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J F Regal

Publications and source records attributed to J F Regal.

At least 37 records · Page 2Linked to original sources
PubMed1988

Effect of adenosine on histamine release and atrioventricular conduction during guinea pig cardiac anaphylaxis.

Anaphylactic events occurring in cardiac tissue can result in severe metabolic imbalances. The present study addresses the question of whether adenosine, produced in response to this stress, influences either the antigen-antibody-induced alterations in cardiac function or the release of histamine, which is known to be one of the important mediators of the anaphylactic reaction. Isolated hearts of passively sensitized guinea pigs were perfused at constant flow in a Langendorff preparation with physiological salt solution. Under control conditions, antigen challenge evoked a rapid transient release of histamine, an increase in coronary vascular resistance and beating rate, and an increase followed by a decrease in left ventricular systolic pressure. The antigen-induced transient increase in adenosine release from 0.26 +/- 0.07 to 4.66 +/- 0.48 nmol/min/g was associated with a 75 +/- 9% increase in the PR interval in all hearts and atrioventricular blocks in six of 17 hearts. Antigen challenge was also conducted in the presence of theophylline, 8-(4-sulfophenyl) theophylline (SP-T), erythro-9-(2-hydroxy-3-nonyl) adenosine hydrochloride (EHNA), or exogenous adenosine. The major findings were that 1) the antigen-induced prolongation of the PR interval was attenuated by the adenosine receptor blockers theophylline (to 23 +/- 6%) and SP-T (to 15 +/- 4%); 2) the incidence of antigen-induced atrioventricular blocks tended to be decreased by theophylline (to three of 10 hearts) and SP-T (to zero of seven hearts) and to be increased by the adenosine deaminase inhibitor, EHNA (to six of 10 hearts); 3) none of the interventions had major influences upon antigen-induced alterations in vascular resistance, atrial automaticity, or systolic pressure; and 4) EHNA and adenosine both significantly increased adenosine levels before anaphylaxis and also enhanced the total histamine release induced by antigen challenge from a control value of 2,321 +/- 244 ng/g to 3,424 +/- 307 ng/g and 4,298 +/- 616 ng/g, respectively. We conclude from our data that increases in levels of endogenous adenosine during cardiac anaphylaxis may contribute to the development of atrioventricular conduction delays and blocks and that increases in levels of adenosine before antigen challenge may increase the amount of histamine released during cardiac anaphylactic reactions.

Adenosine↗
PubMed1988

Role of arachidonate metabolites in C5a-induced bronchoconstriction.

The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine pyrilamine and the cyclooxygenase inhibitor indomethacin inhibited the C5a-induced bronchoconstriction but the leukotriene (LT)D4 antagonist L-649,923 did not. As an extension of those studies, the purpose of the present study was to determine the contribution of specific cyclooxygenase products and/or LTB4 in mediating C5a-induced bronchoconstriction. To assess the role of the various potential mediators, plasma levels of thromboxane (TX)B2, prostaglandin (PG)D2 and PGF2 alpha were monitored. In addition, guinea pigs were treated either with the TX synthetase inhibitor U-63557A, treated with the TX receptor antagonist SQ 29,548 or made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a challenge caused an increase in plasma concentrations of TXB2, which peaked before the maximum of the bronchoconstriction. However, no significant increase in plasma concentrations of PGD2 or PGF2 alpha was seen. Both U-63557A at 80 mg/kg and SQ 29,548 significantly inhibited the C5a-induced bronchoconstriction, whereas 10 mg/kg of U-63557A did not. The inability of 10 mg/kg of U-63557A to inhibit the response could be explained by both incomplete inhibition of TX synthesis as well as possibly by the increased plasma concentrations of the potent bronchoconstrictor PGD2, which occurred with C5a challenge in the presence of U-63557A. In animals tachyphylactic to LTB4, the maximum of the C5a-induced bronchoconstriction was no different from control.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1987

Mediators of C5a-induced bronchoconstriction.

Previous studies had suggested that histamine and products of arachidonate metabolism were mediators of the bronchoconstriction induced in guinea pigs by the complement cleavage product C5a. The present study was conducted to further define the arachidonate metabolite(s) involved. Tracheal airflow and transpulmonary pressure were measured in anesthetized and artificially ventilated guinea pigs and pulmonary resistance and dynamic lung compliance were calculated as a measure of bronchoconstriction. The effect of the peptido-leukotriene antagonist L-649,923 and the thromboxane synthetase inhibitor U-63557A on the C5a-induced bronchoconstriction was determined. Also, the response to C5a was evaluated in animals made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a-induced bronchoconstriction was not altered in animals treated with L-649,923 or made tachyphylactic to LTB4 suggesting that LTB4 and peptido-leukotrienes are not major mediators of the response. C5a challenge caused a significant increase in plasma thromboxane B2 levels which was prevented in part by the thromboxane synthetase inhibitor U-63557A. In addition, C5a-induced bronchoconstriction was significantly inhibited by U-63557A. Thus, these studies suggest that thromboxane is the arachidonate metabolite at least in part responsible for C5a-induced bronchoconstriction.

Animals↗
PubMed1987

Mediators of C5a-induced bronchoconstriction in the guinea pig.

The effect of intravenous injection of C5a on pulmonary resistance and dynamic lung compliance was determined in anesthetized, artificially respirated guinea pigs. A mixture of C5a plus C5ades arg was purified from yeast-activated guinea pig serum and is referred to as C5a. Intravenous injection of C5a caused a dose-related bronchoconstriction as evidenced by a decrease in compliance and increase in resistance. Conversion of the C5a in the mixture to C5ades arg by carboxypeptidase B digestion did not significantly alter the magnitude of the bronchoconstriction. Pharmacological antagonists were employed to determine if histamine, acetylcholine or products of the arachidonate metabolism were mediators of C5a-induced bronchoconstriction. The histamine H1 antagonist pyrilamine inhibited the C5a-induced bronchoconstriction, suggesting the involvement of histamine. The cholinergic receptor antagonist atropine in combination with pyrilamine caused an inhibition of the C5a-induced increase in resistance but not compliance, suggesting acetylcholine does not play a major role in C5a-induced bronchoconstriction beyond its known role in participating in histamine-induced bronchoconstriction. Involvement of arachidonate metabolites was suggested by the ability of the cyclooxygenase inhibitor, indomethacin, to prevent the C5a-induced bronchoconstriction. Because indomethacin also caused a delay in the leukotriene C4 (LTC4)-induced bronchoconstriction, the participation of peptidoleukotrienes in the C5a-induced bronchoconstriction could not be ruled out. The leukotriene antagonists FPL 55712 and L-649,923 were evaluated for their specificity in inhibiting LTC4-induced bronchoconstriction. FPL 55712 was nonselective since it inhibited prostaglandin D2 and histamine-induced bronchoconstriction as well as LTC4-induced bronchoconstriction. L-649,923 inhibited only the LTC4-induced bronchoconstriction and was without effect on the C5a-induced bronchoconstriction, suggesting that peptidoleukotrienes are not important mediators of C5a-induced bronchoconstriction. Using radioimmunoassay, the change in peptidoleukotriene levels detected in plasma during C5a-induced bronchoconstriction was not significantly different from 0. Thus, these studies have quantitated the C5a-induced decrease in dynamic lung compliance and increase in pulmonary resistance and suggest that histamine and cyclooxygenase products, but not peptidoleukotrienes, play a major role in C5a-induced bronchoconstriction.

Acetylcholine↗
PubMed1987

Cardiac anaphylaxis in isolated guinea pig hearts perfused at constant flow or constant pressure.

Acute responses to antigen-antibody interactions (anaphylactic reactions) in isolated guinea pig hearts are reported to include decreases in coronary flow, increases in heart rate, prolongation of impulse propagation, development of arrhythmias, and transient increases followed by substantial decreases in ventricular contractile force. It is not clear from these studies, however, whether all of the changes are direct effects of the mediators released by the antigen-antibody reaction or whether some of them are indirect results of the severe reduction in flow evoked by coronary vasoconstriction. Therefore, the present study was designed to assess cardiac anaphylactic events in isolated hearts of guinea pigs passively sensitized with IgG antibody to ovalbumin under conditions in which coronary perfusion pressure was maintained constant and to compare the responses to those of hearts in which coronary flow was maintained at a constant rate. Our data indicate that when coronary flow decreased during anaphylaxis (constant pressure perfusion), hearts responded to antigen challenge with greater prolongation of the PR interval, duration of arrhythmias, suppression of left ventricular systolic pressure, and release of histamine and adenosine plus inosine into the venous effluent than when coronary flow was maintained during anaphylaxis (constant flow perfusion). The data suggest that maintenance of coronary flow during cardiac anaphylaxis may attenuate the severity of the functional derangement.

Adenosine↗
PubMed1985

IgG vs IgE: mediators of antigen-induced guinea pig lung parenchymal contraction.

The present studies were conducted to determine whether different mediators are responsible for antigen-induced contraction of guinea pig lung parenchymal strips sensitized with either IgG or IgE. Passive sensitization was employed using IgG- or IgE-type antibody to ovalbumin which had been separated using Protein A-Sepharose as previously described (Regal, 1984a). Such a system ensures the presence of only one type of cytophilic antibody to mediate antigen-induced contraction of the isolated lung parenchymal strip. Pyrilamine, an H1 antagonist, caused a very slight delay in the onset of the antigen-induced contractions in both IgG- and IgE-sensitized strips, suggesting a very minor role for endogenous histamine in both systems. A combination of the leukotriene antagonist, FPL 55712, and pyrilamine caused a significant reduction in the antigen-induced contraction in IgG- but not IgE-sensitized lung parenchymal strips. Histamine release was detected on antigen challenge of both IgG- and IgE-sensitized lung. Using bioassay techniques, leukotriene release was primarily detected from IgG-sensitized lung and only minimally from IgE-sensitized lung. Thus, our studies have demonstrated a differential antagonism of IgG- and IgE-mediated airway contraction and suggest that leukotrienes are important mediators of antigen-induced lung parenchymal contraction in IgG- but not IgE-sensitized tissues.

Animals↗
PubMed1985

Effect of C5a on isolated guinea pig atria.

Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment, C5a. Previous reports of other researchers indicate that among the biological activities of C5a is an ability to alter cardiac function. However, these studies have varying results. The goal of the present study was thus to determine both the chronotropic and inotropic effects of guinea pig C5a and the tachyphylaxis to guinea pig C5a in isolated atria of the guinea pig. Isolated right atria respond to guinea pig C5a with a consistent concentration-related positive inotropic and chronotropic response. An inotropic response to guinea pig C5a was seen in both spontaneously beating right atria and paced left atria. The inotropic and chronotropic responses to guinea pig C5a in the right atria were clearly tachyphylactic. Studies using the H2 receptor antagonist metiamide indicate that the positive chronotropic response to guinea pig C5a is at least in part a histamine-mediated response. Further studies are required to determine whether the conflicting results in various studies are due to the use of C5a from various species.

Adrenergic beta-Antagonists↗
PubMed1984

IgG vs IgE: mediators of antigen-induced guinea pig tracheal contraction.

Guinea pig IgG and IgE were employed in these studies to determine whether different mediators were responsible for IgG- and IgE-mediated contraction of guinea pig trachea. Isolated tracheal strips were passively sensitized using IgG- or IgE-type antibody to ovalbumin which had been separated using Protein A Sepharose. The antigen-induced contraction of tracheae sensitized with either IgG or IgE was delayed by diphenhydramine (10(-5) M) and significantly enhanced by aspirin (1.1 X 10(-4) M). The leukotriene antagonist FPL 55712 (1.9 X 10(-5) M) decreased the duration of the IgG-mediated contraction but not that of the IgE-mediated contraction. Diphenhydramine in combination with FPL 55712 caused a greater inhibition of the IgG-mediated tracheal contraction than either antagonist alone. In contrast, the IgE-mediated response was inhibited to the same extent by a combination of FPL 55712 and diphenhydramine as with diphenhydramine alone. The lipoxygenase inhibitor nordihydroguaiaretic acid in combination with diphenhydramine inhibited the antigen-induced contraction to a greater extent than diphenhydramine alone in the IgG, but not in the IgE-sensitized trachea. Leukotriene release from trachea was assessed by contraction of the longitudinal muscle of an unsensitized guinea pig ileum mounted in the same tissue bath. On ovalbumin challenge, leukotriene release was detected from IgG-sensitized trachea but only minimally from IgE-sensitized trachea. Histamine release was detectable on antigen challenge of IgG- and IgE-sensitized trachea. Heating IgG (56 degrees C for 4 h) did not alter its ability to mediate histamine or leukotriene release.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Immunoglobulin G- and immunoglobulin E-mediated airway smooth muscle contraction in the guinea pig.

Guinea-pig antibody to ovalbumin was separated into two pools using Protein A Sepharose. The antibody pool retained by the Protein A Sepharose [immunoglobulin (Ig) G pool] was heat stable and persisted in skin sites of the guinea pig less than 7 days. The antibody pool which did not bind to Protein A Sepharose (IgE pool) was heat labile and persisted in guinea-pig skin at least 10 days. Both antibody pools were capable of mediating contraction of isolated guinea-pig tracheal and lung parenchymal strips using airway strips passively sensitized in vivo or in vitro. Although the majority of the skin sensitizing ability of the IgE pool was destroyed by heating at 56 degrees C for 4 hr, its ability to mediate airway contraction was only partially inhibited. Experiments examining [125I]Protein A binding of the antibody pools indicated that the contractions seen in airways sensitized with IgE pool was not due to contamination with IgG. These studies provide a system for examining antagonism of and mediators responsible for IgG-vs. IgE-mediated airway contraction and for evaluating the apparently heat stable properties of IgE.

Airway Resistance↗
PubMed1983

Effects of C5a on guinea pig lung: histamine release and mechanism of contraction.

C5a, a product of complement system activation, causes a significant contraction of the isolated guinea pig trachea, and the antihistamine diphenhydramine does not alter the rate, amplitude, or duration of the contraction (Regal et al., 1980). The present study demonstrates that over the range of C5a concentrations investigated, the C5a-induced contractile response of the trachea maximized, whereas the contraction of lung parenchymal strips and the release of histamine from chopped lung did not. In addition, the antihistamines, diphenhydramine and pyrilamine, caused a significant delay in the onset of the C5a-induced contraction of lung parenchymal strips. When parenchymal strips from nonperfused lung were used, the maximum of the contraction was also reduced by pyrilamine. Aspirin and indomethacin effectively inhibited the C5a-induced contraction of lung parenchymal strips, and inhibition by a combination of aspirin and pyrilamine was the sum of the inhibition by aspirin and the inhibition by pyrilamine. The SRS-A antagonist, FPL 55712, caused a more rapid relaxation of the C5a-induced response over control. These studies suggest that products of the cyclo-oxygenase pathway are mediators involved in the C5a-induced contraction of lung parenchyma, with histamine and leukotrienes contributing as well.

Animals↗
PubMed1983

C5a and antigen-induced tracheal contraction: effect of a combination of an antihistamine and cyclo-oxygenase inhibitors.

Our previous studies with C5a, a cleavage product of the fifth component of complement, have shown that the antihistamine diphenhydramine and the cyclo-oxygenase inhibitor aspirin do not inhibit the C5a-induced contraction of isolated guinea pig trachea (Regal, Eastman & Pickering, 1980; Regal & Pickering, 1981). We investigated the effect of cyclo-oxygenase inhibitors in the presence of diphenhydramine to determine if cyclo-oxygenase products were contributing to the contraction beyond any effect they might have on histamine release. A combination of a cyclo-oxygenase inhibitor and diphenhydramine caused a delay in onset and decrease in magnitude and duration of the C5a-induced contraction. Indomethacin itself also caused a slight inhibition. In contrast, a combination of aspirin and diphenhydramine did not inhibit the initial portion of antigen-induced tracheal contraction any more than diphenhydramine alone and enhanced the later portion just as aspirin alone. Cross tachyphylaxis experiments demonstrated that antigen pretreatment significantly inhibited a subsequent C5a-induced tracheal contraction, though C5a pretreatment did not affect a subsequent antigen-induced contraction. Thus, cyclo-oxygenase products do contribute to C5a-induced tracheal contraction, and histamine participation in the presence of cyclo-oxygenase inhibitors is suggested. Our studies demonstrate the dissimilarities of C5a and antigen-induced contraction as regards inhibition by aspirin plus diphenhydramine, yet suggest common pathways leading to the contractile response as evidenced by cross tachyphylaxis experiments.

Animals↗
PubMed1983

C5a-induced histamine release. Species specificity.

C5a has long been known to cause histamine release from isolated perfused guinea pig lung, isolated human basophils, rat and guinea pig mast cells, and guinea pig skin. The purpose of the present study was to compare the ability of guinea pig C5a to cause histamine release from lung fragments of dog, rabbit and rat with that released from guinea pig lung fragments. In addition, C5a-induced histamine release from the skin of the guinea pig, rabbit, and rat was investigated by examining antihistamine inhibition of C5a-induced vascular permeability changes. Guinea pig C5a caused a concentration-related release of histamine from guinea pig lung fragments with only minimal amounts of histamine being released from dog, rat, and rabbit lung fragments over the same concentration range. Guinea pig C5a also caused increased vascular permeability in guinea pig skin which was markedly inhibited by H1 antagonists. In rabbit skin, guinea pig C5a increased vascular permeability in the presence of PGE2 but the vascular leakage was unaffected by antihistamines. Rat skin was virtually unresponsive to C5a with or without PGE2. This data emphasize the differences between reactivity of species to C5a and the danger of extrapolating results obtained in one animal species to models employed with another species.

Animals↗
PubMed1982

C5a-induced aortic contraction: effect of an antihistamine and inhibitors of arachidonate metabolism.

Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment, C5a, historically referred to as anaphylatoxin. Among the biological activities of C5a is the ability to contrast isolated smooth muscle. This report is concerned with initial studies identifying mediators responsible for C5a-induced contraction of isolated guinea-pig aortic rings. C5a, purified from yeast-activated guinea-pig serum, caused a concentration-related contraction of the isolated guinea-pig aorta. The H1 antagonist diphenhydramine partially inhibited the response of the aorta to C5a, indicating that released histamine was, at least in part, responsible for the contraction. 5,8,11,14-Eicosatetraynoate, an inhibitor of both the lipoxygenase and cyclooxygenase pathway of arachidonate metabolism, inhibited the C5a-induced aortic contraction to an even greater extent than diphenhydramine, suggesting that products of arachidonate metabolism also play a role in the contraction. The cyclooxygenase inhibitors aspirin and indomethacin did not inhibit the C5a-induced aortic contraction, yet a combination of aspirin and diphenhydramine or indomethacin and diphenhydramine completely inhibited the aortic response to C5a. The presence of aspirin did not affect the ability of diphenhydramine to inhibit the response of the aorta to exogenous histamine, thus suggesting that cyclooxygenase products were not affecting the reactivity of histamine at the target smooth muscle. These studies indicate that both histamine and cyclooxygenase products are mediators responsible for C5a-induced aortic contraction.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1981

C5a-induced tracheal contraction: effect of an SRS-A antagonist and inhibitors of arachidonate metabolism.

C5a, a peptide derived from the fifth component of complement, has been shown to cause significant prolonged smooth muscle contraction in isolated guinea pig trachea. This contraction was not affected by the antihistamine diphenyhydramine. To assess further the potential role that C5a may play in allergic bronchospasm, we investigated the role of products of arachidonate metabolism in the C5a-induced tracheal contraction. 5,8,11,14-Eicosatetraynoic acid, an inhibitor of lipoxygenase and cyclooxygenase, virtually eliminated the tracheal contraction induced by C5a. The prostaglandin synthesis inhibitor, acetylsalicylate, did not inhibit the C5a-induced tracheal contraction and enhanced the tracheal response to acetylcholine. FPL 55712, an antagonist of slow reacting substance of anaphylaxis (SRS-A), almost completely inhibited the tracheal response to C5a and at higher concentrations employed, FPL 55712 also inhibited the tracheal response to exogenous prostaglandin F 2 alpha. These studies indicate that C5a-induced tracheal contraction is mediated by a product or products of arachidonate metabolism, and is, at least in part, mediated by SRS-A.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1980

C5a induced tracheal contraction: a histamine independent mechanism.

C5a, a peptide derived from the fifth component of complement, caused significant prolonged smooth muscle contraction in isolated guinea pig trachea. Diphenhydramine, a histamine receptor antagonist of the H1 type, had no effect on either the rate, amplitude or duration of C5a induced tracheal contraction, whereas it significantly inhibited the tracheal response to exogenous histamine. Diphenhydramine also caused a significant delay in the response to compound 48/80 in normal guinea pig trachea and to antigen in actively sensitized trachea, indicating that the antihistamine was capable of inhibiting tracheal contractions to endogenously released histamine. C5a induced tracheal smooth muscle contraction was also unaffected by antagonists of H2, muscarinic cholinergic and alpha adrenergic receptors. These results indicate that C5a induced tracheal contraction is independent of histamine and is potentially a mediator of allergic bronchospasm.

Animals↗
PubMedDate not supplied

C5a/C5ades-Arg-induced increase in blood pressure in the guinea pig: role of thromboxane.

Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment C5a. Knowledge of the alterations in blood pressure induced by C5a as well as the mediators responsible for the blood pressure changes may provide information concerning the potential role of C5a in the adverse hemodynamic responses associated with complement activation. The purpose of this study was to characterize changes in mean arterial pressure in the guinea pig after intravenous challenge with a combination of guinea pig C5a plus C5a(des-Arg) (C5a/C5a(des-Arg)) and determine the mediators responsible for the transient increase in blood pressure which was observed. Mean arterial pressure was monitored in mechanically ventilated pentobarbital-anesthetized guinea pigs. Intravenous injection of C5a/C5a(des-Arg) consistently caused a marked but transient rise in blood pressure. A transient hypotensive response was also seen with injection of markedly higher doses of guinea pig C5a/C5a(des-Arg). Various pharmacological antagonists were used to determine the mediators responsible for the increase in blood pressure induced by guinea pig C5a/C5a(des-Arg). We found that the LTD4 antagonist L-649,923 did not inhibit the transient rise in blood pressure. However, the cyclooxygenase inhibitor indomethacin inhibited the C5a/C5a(des-Arg)-induced pressor response as did the thromboxane synthetase inhibitor U-63557A and the thromboxane receptor antagonist SQ 29,548. In addition, the C5a/C5a(des-Arg)-induced pressor response was not inhibited by the H1 antagonist pyrilamine, but was inhibited in part by the alpha-adrenergic antagonist phentolamine. Also, the response was reduced in animals depleted of circulating platelets or white blood cells. Thus, the results of our studies suggest that intravenously injected guinea pig C5a/C5a(des-Arg) causes release of the vasoconstrictor thromboxane, most likely from circulating white blood cells or platelets, resulting in a transient rise in blood pressure in the guinea pig. In addition, release of catecholamines may contribute to the pressor response observed.

Adrenergic alpha-Antagonists↗