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Biomedical subjects

H Lippton

Publications and source records attributed to H Lippton.

10 recordsLinked to original sources
PubMed1992

Contrasting effects of misoprostol on systemic and intrapulmonary lipopolysaccharide-induced tumor necrosis factor-alpha.

Tumor necrosis factor-alpha (TNF), a cytokine produced by mononuclear phagocytes in response to lipopolysaccharide stimulation, is a potent mediator of the inflammatory cascade. However, the immunomodulatory signals regulating TNF expression in the host are poorly defined. Recently, metabolites of the prostaglandin E series have been shown to inhibit TNF production in vitro. In order to determine if PGE1 alters TNF activity in vivo, rats were given misoprostol, a synthetic PGE1 analogue, or saline by gavage and subsequently challenged with either intravenous or intratracheal Escherichia coli lipopolysaccharide. These in vivo data show that PGE1 is a potent inhibitor of TNF production by systemic mononuclear phagocytes. In contrast, alveolar macrophages appear to be refractory to misoprostol's suppressive effects on LPS-induced TNF. This study supports in vitro observations that mononuclear phagocytes within different compartments exhibit differential responsiveness to immunomodulators.

Animals↗
PubMed1992

CGRP and somatostatin modulate chronic hypoxic pulmonary hypertension.

Chronic hypoxic pulmonary hypertension (PH), associated with increased pulmonary arterial pressure (PPA) and right ventricular hypertrophy (RVH), correlates significantly with calcitonin gene-related peptide (CGRP) and somatostatin (SOM) levels in lung and blood. CGRP's role in regulation of PPA in chronic hypoxia and its potential interactions with SOM were investigated. CGRP, its antibody (ab) and blocker, CGRP-(8-37), SOM-14, SOM-28, and SOM-ab, respectively, were infused into the pulmonary circulation of hypobaric hypoxia rats for 4, 8, and 16 days. Thereafter, under pentobarbital sodium anesthesia, PPA was measured in the right ventricle and main pulmonary artery. Chronic CGRP infusion prevented PH at all times, whereas immunoneutralization and receptor blocking exacerbated PH. SOM-28 also exacerbated while SOM-14 and SOM-ab decreased PH. RVH generally reflected the PPA. Radioimmunoassay confirmed successful infusion of the peptides with negligible peptide degradation in the pumps throughout 16 days and showed complete immunoneutralization of CGRP with its ab. Peptide levels in lung tissue suggest inhibition of CGRP release by SOM-28 and increased plasma SOM with CGRP infusion. In vitro pharmacological studies suggest that CGRP exerts a receptor-mediated nonadrenergic, nonmuscarinic vasodilatory effect in the lung which is independent of endothelium-derived relaxing factor and does not involve ATP-dependent potassium channels. We conclude that endogenous CGRP plays an important role in pulmonary pressure homeostasis during hypoxia, by directly dilating pulmonary vasculature, thus ameliorating the development of chronic hypoxic pulmonary hypertension in rats.

Animals↗
PubMed1992

Relapsing polychondritis: new pulmonary manifestations.

Relapsing polychondritis is purported to be an autoimmune disease characterized by inflammation of cartilaginous structures including the nose, ears, glottis, trachea, and mainstem bronchi. Arthropathy, aortopathy, scleritis, conjunctivitis, iritis, vertigo, otitis media, glomerulonephritis, and skin lesions are common manifestations. We have recently cared for an elderly nonsmoker with a history of abdominal aortic aneurysm repair and recurrent bouts of painful ear swelling who presented with a pulmonary infiltrate and pulmonary function studies suggestive of small airways disease. Subsequent transbronchial biopsy revealed no pathogens but was associated with excessive bleeding, perhaps suggestive of a vasculitic process in the lung. The pulmonary infiltrate cleared over a 2-month interval with the use of corticosteroids. Unusual in this otherwise classical case of relapsing polychondritis was that the pulmonary infiltrate and small airways disease were the prominent pulmonary manifestations and no tracheobronchial abnormalities were visualized.

Adrenal Cortex Hormones↗
PubMed1990

Endothelin and platelet function.

The effects of newly discovered vasoconstrictor peptide endothelin was studied on human, rabbit and canine platelet function. Endothelin (0.01 nM-1 microM) did not promote platelet aggregation. In human platelets, endothelin (0.1 microM) did not significantly affect aggregation responses to ADP, collagen, epinephrine, arachidonic acid, PGH2 or thrombin. Endothelin did not promote the mobilization of intracellular calcium in Fura2 loaded human platelets. In rabbit and canine platelets endothelin produced significant potentiation of platelet aggregation mediated by low concentrations of ADP. Aggregation responses to higher concentration of ADP (5 microM) were unaffected by endothelin. These data reveal that under certain circumstances endothelin may potentiate rabbit and canine platelet aggregation responses to ADP, however endothelin does not produce direct effects on human platelet function.

Adenosine Diphosphate↗
PubMed1990

Pentoxifylline inhibits lipopolysaccharide-induced serum tumor necrosis factor and mortality.

Tumor necrosis factor, a mononuclear phagocyte-derived peptide produced in response to lipopolysaccharide, has been shown to mediate certain aspects of septic shock and multiple organ failure resulting from gram-negative septicemia. In the present investigation, pretreatment of animals with pentoxifylline inhibited lipopolysaccharide-induced serum tumor necrosis factor in a dose-dependent fashion. Pentoxifylline prevented the sequestration of neutrophils seen in animals given intravenous lipopolysaccharide. Furthermore, pentoxifylline protected animals from the lethal effects of an intravenous challenge with lipopolysaccharide. These data indicate that pentoxifylline inhibits lipopolysaccharide-induced tumor necrosis factor and may be an effective agent in mitigating the lethal consequences of sepsis and other disease processes mediated by this cytokine.

Animals↗
PubMed1990

Vasodilator activity of endothelin-1 and endothelin-3: rapid development of cross-tachyphylaxis and dependence on the rate of endothelin administration.

In pentobarbital anesthetized cats, i.v. bolus injections of endothelin-1 (ET-1, 1 microgram) and ET-3 (3 micrograms) produced a rapidly appearing but short-lasting fall in aortic blood pressure followed in the case of ET-1 only by a small pressor response. When these peptides were administered repeatedly after 10- to 12-min intervals, there was a gradual attenuation of the hypotension that by the fourth injection was replaced by a monophasic pressor response. The i.v. infusion of ET-1 (0.3 microgram/min) or ET-3 (0.9 microgram/min) for 20 min produced sole systemic vasoconstriction. The decrease in blood pressure produced by an i.v. bolus injection of ET-1 and ET-3 was no longer observed 5 min after the end of the ET-1 or ET-3 infusion. In contrast, the hypotensive activity of bradykinin was not modified after the depressor responses to ET-1 and ET-3 had disappeared. Thus, the failure of i.v. bolus injections of ET-1 and ET-3 to lower blood pressure under these experimental conditions cannot be attributed to the development of tachyphylaxis to endogenous endothelium-derived relaxant factor, which is known to mediate the effects of bradykinin. These results suggest that ET-1 and ET-3 share a single vascular receptor for vasodilation, which becomes refractory upon repeated or maintained exposure to these peptides. Alternatively, this refractoriness may be due to depletion of an intracellular mediator(s) that is jointly used by the membrane binding sites of ET-1 and ET-3. Moreover, the present data suggest that the vasodilator activity of ETs depends on the rate of the peptide administration.

Animals↗
PubMed1990

Hemodynamic and pharmacological evaluation of the vasodilator and vasoconstrictor effects of endothelin-1 in rats.

In awake normotensive and spontaneously hypertensive rats as well as pentobarbital-anesthetized normotensive rats, endothelin-1 (ET-1, 0.063-0.5 nmol/kg i.v.) produced rapidly appearing, transient, dose-related falls in mean carotid artery blood pressure followed by slowly developing small pressor responses. In the latter preparation, the hypotension was due to a decrease in systemic vascular resistance inasmuch as cardiac output increased slightly. Bilateral vagotomy, BW 755c, glibenclamide, idazoxan, propranolol, methylatropine, methysergide or promethazine pretreatment failed to modify the hypotension induced by ET-1 (0.25 nmol/kg i.v.), but this effect was blocked entirely when ET-1 was injected 8 min after starting an i.v. infusion of ET-1 (0.1 nmol/kg/min for 10 min). In pithed rats, ET-1 (0.125-1.0 nmol/kg i.v.) produced sustained pressor responses which were accompanied by reductions in cardiac output. This peptide (0.25 nmol/kg i.v.) did not affect renal vascular resistance significantly but increased (200%) mesenteric resistance substantially more (3-fold) than systemic or hindquarter resistance. The pressor effects of ET-1 were reduced by diltiazem, nitrendipine, verapamil or cromakalim and unchanged after BW 755c, desipramine, enalapril, indomethacin, methysergide, phentolamine or SK&F 100273. The sustained pressor response evoked by an i.v. infusion of ET-1 (0.25 nmol/kg/min/60 min) was also antagonized markedly by nitrendipine and cromakalim. In pithed rats with vasopressin-supported blood pressure, ET-1 produced a short-lasting hypotension which faded entirely after three successive injections of the peptide. Finally, ET-1 (0.4-0.8 nM) evoked greater contractile responses in rat aortic rings deprived of a functional endothelium than in intact preparations. However, in the latter preparation precontracted with norepinephrine, ET-1, in contrast to acetylcholine, failed to evoke vasorelaxation. In aortic rings, the sustained contractile effects of ET-1 (3.2 nM) were reduced moderately by nitrendipine (50 nM) and markedly by cromakalim (0.8 microM). In contrast, the latter compounds antagonized strongly the contractile response to KCl (25 mM). In conclusion, ET-1 appears to produce active vasorelaxation and vasoconstriction via stimulation of specific receptors on blood vessels. The tolerance to the hypotensive effect of ET-1 may indicate that either the receptor site for ET-1 becomes refractory or, alternatively, it is coupled to easily depletable endogenous hypotensive mediators. Finally, inasmuch as the vasoconstrictor effects of ET-1 can be easily counteracted by calcium antagonists under in vivo but not in vitro conditions, the membrane coupling mechanism for ET-1 may not be exactly the same in conductance or resistance vessels.

Animals↗
PubMed1989

Adenosine does not mediate the pulmonary vasodilator response of adenosine 5'-triphosphate in the feline pulmonary vascular bed.

Adenosine and ATP produce dose- and tone-dependent responses in the feline pulmonary vascular bed. That is, at baseline (low) pulmonary vascular tone adenosine and ATP produce vasoconstrictor responses and at elevated pulmonary vascular tone adenosine and ATP produce vasodilator responses. The mechanism mediating the vasodilator responses to adenosine and ATP was investigated in the intact-chest cat under conditions of controlled pulmonary blood flow and left atrial pressure. When lobar vascular resistance was raised with U46619, intralobar injections of adenosine and ATP caused dose-related decreases in lobar arterial pressure. The pulmonary vasodilator responses to ATP and adenosine were not altered by atropine, propranolol, meclofenamate or cimetidine indicating that these responses were not mediated by the release of vasodilator prostaglandins or to activation of beta adrenergic, muscarinic or histamine (H2) receptors. The decreases in lobar arterial pressure in response to adenosine were reduced significantly by BWA1433U, an adenosine (P1) receptor antagonist. BWA1433U induced a parallel shift of the adenosine dose-response curve to the right; however, it had no significant inhibitory effect on the decrease in lobar arterial pressure in response to ATP. The P1 receptor antagonist in doses of 10 and 30 mg/kg i.v. had no significant effect on the vasodilator response to nitroglycerin. The present data suggest that vasodilator responses to adenosine in the feline pulmonary vascular bed are mediated by adenosine (P1) receptors, whereas responses to ATP are mediated by a different mechanism that does not involve release of a vasodilator prostaglandin.

Adenosine↗
PubMedDate not supplied

Hemodynamic actions of endothelin in conscious and anesthetized dogs.

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.

Anesthesia, General↗