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Biomedical subjects

R Levi

Publications and source records attributed to R Levi.

At least 163 records · Page 9Linked to original sources
PubMed1986

Effect of PGD2 on cardiac contractility: a negative inotropism secondary to coronary vasoconstriction conceals a primary positive inotropic action.

The purpose of this study was to characterize by pharmacological means the inotropic action of prostaglandin D2 (PGD2) in the guinea-pig heart. In the whole heart perfused at constant pressure, PGD2 (0.01-10 micrograms) reduced coronary flow rate and decreased left ventricular contractile force in a dose-dependent manner. When the coronary vasoconstricting effect of PGD2 was antagonized by the PG antagonist sodium p-benzyl-4[1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl]phenyl phosphonate (N-0164), by the cyclooxygenase inhibitor indomethacin or by the thromboxane synthetase inhibitor sodium (E)-3-[4-(1-imidazolyl-methyl)phenyl]-2-propanoate (OKY 046), the negative inotropic response to PGD2 was attenuated or completely abolished and a positive inotropic effect was unmasked. In the isolated left atrium or right ventricular papillary muscle preparations, PGD2 induced only a positive inotropic response. The atrial response to PGD2 was unaffected by N-0164, indomethacin or propranolol but was markedly decreased by carbachol or adenosine. Conversely, the response of the papillary muscle to PGD2 was potentiated by papaverine. Thus, these data indicate that PGD2 has a primary positive inotropic effect, which may involve cyclic AMP metabolism. On the other hand, because PGD2 is also a potent coronary vasoconstrictor, the secondary negative inotropic effect of PGD2 predominates.

Animals↗
PubMed1985

Cardiac dysfunction caused by purified human C3a anaphylatoxin.

The purpose of this investigation was to define the cardiac effects of complement-derived C3a anaphylatoxin, in view of the possibility that cardiac dysfunction may occur as a result of complement activation. Purified human C3a was administered by intracoronary bolus injections into isolated guinea pig hearts. As a function of dose, C3a caused tachycardia, impairment of atrioventricular conduction, left ventricular contractile failure, coronary vasoconstriction, and histamine release. These effects were abolished by cleavage of the COOH-terminal arginine by carboxypeptidase B. The magnitude of C3a-induced tachycardia correlated with the amount of endogenous cardiac histamine released into the coronary effluent. Whereas the tachycardia was markedly reduced by the histamine H2 antagonist cimetidine, the contractile failure and the coronary vasoconstriction caused by C3a were antagonized by the leukotriene antagonist FPL 55712 and by the cyclooxygenase inhibitor indomethacin, respectively. This suggests that histamine, leukotrienes, and vasoactive prostanoates may mediate the various cardiac effects of C3a. Our findings indicate that C3a anaphylatoxin has marked cardiac effects at concentrations that are likely to be attained with a degree of C3 activation commonly seen in various disease states. Thus, our data are compatible with the hypothesis that generation of anaphylatoxins may induce cardiac dysfunction in clinical conditions.

Anaphylatoxins↗
PubMed1984

A computerized decision support system for patient selection in dental education.

A computerized decision support system is presented. The system is used to aid in the situation of patient selection for the purpose of dental education and utilizes the PERT/CPM methodology and decision tables. It runs on a microcomputer and written in Basic. The input is a list of patient's needs, and the output is a tentative treatment plan, the chair time needed to complete the treatment, its cost, and the probability that the student will finish it on time.

Appointments and Schedules↗
PubMed1984

Channel currents during spontaneous action potentials in embryonic chick heart cells. The action potential patch clamp.

Single-channel currents were recorded with the cell-attached patch-clamp technique from small clusters (2-20 cells) of spontaneously beating 7-d embryo ventricle cells. Because the preparation was rhythmically active, the trans-patch potential varied with the action potential (AP). The total current through the patch membrane was the patch action current (AC). ACs and APs could be recorded simultaneously, with two electrodes, or sequentially with one electrode. Channel activity, which varied depending on the number and type of channels in the patch, was present during normal cell firing. This method can reveal the kinetics and magnitudes of the specific currents that contributed to the AP, under conditions that reflect not only the time and voltage dependence of the channels, but also environmental factors that may influence channel behavior during the AP.

Action Potentials↗
PubMed1984

Acetyl glyceryl ether phosphorylcholine (AGEPC). A putative mediator of cardiac anaphylaxis in the guinea pig.

Platelet-activating factor is a novel phospholipid that has been implicated as an important mediator of acute allergic reactions. The intravenous administration of acetyl glyceryl ether phosphorylcholine, a pure, synthetic platelet-activating factor, causes electrocardiographic changes in the rabbit similar to those which are characteristic manifestations of systemic anaphylaxis. To determine whether platelet-activating factor contributes to anaphylactic cardiac dysfunction, we measured platelet-activating factor release from the sensitized guinea pig heart challenged in vitro with specific antigen and compared the resulting cardiac dysfunction with that induced by the injection of acetyl glyceryl ether phosphorylcholine into nonsensitized hearts. The results of these studies document that, during anaphylaxis in the isolated guinea pig heart, a platelet-activating factor is released into the coronary effluent that has physicochemical and functional properties similar to those of acetyl glyceryl ether phosphorylcholine. The intracardiac administration of acetyl glyceryl ether phosphorylcholine (10(-14) to 3 X 10(-9) mol) induced dose-related decreases in left ventricular contractile force (-5 to -85%) and coronary flow (-5 to -85%), as well as impaired atrioventricular conduction. The negative inotropic effect of acetyl glyceryl ether phosphorylcholine also was present in hearts perfused at constant flow. Although, in these hearts, acetyl glyceryl ether phosphorylcholine increased coronary resistance, which may have caused regional shunting and ischemia, it is unlikely that the negative inotropic effect of acetyl glyceryl ether phosphorylcholine was secondary to changes in coronary flow, since acetyl glyceryl ether phosphorylcholine also caused a dose-dependent negative inotropic effect in the electrically paced, noncoronary-perfused left atrium and right ventricular papillary muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis↗
PubMed1984

Release of histamine by sympathetic nerve stimulation in the guinea pig heart and modulation of adrenergic responses. A physiological role for cardiac histamine?

Histamine has been reported to attenuate adrenergic responses in cardiovascular tissues. In guinea pig atria preloaded with [3H]norepinephrine, histamine diminishes the field stimulation-induced efflux of radioactivity; this effect has been attributed to an inhibition of norepinephrine release from nerve endings. To assess the possible physiological relevance of these findings, we have reinvestigated the effects of histamine on cardiac sympathetic responses and on the release of endogenous norepinephrine in the guinea pig heart isolated with its intact sympathetic innervation. Heart rate, left ventricular contractile force, and perfusion pressure all increased with increasing frequencies of sympathetic nerve stimulation (2-8 Hz). Histamine (3 X 10(-8) to 3 X 10(-7) M) caused dose-dependent attenuation of the responses to sympathetic stimulation. The ability of histamine to modulate nerve stimulation-induced norepinephrine overflow into the coronary effluent was dependent on whether the heart had been preloaded with norepinephrine. Whereas histamine did not cause a significant reduction in nerve stimulation-induced norepinephrine overflow in hearts from untreated animals, histamine significantly reduced stimulation-induced norepinephrine overflow in hearts from guinea pigs that had been pretreated with norepinephrine before sacrifice. Histamine also attenuated the increases in left ventricular contractile force, perfusion pressure, and heart rate, which result from the intracardiac administration of norepinephrine (0.16-microgram bolus injection). In this respect, histamine was as effective as it was in inhibiting the responses elicited by nerve stimulation. Thus, in normal animals, the negative modulatory effect of histamine on adrenergic responses can be attributed largely, if not totally, to a postjunctional mechanism. In contrast, a prejunctional action of histamine may contribute significantly to the negative modulation observed in norepinephrine-preloaded hearts. Since we have observed a large increase in the amount of endogenous histamine present in the coronary effluent after sympathetic stimulation (930 pg during the 30 seconds poststimulation vs. 240 pg during 30 seconds prestimulation), as well as a prolongation of nerve stimulation-induced cardiac responses in the presence of the H2 receptor antagonist tiotidine, we postulate that histamine plays a physiological role as a modulator of sympathetic responses in the heart.

Animals↗
PubMed1984

Negative inotropic effect of leukotrienes: leukotrienes C4 and D4 inhibit calcium-dependent contractile responses in potassium-depolarized guinea-pig myocardium.

The effects of the sulfidopeptide leukotrienes (LTs) on the contractile response of electrically paced guinea-pig right ventricular papillary muscles in vitro were studied. LTs caused a concentration-dependent (1 nM-20 microM) negative inotropic effect; the order of relative potency was LTC4 greater than or equal to LTD4 greater than LTE4. A maximal 30% decrease in contractility occurred with 1 microM LTC4. The LT-induced decrease in contractile force was not mediated by cyclooxygenase products of the arachidonic acid cascade, as it was not influenced by indomethacin (14 microM). On the other hand, the slow-reacting substance-antagonist compound FPL 55712 (480 nM) caused a marked shift to the right of the LTC4 concentration-response curve. Because the negative inotropic effect of LTD4 was attenuated by increasing [Ca++]o, we next assessed the negative inotropic effect of LTs under conditions in which myocardial contractility depends solely on the slow inward Ca++ current. As a model, we used the isoproterenol- or histamine-induced restoration of contractile response in papillary muscles rendered inexcitable by 22 mMK+. LTC4 (16-480 nM) and LTD4 (20-600nM) inhibited isoproterenol- and histamine-induced restoration of contractility in a dose-dependent manner; a maximal 90% inhibition occurred with 0.48 microM LTC4. This effect of LTs was reversed by an elevation in [Ca++]o from 1.8 to 5.4 mM and prevented by FPL 55712 (480 nM). In muscles maintained at 5.4 mM [K+]o, LTC4 (160 and 480 nM) and LTD4 (1 microM) shifted the force-frequency curve (0.1-2 Hz) downwards in a parallel fashion; a similar alteration was obtained by lowering [Ca++]o to 1 mM.

Animals↗
PubMed1984

Adenosine selectively attenuates H2- and beta-mediated cardiac responses to histamine and norepinephrine: an unmasking of H1- and alpha-mediated responses.

Adenosine is known to attenuate the positive inotropic and chronotropic effects of norepinephrine and histamine by reducing cyclic AMP accumulation. We assessed whether adenosine, while inhibiting the cardiac responses mediated by beta and H2 receptors, leaves unmodified the responses mediated by alpha and H1 receptors. In isolated cardiac preparations from the guinea pig, adenosine antagonized the positive inotropic effect of histamine more than that of norepinephrine. This most likely occurred because, by attenuating H2 and beta responses, adenosine unmasked the H1-negative and alpha-1-positive components of the inotropic effects of histamine and norepinephrine. Consistent with this hypothesis, the pure H2 agonist impromidine appeared to be antagonized by adenosine less than histamine, and norepinephrine less than isoproterenol. In addition, adenosine antagonized the positive inotropic effect of norepinephrine in the presence of the alpha-1 blocker prazosin, whereas it did not affect the inotropic effect of phenylephrine. In the papillary muscle depolarized by 22 mM K+, adenosine antagonized the restoration of contractile responses induced by histamine or norepinephrine. This action of adenosine was reversed by the phosphodiesterase inhibitor papaverine and by the adenylate cyclase activator forskolin, suggesting that adenosine attenuates beta and H2 responses by suppressing the cyclic AMP-dependent facilitation of Ca++ influx promoted by the two amines. Our data indicate that adenosine selectively attenuates H2 and beta but not alpha and H1 responses. Thus, when catecholamines, histamine and adenosine are released together, as in myocardial ischemia, in addition to their individual effects, negative inotropism, decreased impulse conduction velocity and coronary constriction (i.e., H1- and alpha-mediated responses) may result from the adenosine-histamine-norepinephrine interaction.

Adenosine↗
PubMed1983

The isolated human pectinate muscle: a reliable preparation of human cardiac tissue.

We have developed an anatomically and functionally intact preparation of isolated pectinate muscles from readily-available surgical specimens of human right atrial appendage. Individual pectinate muscles (2-3 per specimen) are dissected free and mounted in a tissue bath. Field stimulation is used for electrical pacing, and isometric contractions are recorded. The pectinate muscle develops a stable and large force of contraction and hence is superior to strips cut from atrial appendage specimens. Isolated pectinate muscles develop spontaneous beating or can be induced to beat spontaneously by brief periods of electrical pacing or transient exposure to epinephrine or histamine. Spontaneously-beating muscles increase their rate and force of contraction in response to drugs which have positive chronotropic and inotropic effects in the whole heart. Because the force of contraction of the pectinate muscle is a function of the rate of beating, inotropic effects of agents should also be evaluated in preparations which are electrically paced at a constant rate.

Atrial Function↗
PubMed1982

Dysrhythmias caused by histamine release in guinea pig and human hearts.

Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heart in vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heart in vitro. Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H1 and H2 antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine. We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.

Animals↗
PubMed1982

Reduction of ventricular fibrillation threshold by histamine: resolution into separate H1- and H2-mediated components.

The effects of histamine and the selective agonists impromidine (H2-agonist) and 2-(2-thiazolyl ethylamine)(H1-agonist) on ventricular fibrillation threshold were tested in the isolated guinea-pig heart. All three compounds produced reversible concentration-dependent decreases in ventricular fibrillation threshold. Ventricular fibrillation threshold reduction was not secondary to the positive chronotropic effect of the three compounds. Computer analysis of the data using appropriate theoretical models suggests that the net effect of histamine on ventricular fibrillation threshold is the resultant of two components: H1 and H2. Pyrilamine inhibited the H1-mediated effects of histamine on ventricular fibrillation threshold with a Kb value of 0.449 nM. H1- and H2-receptors mediating ventricular fibrillation threshold reduction differ in their relative sensitivity to histamine (H1 greater than H2; EC50 for histamine, 53.9 nM at H1- and 311 nM at H2-receptors) and in the maximum response which they are capable of producing (H1 congruent to 1/2 that of H2). The finding that extremely low concentrations of histamine (less than 1 pg/ml) can effectively reduce ventricular fibrillation threshold reinforces the concept that histamine is highly arrhythmogenic.

Animals↗
PubMed1982

Leukotrienes C4, D4 and E4: effects on human and guinea-pig cardiac preparations in vitro.

The effects of leukotrienes C4, D4 and E4 (LT C4, D4 and E4) were studied in isolated preparations of guinea-pig and human myocardium in order to assess their contribution to cardiac dysfunction associated with systemic anaphylaxis. LT C4, D4 and E4 all caused long-lasting and dose-related decreases in the contractile force and coronary flow rate of the isolated guinea-pig heart. The rank order of potency was LT D4 greater than C4 greater than E4. The effects of LT C4 and D4 were antagonized by the anti-slow-reacting-substance compound FPL 55712. The negative inotropic effect of LT is unlikely to be secondary to the concomitant reduction in coronary flow because: 1) the same reduction in coronary flow by angiotensin II resulted in a negligible decrease in contractility and 2) the negative inotropic effect of LT also occurred in the electrically paced, noncoronary perfused left atrium and right ventricular papillary muscle of the guinea pig and in pectinate muscles obtained from surgical specimens of human right atrial appendage. LT D4 potentiated the positive chronotropic effect of histamine, supporting the concept that functional interactions occur between the various mediators of immediate hypersensitivity. The cardiac effects of pure synthetic LT are similar to those previously obtained with crude slow-reacting substance of anaphylaxis indicating that the prolonged contractile failure associated with systemic anaphylaxis largely could be due to the negative inotropic effect of LT. Because LT are released in a variety of immunological and inflammatory reactions, their potent myocardial depressant effects may play a role in cardiac dysfunction associated with these reactions.

Abdomen↗
PubMed1982

Cardiac and pulmonary anaphylaxis in guinea pigs and rabbits induced by glycoprotein isolated from tobacco leaves and cigarette smoke condensate.

Cigarette smoking is a major risk factor for heart attack. The pathologic mechanisms responsible for this association are obscure. It has been reported that approximately one-third of human volunteers, smokers and nonsmokers, exhibit immediate cutaneous hypersensitivity to a glycoprotein antigen (TGP) purified from cured tobacco leaves and present in cigarette smoke. It is also known that the heart is a primary target organ for anaphylactic reaction in many animals, including primates. In experiments described herein anaphylaxis was induced in the isolated hearts and lungs of rabbits and guinea pigs previously sensitized by immunization with TGP and challenged with TGP isolated from either tobacco leaf or cigarette smoke condensate. Cardiac anaphylaxis was characterized by sinus tachycardia, decreased contractility, decreased coronary perfusion accompanied by hypoxic electrocardiographic changes, and a variety of rhythm disturbances, including idioventricular tachyarrhythmias. These observations suggest that allergic reactions to tobacco constituents may initiate cardiac arrhythmia and sudden death in some smokers and may, in part, underly the association between cigarette smoking and heart attack.

Anaphylaxis↗
PubMed1981

Immunologic histamine release in vitro from the heart and lung of the cynomolgus monkey.

Immunologic histamine release was evoked from the sensitized fragmented cardiac and pulmonary tissue of the cynomolgus monkey by a reverse anaphylactic reaction. Ventricular and pulmonary tissue released a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and d a similar fraction (approximately 6%) of the total tissue histamine when challenged with antihuman IgE, presumably reflecting the 'active' sensitization of the monkey in vivo. Passive sensitization of these tissues in vitro resulted in significantly greater immunologic histamine release in 6 of the 14 ventricles and in the lungs. The antiallergic compounds, disodium cromoglycate and SK&F 64398, inhibited immunologic histamine release from passively sensitized monkey ventricular tissue. These results demonstrate that ventricular histamine may be immunologically released and that this release process can be pharmacologically inhibited in a manner similar to that of pulmonary tissue.

Anaphylaxis↗
PubMed1981

The arrhythmogenic actions of histamine on human atrial fibers.

We used standard microelectrode techniques to study the effects of histamine on right atrial tissues from patients undergoing corrective cardiac surgery. In the 10(-6) to 10(-4) M range, histamine increased maximum diastolic potential, action potential amplitude, and automaticity. In some preparations, histamine also induced delayed afterdepolarizations and triggered activity. The potency of histamine in increasing automaticity was about 10 times less than that of epinephrine. Propranolol (2 x 10(-7)M), which abolished the chronotropic effect of epinephrine, did not alter the effect of histamine. Conversely, the effect of histamine but not that of epinephrine was antagonized by cimetidine (3 x 10(-6) to 1 x 10(-5) M). This suggests that H2 receptors mediate the chronotropic effects of histamine on the human heart. The slow channel blocker verapamil (2 x 10(-8) to 2 x 10(-6) M) counteracted the effects of histamine on automaticity, delayed afterdepolarizations, and triggered activity, suggesting that in human atrium histamine may act by increasing slow inward (presumably Ca2+) current. If one considers these arrhythmogenic effects of histamine and the fact that human cardiac tissue contains large amounts of histamine, our experiments lend further support to the concept that histamine release can induce arrhythmias.

Action Potentials↗
PubMed1981

Thromboxane and prostacyclin release during cardiac immediate hypersensitivity reactions in vitro.

Cardiac immediate hypersensitivity reactions in vitro are characterized by tachycardia, arrhythmias and coronary constriction. Whereas endogenous cardiac histamine release is responsible for the generation of arrhythmias, metabolites of arachidonic acid mediate the fall in coronary flow. In the present study, we have shown that antigenic challenge of sensitized guinea-pig hearts results in the release into the coronary effluent of immunoreactive thromboxane B2, 6-keto prostaglandin (PG) F1 alpha and PGF2 alpha. Thromboxane B2 was the predominant metabolite generated. After the administration of histamine (1-100 micrograms) or a partially purified preparation of slow-reacting substance of anaphylaxis (5-100 U) to the sensitized heart there was no detectable release of thromboxane B2 into the coronary effluent. After the administration of sodium arachidonate (3 X 10(-6) M) to the sensitized heart 40 min after antigenic challenge, there was a predominant release of 6-keto PGF1 alpha into the coronary effluent. Pretreatment of sensitized hearts with aspirin (5.5 X 10(-5) M), indomethacin (1.4 X 10(-5) M) or 1-(2-isopropylphenyl)imidazole (5.4 X 10(-5) M) resulted in inhibition of antigen-induced thromboxane B2 release and coronary vasoconstriction. These results suggest that during immediate hypersensitivity reactions, the coronary vasculature may be predisposed to ischemic and thrombotic episodes as a result of thromboxane release. Thromboxane formation occurs independently of the actions of histamine and slow-reacting substance of anaphylaxis and, since it is not generated preferentially by the coronary circulation of the sensitized heart in response to arachidonate infusion, it is plausible to suggest that it is of mast cell origin.

6-Ketoprostaglandin F1 alpha↗