PubMed1981

Enhanced beta-adrenergic-receptor responsiveness in hypoxic neonatal pulmonary circulation.

The influence of alveolar hypoxia on pulmonary vascular adrenergic receptors was studied in conscious newborn lambs. In control animals, pulmonary vessels were directly constricted by epinephrine and norepinephrine, but were unaffected by isoproterenol. Pulmonary resistance (PVR) was also unaffected by propranolol, thus implying minimal beta-receptor activity under normoxic conditions. Hypoxia raised PVR but also modified the pulmonary vascular responses to catecholamines: isoproterenol became a dilator, whereas the constrictor effects of epinephrine and norepinephrine were abolished. Although beta-blockade did not alter base-line PVR, propranolol increased the constrictor response to hypoxia, implying that hypoxia increases beta-adrenergic activity or reactivity in the pulmonary circulation. Consistent with this hypothesis are the following: 1) in alpha-blocked lambs, epinephrine was without local effects during normoxia, but caused vasodilation during hypoxia; 2) the absent constrictor response to epinephrine during hypoxia is fully restored by propranolol; and 3) although alpha-blockade blunts the hypoxic constrictor response, the full response is restored when beta-blockade is added. These results indicate that the hypoxic constrictor response is partially opposed by increased beta-mediated vasodilation. These enhanced beta-receptor effects are due, at least in part, to increased beta-receptor reactivity of unknown mechanism.

Animals↗
PubMed1980

Prostaglandins, ductus arteriosus, pulmonary circulation: current concepts and clinical potential.

Research in the past few years has established that prostaglandins, specially prostaglandin (PG) E2, are responsible for keeping the ductus arteriosus patent in the fetus. Another prostaglandin, PGI2, is likely involved in the pulmonary vasodilation occurring at birth. This knowledge has afford a new approach in the management of several pathological conditions of the newborn. PGE2 and structurally related PGE1 are currently in newborns with congenital heart lesions required patency of the ductus to maintain the pulmonary or systemic circulation. Conversely, inhibitors of prostaglandin synthesis are used for closing a patent ductus in the premature infant. Preliminary experience indicates that PGI2 can be useful in the treatment of pulmonary hypertensive disorders of the neonate.

Animals↗
PubMed1980

The response of the isolated ductus arteriosus to transmural stimulation and drugs.

1 Responses of isolated ductus arteriosus preparations from near term guinea-pigs and lambs to transmural electrical stimulation and drugs were studied in a low oxygen medium (Po(2) 19 to 28 mmHg).2 Acetylcholine and noradrenaline contracted both vessels in a dose-dependent manner, their threshold being between 10(-8) and 10(-7) M. Transmural stimulation (pulse width 0.2 to 0.6 ms, typically 20 Hz) also contracted the vessels.3 Atropine and phentolamine or dibenzyline selectively blocked responses to acetylcholine and noradrenaline, respectively.4 In the guinea-pig ductus, part of the response to transmural stimulation was due to activation of intrinsic adrenergic nerves since the responses were reduced by alpha-adrenoceptor antagonists, bretylium or prior reserpine treatment, but not by atropine. The response of the lamp ductus to transmural stimulation varied greatly in magnitude and was inconsistently affected by alpha-adrenoceptor blocking drugs.5 There was no evidence that transmural stimulation activated cholinergic nerves in either species.6 After inactivation of alpha-adrenoceptors with dibenzyline, noradrenaline caused a beta-adrenoceptor-mediated relaxation. Both this effect and isoprenaline-mediated relaxation were blocked by propranolol. beta-Adrenoceptor activity was more prominent in the ductus of the guinea-pig than of the lamb.7 Raising the Po(2) from 19-28 to 92-98 mmHg increased the response of the guinea-pig ductus to transmural stimulation suggesting that, in this species, physiological elevation of oxygen tension at birth may increase transmitter release from intrinsic adrenergic nerves. Whether this mechanism would contribute to ductus closure remains an open question.8 We postulate that beta-adrenoceptor-mediated relaxation has a role in maintaining ductus patency in the guinea-pig foetus.

Acetylcholine↗
PubMed1980

The effect of alveolar hypoxia on pulmonary vascular responsiveness in the conscious newborn lamb.

To determine the effect of alveolar hypoxia and consequent increased pulmonary vascular tone on the responsiveness of the neonatal pulmonary circulation, we studied the local pulmonary vascular effects of acetylcholine, bradykinin, and histamine in the normoxic and hypoxic newborn lamb. Right and left pulmonary flows were continuously monitored from chronically implanted electromagnetic flow probes, agents were injected into only one lung, and changes in the proportion of pulmonary blood flow directed to the injected lung (Qinj/QT) provided a measure of active local pulmonary vascular constriction or dilation. At maximally tolerated doses, hypoxia enhanced the dilatory effects of acetylcholine and diminished the constrictor effects of histamine but hypoxia had a minimal effect on the maximal dilatation induced by bradykinin. Hypoxia did appear to lower the threshold dose for bradykinin's effects. These results demonstrate that base-line conditions may qualitatively alter the responsiveness of the neonatal pulmonary circulation to several drugs. In these agents, increased base-line tone generally augmented dilatory effects and diminished constrictor effects. However, the lack of such an effect on the dilator response to a high dose of bradykinin suggests the possibility that hypoxic-induced changes in pulmonary vascular responsiveness may not be entirely passive. Further, these results do not support the hypothesis that hypoxic-induced vasoconstriction is mediated by decreased production of bradykinin.

Acetylcholine↗