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Biomedical subjects

J M Drazen

Publications and source records attributed to J M Drazen.

At least 271 records · Page 15Linked to original sources
PubMed1983

Effects of indomethacin on the guinea-pig pulmonary response to intravenous leukotrienes C4 and D4.

We measured pulmonary conductance (GL), dynamic compliance (Cdyn.), and arterial pressure in chloralose-urethane anaesthetized guinea pigs for 30 min after intravenous infusion of either leukotriene (LT) C4 (1 microgram/kg) or LTD4 (0.5 microgram/kg) to control or indomethacin-pretreated (30 mg/kg) animals. LT infusion to control animals caused decrements in GL, which were maximal at 30 s and persisted for 7.5 min (LTD4) and 15 min (LTC4), decrements in Cdyn., which were maximal at 30 s and persisted for 30 min, and hypotension. Indomethacin treatment before LT infusion significantly altered the changes in GL by reducing the early (less than 1 min) response and potentiating the later (3-5 min) response, significantly reduced the fall in Cdyn. at all time points, resulting in a change in the GL/Cdyn. ratio to 1.0 and prolonged the hypotensive response. We conclude that cyclo-oxygenase products are responsible for the early (less than 1 min) pulmonary response to LT infusion and modulate the later (3-5 min) response but do not cause hypotension. With cyclo-oxygenase inhibition, the significant primary activity of LT is possibly less preferentially directed to contractile tissues associated with small airways.

Airway Resistance↗
PubMed1983

Effect of nifedipine on constriction of human tracheal strips in vitro.

1 Autopsy specimens of human trachealis muscle were used to investigate the effect of the calcium channel blocker, nifedipine, on airway smooth muscle constriction. With these tracheal strips, two consecutive cumulative concentration-effect curves to histamine (0.1-100 microM) obtained at a 60 min interval were highly reproducible. 2 We examined the effects of adding nifedipine (2.9 microM) to the incubation medium before the second histamine response. The concentration-effect relationships determined after nifedipine incubation were significantly different from control: the response to 100 microM histamine was reduced by approximately one-half (to 2.53 +/- 0.6 g; P less than 0.025), and the concentration of histamine causing 40% of the maximal control contraction (EC40) increased nearly ten fold (to 36.9 +/- 10.5 microM; P less than 0.02). 3 In two additional tracheal strips submaximally constricted with 10 microM histamine, nifedipine 2.9 microM caused complete relaxation to resting tension or below. 4 These results indicate a direct inhibitory effect of nifedipine on airway smooth muscle constriction and partial dependence of human trachealis muscle on calcium ion fluxes for initiation and maintenance of contraction. In addition, the results suggest a potential mechanism for the inhibitory effects of calcium channel blocking drugs in exercise-induced asthma.

Airway Resistance↗
PubMed1983

Inhibition by propranolol of the contractile response of the rat diaphragm to tetanic field stimulation in vitro.

Contraction of the rat isolated diaphragm in response to maximal tetanic stimulation was examined before and after isoprenaline or propranolol. Isoprenaline (10(-4)M) did not affect maximum isometric force, whereas propranolol depressed maximum force in a concentration-dependent manner (10(-6)-10(-4)M). Inhibition due to propranolol (10(-4)M) could not be overcome by increasing the intensity or duration of electrical stimulation, and was only partially reversed (mean 73% +/- 10 s.e. mean) after washing. Pretreatment with isoprenaline did not alter the response of the muscle to propranolol, nor did neuromuscular blockade with (+)-tubocurarine. The response to either stereoisomer of propranolol was similar to that obtained with the racemate. Atenolol, a beta-adrenoceptor blocking agent without membrane stabilizing activity, had minimal (less than 10%) depressant effects on diaphragmatic force development. Lignocaine (8.5 X 10(-6)-8.5 X 10(-5)M) produced a concentration-related decrease in isometric force, similar to that with propranolol. It is concluded that propranolol decreases the contractile force of the rat isolated diaphragm by a mechanism related to stabilization of excitable membranes.

Animals↗
PubMed1983

The effect of indomethacin on the contractile response of the guinea-pig lung parenchymal strip to leukotrienes B4, C4, D4 and E4.

Indomethacin (1 microgram ml-1) almost totally inhibited the dose-dependent contractile response of isolated lung parenchymal strips of the guinea-pig (GPLS) to leukotriene B4 (LTB4) over the concentration range 0.18-18 nM. LTC4 (0.63 pM-63 nM)-induced contractions of GPLS were not significantly inhibited by indomethacin (1.0 and 10.0 micrograms ml-1) except when the highest LTC4 concentration (63 nM) was tested in the presence of indomethacin (10 micrograms ml-1). LTD4 (1.3 fM-13 nM)-induced contractions of GPLS were not significantly inhibited by indomethacin (0.1-10 micrograms ml-1) except for contractions induced by concentrations of LTD4 greater than 0.13 nM and 13 nM. Indomethacin 1 microgram ml-1 and 10 micrograms ml-1 inhibited the contractile response to 13 nM LTD4 by 37 and 16% respectively. LTE4 (2.3 fM-23 nM)-induced contractions of GPLS were not significantly inhibited by indomethacin (0.1-10 micrograms ml-1). Contraction due to LTE4 23 pM was significantly potentiated by indomethacin (1 microgram ml-1). Clotrimazole (10 microM) significantly inhibited LTD4-induced contractions of GPLS at concentrations greater than 13 pM but had no significant effect on LTC4-induced contractions. Cyclo-oxygenase products, probably principally thromboxane A2, are important secondary mediators of LTB4-induced contractions of GPLS but make little or no contribution to contractions of GPLS induced by LTC4, LTD4, and LTE4, except at higher concentrations of LTD4 and possibly LTC4. Certain concentrations of LTE4 may generate bronchodilator PGE2 in GPLS.

Animals↗
PubMed1983

Density dependence of maximal flow in dogs with central and peripheral obstruction.

In 12 anesthetized, tracheotomized, vagotomized, open-chested, mongrel dogs we measured end and side hole airway pressures during forced expiration using a Pitot static probe. Volume was obtained as the integral of flow from a dog plethysmograph with frequency response adequate to 20 Hz. Equal pressure points (EPPs) and choke points (CPs) were located with dogs breathing air or a mixture of 80% helium-20% oxygen (HeO2) before and after partial obstruction of the trachea and intravenous histamine and propranolol. At 50% of vital capacity (VC) the CP was in the trachea in 11 of 12 dogs. Partial obstruction of the trachea decreased flow during the plateau of the maximum expiratory flow-volume curve (MEFVC) with the CP remaining in the trachea. The MEFVC plateau was extended to a lower lung volume. At 50% of VC the EPP moved downstream and density dependence remained high. Histamine and propranolol caused EPPs and CPs to move towards the periphery and density dependence to decrease. The shape of the MEFVC changed as the plateau was shortened and, in some instances, abolished. A plateau on the MEFVC could be regenerated by partial obstruction of the trachea. This was accompanied by return of the CP to the trachea and an increase in density dependence. Changes in density dependence were found to be a result of both the relocation of sites of flow limitation and differences in local CP areas with HeO2 and air.

Airway Obstruction↗
PubMed1983

Indomethacin potentiates the pulmonary response to aerosol leukotriene C4 in the guinea pig.

Aerosol administration of leukotriene (LT) C4 to anesthetized, mechanically ventilated guinea pigs results in significant dose-dependent decrements in dynamic compliance (Cdyn) and pulmonary conductance (GL) when the concentration of LTC4 in the nebulizer is in the range of 0.5 to 5 micrograms/ml. Pretreatment with indomethacin, 30 mg/kg given intraperitoneally, significantly potentiates the decrements in Cdyn and GL elicited by aerosol LTC4 at 1 microgram/ml. Potentiation of the pulmonary response is seen even with an aerosol LTC4 concentration of 0.3 micrograms/ml, which alone produces only minimal changes in pulmonary mechanics in control animals. These findings suggest that bronchodilator prostaglandins are important inhibitory modulators of this pulmonary response and that secondary thromboxane release probably does not contribute to the response to inhaled LTC4. The effect of indomethacin pretreatment in augmenting the pulmonary response to aerosol LTC4 in the guinea pig may have relevance for the phenomenon of asthma induced in humans by ingestion of nonsteroidal anti-inflammatory agents.

Aerosols↗
PubMed1982

Bronchoconstrictor effects of leukotriene C in humans.

Maximum expiratory flow rate at 30 percent of vital capacity above residual volume served as an index of airway obstruction in comparing the effects of leukotriene C and histamine administered by aerosol to five normal persons. Leukotriene C was 600 to 9500 times more potent than histamine on a molar basis in producing an equivalent decrement in the residual volume. The leukotriene C response was slow in onset and prolonged, reminiscent of the effects of aerosol allergen challenge in asthmatic allergic subjects.

Adult↗
PubMed1982

A review of recent contributions on biologically active products of arachidonate conversion.

Leukotrienes (LTs) C4, D4 and E4, the recognized components of slow reacting substance of anaphylaxis (SRS-A), have previously been shown to have contractile activities for guinea pig pulmonary and ileal smooth muscles; LTB4 has been shown to possess chemotactic activity for neutrophils in vitro. Based on data obtained by the use of structural analogs of the SRS-A LTs and of LTB4, we have recently determined a number of the structural bases for the biological function of each moiety. With regard to the SRS-A leukotrienes, analogs differed from the native structures in the position of the peptide side chain and/or the hydroxyl group, the number and position of ethylenic bonds, the chirality at optically-active centers, or the structures of the four polar substituents in the C-1 to C-6 region. Analogs of LTB4, differing in the stereochemistry of their ethylenic bonds, were evaluated for chemotactic activity both in vitro, using human neutrophils, and in vivo intracutaneously in the rhesus monkey. We propose that true receptors exist on the pulmonary parenchyma of the guinea pig for the SRS-A LTs and on the primate neutrophil for LTB4. Further, LTC4, LTD4 and LTE4 have been shown to elicit a wheal and prolonged flare in human skin, whereas LTB4 evokes a time-dependent induration. The interaction of these secondary mediators may be critical to a fully developed host inflammatory response to both immunologic and non-immunologic injury.

Animals↗
PubMed1982

Density dependence of maximum expiratory flow in the dog.

Airway lateral and impaction pressures were measured during expiratory flow limitation in six anesthetized, vagotomized, tracheally intubated, open-chest dogs with the lungs filled with air or a mixture of 80% helium-20% oxygen (HeO2). Pressures were measured in the vicinity of equal pressure points (EPP) and choke points (CP). Maximum flow (Vmax) was ensured by demonstrating no increase in flow with a 50% increase of driving pressure. At 50% vital capacity, mean density dependence (VmaxHeO2/Vmaxair) was 1.58, which was less than 1.69 predicted for fully density-dependent flow. Transmural pressure and airway area at CP and EPP (located on air) were significantly less with HeO2 than with air. Frictional losses between the alveoli and CP were 40% greater with HeO2 than with air. These enhanced losses were mostly peripheral to the EPP. Frictional loss upstream from the EPP was 47% of the total pressure loss on air and increased to 70% on HeO2. The data at 50% VC suggest that these higher frictional losses with HeO2 resulted in decreased density dependence of Vmax due to different pressure distribution along the airway with a lower transmural pressure and smaller area at the CP.

Air↗
PubMed1982

CO2 elimination by high-frequency oscillations in dogs--effects of histamine infusion.

Effective gas exchange can be achieved in normal dogs by ventilation at frequencies of 4-20 Hz using stroke volumes (SV) smaller than the anatomic dead space. CO2 elimination is largely a function of tracheal SV-frequency product (Vosc) in anesthetized, paralyzed dogs with normal lungs. To determine the effect of constriction of small airways on gas exchange during such high-frequency ventilation (HFV), we ventilated five anesthetized, paralyzed, and vagotomized dogs via a tracheal cannula before and during intravenous histamine infusion. Vosc was varied by varying the frequency while keeping SV constant. For low Vosc, CO2 elimination (VCO2) increased directly with Vosc during control and histamine experiments. At high Vosc, VCO2 continued to increase directly with Vosc during the control study, but during histamine infusion VCO2 was lower than control values. Eucapnia could be maintained in each dog during HFV, even during airway constriction. During histamine infusion the frequency-dependent mechanical properties of the lung influence the delivery of the HFV SV to the respiratory zone, and this may explain the lower VCO2 observed.

Animals↗
PubMed1982

Inhibition of bronchoconstriction in the guinea pig by a calcium channel blocker, nifedipine.

We investigated the inhibitory effects of nifedipine, a calcium channel blocker, on airway smooth muscle constriction in the guinea pig. In vitro, nifedipine (0.003 to 3.0 microM) caused significant dose-dependent reversal of intrinsically existing tone in both tracheal spirals and parenchymal strips. Nifedipine also inhibited the constriction of tracheal spirals and parenchymal strips induced by two different agonists, histamine and carbachol. At a concentration of 3.0 microM, nifedipine increased by 48-fold the concentration of carbachol required to produce a 50% of maximal contraction of parenchymal strips, and by 5-fold the concentration of histamine. Increasing extracellular calcium ion concentration in the tissue baths significantly diminished the inhibitory action of nifedipine. In vivo, nifedipine (30 micrograms/kg body weight given intravenously) did not alter pulmonary resistance or dynamic compliance. It did, however, attenuate histamine-induced bronchoconstriction in 3 of 5 animals studied. In response to the maximal dose of histamine infused, mean pulmonary resistance rose 40 +/- 16% (SEM) after nifedipine versus 182 +/- 65% in the control animals (p less than 0.025) and mean dynamic compliance decreased 35 +/- 8% after nifedipine versus 58 +/- 6% in the control animals (p less than 0.01). Thus, this calcium channel blocker inhibits mediator-induced constriction of both central and peripheral airway contractile tissues, a finding of potential clinical applicability.

Animals↗
PubMed1982

Effects of leukotriene E on pulmonary mechanics in the guinea pig.

The effects of intravenously infused 5(S)hydroxy-6(R)-S-cysteinyl-7,9,-trans,11,14,-cis eicosatetraenoic acid (leukotriene E) (LTE), one of the leukotriene constituents of slow-reacting substance of anaphylaxis (SRS-A), on pulmonary resistance (RL) and dynamic compliance (Cdyn), breathing frequency, and mean systemic arterial pressure were determined in both anesthetized and unanesthetized guinea pigs. The LTE caused a dose-dependent increase of RL and decrease in Cdyn over the range of doses from 100 to 10,000 ng/kg with significance effects at the highest doses. The onset of effect after a significant dose occurred within 30 s and was maximal 1 to 3 min after infusion. The LTE elicits a significantly greater effect on RL for a given change in Cdyn than occurs with LTC or LTD indicating that LTE is a less selective peripheral airway agonist than LTC or LTD. The LTD infusion resembled LTC or LTD in evoking a systemic arterial hypotension that was preceded by a brief initial period of hypertension in unanesthetized animals.

Airway Resistance↗
PubMed1982

Experimental induction of chronic bronchitis in dogs: effects on airway obstruction and responsiveness.

Chronic bronchitis was induced in 6 mongrel dogs by chronic exposure to SO2 gas; the degree of chronic airway obstruction and the effects on airway responsiveness to inhaled histamine, carbachol, and prostaglandin F2 alpha were examined. Five dogs developed chronic airway obstruction, as indicated by an increase in pulmonary resistance, and clinical mucous hypersecretion. In addition, in each of the animals in which chronic airway obstruction developed there was a decrease in the airway responsiveness to inhaled mediators. Those findings demonstrate that induction of chronic bronchitis in dogs results in hyporesponsiveness to inhaled mediators, a finding distinctly different from that reported in human subjects with naturally occurring disease.

Airway Resistance↗