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Biomedical subjects

A Genovese

Publications and source records attributed to A Genovese.

At least 55 records · Page 3Linked to original sources

Pathophysiology of human basophils and mast cells in allergic disorders.

Basophil leukocytes and tissue mast cells are inflammatory cells that are found in virtually all human tissues. They appear to be involved in the pathogenesis of such allergic diseases as allergic rhinitis, bronchial asthma, anaphylaxis, atopic and contact dermatitis, chronic urticaria, and hypersensitivity pneumonitis. By releasing a variety of chemical mediators, they could also play a role in the pathophysiology of a wide range of inflammatory disorders of the joints, and of intestine, lung, coronary, and myocardial diseases. Although these two cell types are similar in several aspects, striking differences have also been observed. Moreover, human mast cells from different anatomical sites and within an individual tissue synthesize different mediators and have different release mechanisms. The recent advent of techniques that yield highly purified basophils and mast cells from diverse tissues will probably lead to major advancements in understanding the biochemical and pharmacological mechanisms that control the release process of these cells. The release of mediators from these cells is also controlled by a series of largely undefined biochemical steps that represent the basis of the concept of basophil and mast cell releasability. Alterations of basophil or mast cell releasability have already been detected in patients with allergic rhinitis, bronchial asthma, atopic dermatitis, and chronic urticaria. Taken together, these findings demonstrate that basophils, mast cells, and their chemical mediators play a pivotal role in several inflammatory disorders.

Animals↗

Adenosine promotes histamine H1-mediated negative chronotropic and inotropic effects on human atrial myocardium.

Because histamine and adenosine are coreleased from the ischemic heart, we investigated the effects of their interaction on human myocardium. Surgical specimens of human right atrium (i.e., pectinate muscles) responded to histamine with increases in spontaneous rate and contractile force. Adenosine, and the A1-selective adenosine agonist N6-cyclopentyladenosine (CPA), reduced the spontaneous rate and suppressed the positive chronotropic and inotropic effects of histamine. CPA was more potent than adenosine in slowing the spontaneous rate and in suppressing histamine's positive chronotropic effect, suggesting that the responses to CPA and adenosine are A1-mediated. CPA was also more potent than adenosine in attenuating histamine's positive inotropic effect on human ventricular papillary muscle. The adenosine-induced suppression of histamine's effects on pectinate muscles was mimicked by carbachol, which like adenosine is known to attenuate H2-mediated histamine-induced adenylate cyclase activation. The H1-selective histamine antagonist pyrilamine potentiated histamine's chronotropic and inotropic responses, and inhibited the attenuation of these responses by adenosine or carbachol. In contrast, pyrilamine failed to modify the adenosine-induced attenuation of the cardiac stimulatory effects of dimaprit, an H2-selective histamine agonist. Our data suggest that adenosine-induced suppression of histamine's positive chronotropic and inotropic effects on human myocardium results both from an A1-mediated attenuation of H2-stimulatory effects and from the uncovering of H1 negative chronotropic and inotropic effects. Thus, the results of the histamine-adenosine interaction may exceed the "retaliatory" purpose of adenosine release and uncover H1-mediated myocardial depression.

Adenosine↗

Inhibition of IgE-mediated release of histamine and peptide leukotriene from human basophils and mast cells by forskolin.

Forskolin, a diterpene compound isolated from the roots of Coleus forskohlii, activates adenylate cyclase in membranes from a variety of mammalian tissues. We found that forskolin (10(-7) to 3 X 10(-5) M) caused a concentration-related inhibition of IgE-mediated release of histamine and peptide leukotriene C4 (LTC4) from human basophils and lung mast cells. There was a significant linear correlation between the per cent inhibition of histamine and LTC4 release from both cell types. However, in both systems forskolin exerted a significantly greater inhibitory effect on LTC4 release than on histamine release. The concentration-response inhibition curve was paralleled by a forskolin-induced rise in cAMP levels in human leukocyte and mast cell preparations. The relationship between the effect of forskolin and the cAMP concentration was supported by the finding that forskolin inhibited the "first stage" of antigen-induced histamine release, but not the release caused by the Ca2+ ionophore, A23187. Propranolol, a competitive beta-receptor antagonist, did not block the inhibition of mediator release or the cAMP accumulation caused by forskolin. These data suggest that forskolin modulates the release of mediators of immediate hypersensitivity reactions via the activation of adenylate cyclase in human basophils and mast cells.

Adenylyl Cyclases↗

Betamethasone modulates the biological function of human polymorphonuclear leukocytes.

We have examined the influence of betamethasone (BT) on cyclic AMP (cAMP) metabolism and lysosomal enzyme release from highly purified (approximately equal to 99%) human polymorphonuclear leukocytes (PMNs). Preincubation (1-24 h) of human PMNs with BT (10(-9)-10(-5) M) had no effect on either cAMP content or on beta-glucuronidase release induced by formyl-containing tripeptide (f-met peptide). Preincubation (16-24 h) of PMNs with BT (10(-8)-10(-7) M) dose-dependently potentiated the cAMP accumulation caused by beta-agonists (isoproterenol), adenosine A2/Ra agonist (NECA), prostaglandin E1 (PGE1) and histamine in PMNs. Similarly, BT potentiated the inhibition of f-met peptide-induced beta-glucuronidase release from human PMNs caused by PGE1 (10(-6) M), histamine (2 X 10(-5) M), NECA (10(-4) M) and isoproterenol (10(-6) M).

Adenylyl Cyclases↗

Adenosine antagonizes the histamine-induced stimulation of human atrial myocardium: protection by H1-receptor blockade.

The inotropic effect of histamine on the human myocardium consists of two opposing components: positive, H2-mediated, and negative, H1-mediated. Because adenosine is known to antagonize histamine H2-responses, we assessed whether adenosine may unmask H1-mediated histamine responses in human myocardium. We found that adenosine modulates the stimulatory effects of histamine on pectinate muscles isolated from human right atrium and converts them as a function of its concentration from positive to negative. Further, histamine potentiated the tendency of adenosine to induce cardiac arrest. The H1-blocker pyrilamine antagonized the adenosine-induced suppression of the positive inotropic and chronotropic effects of histamine. Thus, our data indicate that the negative inotropic and chronotropic effects of histamine in the presence of adenosine result in part from an antagonism of H2-mediated increases in rate and contractility, and in part from an unmasking of H1-mediated decreases in the same parameters. Adenosine and histamine may be co-released in response to hypoxia or ischemia. In spite of the protection that adenosine may afford the human myocardium against excessive histamine stimulation, adenosine may also unmask the inhibitory actions of histamine, promoting dysrhythmia, and negative inotropic and chronotropic effects.

Adenosine↗

Negative inotropic effect of platelet-activating factor on human myocardium: a pharmacological study.

Because platelet-activating factor (PAF) has prominent depressant effects on cardiac contractility in various mammalian species, we assessed the negative inotropic effect of PAF on non-coronary perfused human right atrial pectinate muscles paced at constant rate. We found that PAF is a potent negative inotropic agent (EC50 approximately equal to 160 pM), whose action is unmodified by atropine, indomethacin and the leukotriene receptor antagonist compound FPL 55712. The negative inotropic effect of PAF was, however, antagonized by drugs known to inhibit PAF-induced platelet aggregation: the order of relative potency was SRI 63-441 greater than CV-3988 greater than alprazolam greater than or equal to triazolam; i.e., the same order in which these compounds antagonize the effects of PAF on platelets. Thus, the potent negative inotropic effect of PAF on human myocardium is independent of coronary flow changes, involves neither cholinergic mechanisms nor arachidonate metabolites and is probably mediated by specific receptors.

Calcium↗

Iatrogenic occlusion of the left anterior descending coronary artery. A case report.

A 27-year-old man with mixed aortic stenosis and regurgitation formerly stabbed in the left anterior part of the chest was admitted to our department with dyspnea. Coronary arteriography, performed during cardiac catheterization, showed total occlusion of the left anterior descending coronary artery. The Authors point out the iatrogenic cause of the coronary occlusion. It was due to ligation of the artery when suturing the ventricular wound.

Adult↗

Evidence for an adenosine A2/Ra receptor on human basophils.

5'-N-ethylcarboxamideadenosine (NECA) greater than 2-chloroadenosine greater than adenosine greater than (-)-N6-(R-phenyl-isopropyl)-adenosine greater than (+)-N6-(S-phenylisopropyl)-adenosine, in that order of potency, inhibited in vitro antigen-induced histamine release from human basophils in a dose-dependent fashion. Inhibition occurred only during the first stage of antigen-induced histamine release and the nucleosides failed to inhibit the release caused by the Ca2+ ionophore, A23187. 6-nitrobenzylthioinosine and dipyridamole, which inhibit adenosine uptake, and erythro-9-(2-hydroxy-3-nonyl)adenine, which blocks adenosine metabolism, did not impair the inhibition caused by NECA and adenosine. 8-phenyltheophylline and theophylline, two competitive antagonists of adenosine receptors, blocked the inhibition caused by NECA and adenosine. These data suggest that NECA and other adenosine analogs activate a specific cell surface adenosine receptor which possesses properties similar to those of an adenosine A2/Ra receptor.

Adenosine↗

Non-invasive assessment of electrophysiological effects of histamine infusion in man.

The electrophysiological changes induced by sequential infusion of histamine (H) (0.4 and 1.0 mcg/kg/min for 10 min each) were investigated by conventional ECG and High Resolution ECG (H.R.ECG). The latter permits external non-invasive recording of the potentials generated in the cardiac conduction system. H was infused i.v. in 5 normal volunteers with a mean age of 30 years. H infusions were begun with 0.4 mcg/kg/min and continued for 10 min. After a 60 min recovery period a second 10 min infusion (1 mcg/kg/min) was administered. In man H produced a dose-dependent increase in heart rate, a significant depression of the ST-T complex, and a depression in STJ point. The QRS complex duration was unmodified. H.R.ECG showed significant changes in the morphology and voltage of the atrial activity. The electrophysiological effects disappeared within a few minutes after discontinuing the infusions of H.

Adolescent↗

Histamine and human heart.

Heart fragments obtained from human right atrium contain 1.5 +/- 0.2 micrograms of histamine per gram of wet tissue. Human heart spontaneously synthesizes significant amounts of PGI2, PGF2 alpha, PGE2 and TxA2. The Ca2+ ionophore A 23187 (0.5-3 micrograms/ml) dose-dependently induces histamine release and prostanoid production. Histamine (0.5-1 micrograms/kg/min) infusion in 10 normal donors produced an increase in heart rate and a significant depression of the ST segment. Selective H1 receptor stimulation in patients undergoing cardiac catheterization resulted in a decrease of the mean aortic pressure and of coronary vascular resistance.

Basophils↗

Myocardial hypertrophy in rats exposed to simulated high altitude.

Myocardial hypertrophy in Sprague-Dawley adult rats exposed to hypobaric hypoxia (0.40 atmosphere of air/18 h daily for 7 days) in a hypobaric chamber was investigated. Changes in the myocardial mass were evaluated on the basis of the dry heart weight and expressed as mg/100 g of total body weight (mean +/- SEM). Data are presented indicating that: chronic hypobaric hypoxia causes a significant degree of myocardial hypertrophy in rats; hypertrophic process involves both ventricles (the right more than the left); removal of the hypoxic stimulus leads to the disappearance of hypertrophy when evaluated as an increase in dry heart weight; hypoxia affects the synthesis of a significant amount of connective tissue in the left ventricle, which is not exposed to pressure load. The rôle of neurohumoral factors (i.e., adrenergic stimulation and catecholamines) in the development of the ventricular hypertrophy is suggested.

Altitude↗

Adrenergic activity as a modulating factor in the genesis of myocardial hypertrophy in the rat.

Sprague Dawley male rats (200-220 g) were subjected to a long-term treatment with low doses of catecholamines in an attempt to assess the effect of the adrenergic stimulation on ventricular weights, hemodynamics, and hydroxyproline content in the myocardium. Data are presented indicating that both exogenous catecholamines (i.e., isoproterenol) and endogenous catecholamines (released from tyramine) are able to bring about a degree of myocardial hypertrophy associated with a significant increase in the ventricular concentrations of hydroxyproline, without affecting hemodynamic parameters (blood pressures and heart rate). Thus the modulation of sympathetic tone in the genesis of cardiac hypertrophy is demonstrated, and a direct effect of the catecholamines on cardiac cells is postulated which is independent of hemodynamic changes.

Animals↗

Effect of experimental infarct on the mortality rate in alloxan-diabetic rats.

The authors report the wide mortality observed in alloxan diabetic rats infarcted with large doses of isoproterenol. The experimental data are in line with the results of clinical studies testifying that the diabetic disease involves the cardiovascular system and affects the prognosis of myocardial infarct. These experiences do not permit to define the direct mechanism(s) responsible for the high mortality in diabetic infarcted rats over controls (diabetic not infarcted); however these results give rise to a discussion on the following topics: 1. The damage of intramural coronary vessels as a cause of depressed cardiac contractility in diabetic rats. 2. The role of reduced plasmatic levels of insulin in depressing myocardial performance in alloxan diabetic rats. 3. The hyperglycaemia-provoking effect of isoproterenol as a contributing factor in the death of diabetic rats. 4. The possible direct action of diabetogenic doses of alloxan on the myocardium.

Alloxan↗

Diastolic time during exercise in normal subjects and in patients with coronary artery disease. A plethysmographic study.

Percent diastole (%D) was evaluated at rest and during effort (submaximal upright exercise) in 13 normal subjects and in 14 age-matched patients with coronary artery disease (CAD). Systolic time intervals were also simultaneously recorded by using the thermistor pulse transducer. At rest, in both groups, a positive linear regression was found between %D and cycle length (RR) (%D = 19.1 + 0.044RR, r = 0.83 in normals; %D = 21.2 + 0.044RR, r = 0.88 in CAD). During effort, while in normals no correlation was found between %D and RR values, in CAD patients %D and RR were linearly related (%D = -12.81 + 0.087RR, r = 0.67). These results prove that diastolic time is differently affected by the exercise in the two examined groups and that in CAD patients an abnormal reduction of %D occurs during stress test.

Adult↗

Inhibition of IgE-mediated histamine release from human basophils and mast cells by fenoterol.

Fenoterol, a beta 2-adrenergic agonist recently introduced to treat asthmatic disorders, inhibits antigen-induced histamine release from human basophil leukocytes and lung mast cells in a dose-dependent fashion. The dose-response inhibition curve is paralleled by a fenoterol-induced increase in the cAMP levels of human leukocyte preparations. The relationship between the effect of fenoterol and cAMP level is supported by the finding that the beta 2-adrenergic agonist only inhibits the first stage of antigen-induced histamine release and not the release caused by the Ca2+ ionophore, A23187. Propranolol, a competitive antagonist of beta 2-adrenergic receptor, blocks the inhibition of release and the cAMP accumulation caused by fenoterol. Finally, theophylline, a cAMP phosphodiesterase inhibitor, synergistically potentiates the inhibitory effect of fenoterol on histamine release and the accumulation of cAMP. These data suggest that fenoterol may modulate the in vivo release of the mediators of immediate hypersensitivity reactions via the activation of beta 2-adrenergic receptor linked to adenylate cyclase on human basophils and mast cells.

Adolescent↗

Possible role of calmodulin in the control of lysosomal enzyme release from human polymorphonuclear leukocytes.

Human polymorphonuclear leukocytes (PMNs) were found to contain a mean +/- S.E.M. of 21.7 +/- 7.9 ng of immunoreactive calmodulin (CaM)/10(6) PMNs, which represents 0.032 +/- 0.001% of the total cellular protein. The functional role of CaM in the control of lysosomal enzyme release from human PMNs was investigated using several CaM antagonists. Trifluoperazine (TFP) (10(-6)-2 X 10(-5) M), pimozide (10(-6)-1.5 X 10(-5) M), chlorpromazine (CPZ) (10(-5)-10(-4) M) and promethazine (2 X 10(-5)-10(-4) M) inhibited in vitro lysosomal enzyme release from human PMNs induced by immunological (serum-treated zymosan, concanavalin A and formyl-L-methionyl-L-leucyl-L-phenylalanine) and nonimmunological (Ca++ ionophore A23187) stimuli. Trifluoperazine sulfoxide (TFP-S) and chlorpromazine sulfoxide (CPZ-S), which have very low affinity for CaM, had practically no inhibitory effect on lysosomal enzyme release. The inhibitory effect of TFP could be made irreversible by irradiating the cells with UV light. A sulfonamide derivative, W-7, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (10(-5)-2 X 10(-4) M), which selectively binds to CaM, inhibited the release of lysosomal enzymes from PMNs. In contrast, the chloride-deficient analog, W-5, N-(6-aminohexyl)-1-naphthalenesulfonamide hydrochloride, which interacts only weakly with CaM, had practically no inhibiting effect. The IC50 for enzyme release by a series of eight CaM antagonists was closely correlated (r = 0.89; P less than .001) with their affinity for binding to CaM, supporting the concept that these agents act by binding to CaM and thereby inhibiting lysosomal enzyme release.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗

Response of the left ventricular connective tissue to hypoxia.

The collagen content (measured as myocardial concentration of hydroxyproline) and dry weight (expressed as ventricle weight to body weight ratio) were determined in the left ventricle of male Sprague-Dawley rats (200--220 g b.wt.) exposed to a simulated altitude of 7,000 m for 18 h a day for 10 days in a hypobaric chamber. Hypoxia resulted in a significant increase (P less than 0.001) in the mass of the left ventricle with a concomitant significantly increased collagen concentration (P less than 0.001). The data indicate that hypoxia effects the synthesis of a significant amount of connective tissue in the left ventricle, which is the ventricle not exposed to pressure load. These results may be related to clinical, hemodynamic, and pathologic observations showing the left ventricular dysfunction in patients with chronic respiratory insufficiency. Since the amount of collagen in the left ventricle might interfere with contractile function, it is suggested that the hypoxia in these patients could affect the left ventricular myocardium via a direct action on the connective metabolism.

Aerobiosis↗