Search PubMed⌕ Search

Biomedical subjects

R C Levitt

Publications and source records attributed to R C Levitt.

71 records · Page 4Linked to original sources
PubMed1990

A genetic model for evaluation of susceptibility to ozone-induced inflammation.

We examined ozone-induced airway inflammatory responses in inbred mice, and progeny of crosses between them, to investigate genetic susceptibility to ozone. Nine strains of male mice (18-23 g, 5-7 wk) were exposed for 3 h to 2 ppm ozone (O3) or filtered air (control), and pulmonary inflammation was assessed 2, 6, and 24 h after exposure by inflammatory cell counts and total protein content in bronchoalveolar lavage (BAL). The time course of the response to O3 was consistent between the strains. The maximum change in polymorphonuclear leukocytes (PMNs) was detected 6 h after O3, and the maximum increase in BAL protein occurred 24 h postexposure. Air controls exhibited no detectable changes in the parameters of inflammation at any time. The phenotypes of the C57BL/6J (B6, termed susceptible) and C3H/HeJ (C3, termed resistant) strains were easily distinguished by the magnitude of their inflammatory responses to O3. A 22-fold difference in PMNs was detected between the two strains 2 h after O3 (P less than 0.001), and a sixfold difference was found 6 h after O3 (P less than 0.001). Total BAL proteins were also significantly different between the B6 and C3 strains 6 h (P less than 0.01) and 24 h after O3 (P less than 0.001). To further evaluate the potential genetic contribution to the inflammatory response, the F1, F2, and backcross progeny from crosses between B6 and C3 strains were examined. The phenotypes of these progeny were consistent with the hypothesis that a single autosomal recessive gene at the Inf locus confers susceptibility to acute O3-induced influx of PMNs, but the genetic control of altered permeability is not clear.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

In vitro tracheal responses from mice chosen for in vivo lung cholinergic sensitivity.

We selected two inbred strains of mice based on their different in vivo lung responses to intravenous acetylcholine for studies on the in vitro tracheal responses to contractile and relaxing agents. In addition, we studied the role of cyclooxygenase products on the in vitro responses. Tracheal rings were contracted with increasing concentrations of carbachol and KCl and relaxed with increasing concentrations of isoproterenol after contraction with carbachol at the concentration that produced 30, 50, and 70% of the maximal contraction (EC30, EC50, and EC70, respectively) and KCl at the EC50. Half the tracheae simultaneously underwent the same protocols after pretreatment with indomethacin (3 X 10(-6) M). Despite a severalfold difference in the maximal response to cholinergic agents in vivo, there were no significant differences between the strains in the tracheal responses to carbachol (P = 0.78) or KCl (P = 0.13) in vitro. Both strains showed inhibition of the isoproterenol relaxation by carbachol (P less than 0.0001). Multiple linear regression analysis showed that the strain that was more sensitive to carbachol in vivo was also more sensitive to isoproterenol in vitro after carbachol contraction (P = 0.014). The greater isoproterenol sensitivity of the tracheae from this strain was not present after contraction with KCl, nor were these tracheae more sensitive to relaxation with sodium nitroprusside. Indomethacin pretreatment of the tissues in vitro augmented the maximal response and the sensitivity to carbachol (P less than 0.001) and KCl (P = 0.0006), and this effect was similar in both strains. Evaluation of isoproterenol relaxation after indomethacin pretreatment was confounded by the lower concentrations of carbachol needed for contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Succinylcholine potentiates responses to intravenous acetylcholine in the canine lung periphery.

Using the wedged bronchoscope technique to measure collateral resistance (Rcs), we evaluated the effect of succinylcholine (SCh) on the response to acetylcholine (ACh) and methacholine (MCh) in the lung periphery in six mongrel dogs. Dogs were anesthetized, intubated, and mechanically ventilated. After a stable baseline Rcs was obtained, responses to intravenous ACh (25-200 micrograms), intravenous MCh (3-30 micrograms), and aerosolized ACh (30-100 micrograms/ml for 15 s) were measured. We compared the Rcs responses with 1) ACh alone, 2) ACh 2 min after SCh (0.5 mg/kg), 3) ACh 2 min after SCh and during hexamethonium infusion (5 mg/kg + 10 mg.kg-1.h-1), 4) MCh 2 min after SCh, and 5) ACh aerosol 2 min after SCh. SCh did not significantly alter baseline airway tone. SCh increased the Rcs response to ACh by 48 +/- 17% (SE) (P less than 0.01). SCh in the presence of hexamethonium increased the Rcs response by 10 +/- 3% (P less than 0.05), while hexamethonium itself increased the response to ACh by 69 +/- 27%. Because SCh did not increase the Rcs response to intravenous MCh or to aerosolized ACh, SCh probably enhances airway reactivity to intravenous ACh by competing for pseudocholinesterase in plasma. We conclude that the level of muscle relaxant must be taken into account in interpreting studies of airway reactivity when intravenous ACh is employed.

Acetylcholine↗
PubMed1989

Autosomal recessive inheritance of airway hyperreactivity to 5-hydroxytryptamine.

We have previously reported that airway hyperresponsiveness to acetylcholine (ACh) is inherited as an autosomal recessive trait in A/J and C3H/HeJ mice and the progeny of crosses between them (FASEB J. 2: 2605-2608, 1988). In the present report, we have extended these studies by evaluating the biological variability in the airway response to 5-hydroxytryptamine (5-HT) and ACh among multiple genetically standardized inbred strains of mice. The pattern of airway responsiveness to ACh differed significantly from that of 5-HT in nine inbred strains of mice. A/J mice showed nonspecific airway hyperresponsiveness to both 5-HT and ACh. DBA/2J mice were hyperresponsive to 5-HT but not to ACh. An airway phenotype that resembled these inbred strains is termed HYPERREACTIVE. The C3H/HeJ and C57BL/6J inbred strains were minimally reactive to either ACh or 5-HT. Airway phenotypes that resembled these minimally reactive strains are termed HYPOREACTIVE. The frequency of HYPERRACTIVE and HYPOREACTIVE offspring from crosses between A/J and C3H/HeJ mice or DBA/2J and C57BL/6J mice is consistent with a single autosomal recessive gene, primarily determining airway hyperresponsiveness to 5-HT. We report linkage studies which suggest that these genes are not closely linked and that 5-HT and ACh airway hyperresponsiveness is inherited independently. The results of these studies suggest that murine nonspecific airway hyperresponsiveness is determined by multiple genes.

Acetylcholine↗
PubMed1988

Expression of airway hyperreactivity to acetylcholine as a simple autosomal recessive trait in mice.

An increased airway response to various bronchoconstricting agents is one of the hallmarks of asthma. An interdependence of heredity and environment appears to determine this nonspecific hyperreactivity of the airways. The present study describes the patterns of inheritance of the airway response to a direct mediator of smooth muscle contraction (acetylcholine) in A/J and C3H/HeJ inbred mice and their offspring. The mean airway response to acetylcholine was greater than sixfold higher in A/J mice as compared with C3H/HeJ mice. Two phenotypes were easily distinguished on the basis of airway responses to acetylcholine in the progeny of A/J and C3H/HeJ mice. These two phenotypes were termed HYPERREACTIVE (after the A/J strain) and HYPOREACTIVE (after the C3H/HeJ strain). The observed frequencies of HYPERREACTIVE and HYPOREACTIVE phenotypes in the (A/J x C3H/HeJ) F1; (C3H/HeJ x A/J) F1 x C3H/HeJ (C3H/HeJ backcross); and the [(A/J x C3H/HeJ) F1 x (C3H/HeJ x A/J) F1] F2 are consistent with a single autosomal recessive gene primarily controlling acetylcholine-mediated airway responses. This single gene difference in airway response is completely inhibited by atropine and therefore mediated entirely by the muscarinic acetylcholine receptor.

Acetylcholine↗
PubMed1984

Effects of cimetidine on theophylline, acetaminophen, and zoxazolamine toxicity in the intact mouse.

3-Methylcholanthrene treatment of C57BL/6N mice induces significant amounts of cytochromes P1-450, whereas P1-450 levels in 3-methylcholanthrene-treated DBA/2N mice are no different from those in control C57BL/6N or DBA/2N mice. Comparison of 3-methylcholanthrene-treated C57BL/6N and DBA/2N mice thus provides a convenient means of determining the role of P1-450 metabolism in two strains of mice following identical drug treatment regimens. 3-Methylcholanthrene-induced P1-450 is shown to be more effective than other forms of P-450 in detoxifying theophylline and zoxazolamine and in enhancing the toxicity of acetaminophen. Cimetidine in vivo blocks these metabolic pathways, resulting in increased toxicity of theophylline and zoxazolamine and protection against acetaminophen toxicity. These data illustrate the double-edged sword nature of P1-450 metabolism and the possibility of a paradoxical effect of cimetidine during drug-drug interactions in vivo. Cimetidine is shown to inhibit in vivo and in vitro the metabolism by both 3-methylcholanthrene-induced P1-450 and control forms of P-450; these data suggest that cimetidine may be acting at the level of P-450 reduction by NADPH-P-450 oxidoreductase. This same mechanism of action has been previously suggested for ellipticine.

Acetaminophen↗
PubMed1983

Screening of 16 common therapeutic drugs. Possible association with the Ah locus.

16 common therapeutic agents were screened for differences in sedation or lethality between C57BL/6N and DBA/2N inbred mouse strains that had been previously treated with beta-naphthoflavone. No differences were observed for meprobamate, valium, promethazine, valproic acid, lincomycin, imipramine, terbutaline, propoxyphene, nitrofurantoin, amphotericin B, or diphenhydramine. C57BL/6N mice appeared to be more resistant than DBA/2N mice to the lethal effects of isoxsuprine, niridazole, pentazocine, isoniazid, and hydralazine. None of these latter five drugs had any capacity to displace [3H-1,6]2,3,7,8-tetrachlorodibenzo-p-dioxin from the liver cytosolic Ah receptor in C57BL/6N mice. With the use of beta-naphthoflavone-pretreated offspring from the (C57BL/6N) (DBA/2N)F1 X DBA/2N backcross, a strict correlation (100% of 24 individuals in each case) was found between the Ahb allele and resistance to the lethal effects of isoxsuprine or niridazole. No correlation between the Ah locus and pentazocine, hydralazine, or isoniazid lethality was apparent. These results indicate that presence of the Ahb allele is associated with increased protection against isoxsuprine and niridazole lethality. This increased protection may reflect enhanced detoxication metabolic pathways (e.g., induced cytochrome P1-450 and/or uridine diphosphate glucuronosyltransferase controlled by the Ah locus). The increased protection is not related to interaction of these drugs with the Ah receptor. It should be kept in mind that gene-environment interactions involving the Ah locus and isoxsuprine or niridazole may be important in certain clinical instances.

Animals↗
PubMedDate not supplied

Differential susceptibility to ozone-induced airways hyperreactivity in inbred strains of mice.

Individuals with heightened airways reactivity, such as asthmatics, may be at risk to inflammatory effects of oxidant air pollutants. In the inbred mouse, significant interstrain variation in airways reactivity to acelycholine (ACh) and differential susceptibility to ozone (O3)-induced airways inflammation has been described previously. This study used these murine models to test hypotheses that (1) O3-induced hyperreactivity to ACh is a function of inherent baseline ACh reactivity, and (2) susceptibility to O3-induced inflammation is associated with O3-induced hyperreactivity. Strains (15-25 g, 6-8 weeks) with HYPERREACTIVE (DBA/2J, AKR/J, A/J), HYPOREACTIVE (C3H/HeJ, C57BL/6J, SJL/H), or INTERMEDIATE (129/J) phenotypes for ACh reactivity were exposed for 3 h to 2.0 ppm O3 or air (control). ACh reactivity (25 and 50 micrograms/kg, IV) was assessed 0 and 24 h after exposure. Relative to air controls, mean airways responses to 25 and 50 micrograms/kg ACh 24 h post-O3 increased significantly in the HYPERREACTIVE A/J strain (p < .05). Among HYPOREACTIVE strains, O3 significantly (p < .05) increased the response to 50 micrograms/kg ACh in C57BL/6J and SJL/J strains 24 h postexposure. A/J, C57BL/6J, and SJL/J mice are susceptible to O3-induced lung injury. O3 did not alter ACh reactivity in the other strains. O3 also did not affect airways reactivity to methacholine or carbachol, observations consistent with the hypothesis that O3-induced hyperreactivity to ACh may be due, in part, to O3 effects on cholinesterase function. Treatment of C57BL/6J and A/J mice with an immunosuppressant (cyclophosphamide) or an anti-PMN antibody significantly (p < .05) attenuated circulating and infiltrating polymorphonuclear leukocytes (PMNs), but did not affect O3-induced hyperreactivity. Therefore, O3-induced ACh hyperreactivity was not a function of baseline reactivity, but correlated with susceptibility to acute O3-induced airways injury and inflammation. Pharmacologic studies suggest that although PMNs were associated with O3-induced hyperreactivity, these cells were not the cause of the effect, and that these two events are not codependent.

Acetylcholine↗