Biomedical subjects

C M Schramm

Publications and source records attributed to C M Schramm.

28 records · Page 2Linked to original sources

PubMed1994

Maturation of catecholamine response and extraneuronal uptake in rabbit trachea.

The present study investigated whether maturational changes in extraneuronal catecholamine clearance accounted for the ontogenetic attenuation of isoproterenol responsiveness in rabbit tracheal segments. Following half-maximal contraction with acetylcholine (ACh) or KCl, tracheal ring segments (TS) isolated from newborn, 1-mo, and adult rabbits were relaxed with cumulative administration of isoproterenol. With postnatal maturation, there occurred a significant decrease in both maximal relaxation and sensitivity to isoproterenol in both ACh- and KCl-contracted TS. Inhibition of extraneuronal catecholamine uptake with methylprednisolone resulted in enhanced sensitivity to isoproterenol in 1-mo and adult, but not in newborn tracheal segments. In separate studies, extraneuronal catecholamine uptake was directly assayed in tracheal segments isolated from rabbits of similar age and pretreated with neuronal uptake and monoamine oxidase inhibitors. Maximal extraneuronal uptake of [3H]norepinephrine significantly decreased with age in tracheal tissues. In contrast, the sensitivity of the uptake process to norepinephrine increased with age. The relative catecholamine reserve markedly decreased with age in rabbit tracheal segments and was directly related to the maximal degree of relaxation elicited with the beta-adrenergic catecholamine, isoproterenol, in age-matched TS precontracted with either ACh or KCl. These findings suggest that, with maturation, extraneuronal uptake more effectively competes with beta-adrenoreceptor stimulation and, accordingly, may contribute to the ontogenetic attenuation of beta-adrenergic responsiveness in rabbit tracheal tissues.

Aging↗

PubMed1993

Predictive value of pulmonary function testing during pulmonary exacerbations in cystic fibrosis.

The optimal duration of therapy for acute exacerbations of cystic fibrosis (CF) has not been defined, and the utility of serial pulmonary function testing in predicting the duration of therapy has yet to be established. In a review of 90 pulmonary exacerbations of 39 patients with CF requiring hospitalization, we found that 72% of the patients recovered following 2 weeks of intravenous antibiotics and aggressive chest physiotherapy, and that 28% required an extended third week of therapy. Recovery was delayed in patients with more severe chronic pulmonary disease, but the rate of improvement was independent of the degree of pulmonary deterioration with the acute exacerbation. A 40% recovery of FEV1 at 1 week was found to correlate significantly with the duration of hospitalization in the 90 patients. When prospectively applied to a second series of consecutively hospitalized patients with CF, 25/28 patients admitted for 2 weeks demonstrated > 40% improvement in FEV1 at 1 week, as compared to 5/10 patients subsequently treated for > or = 3 weeks (P = 0.030). The predictive values for 2- or 3-week hospitalizations with 1-week interval recovery of > 40% or < or = 40% in FEV1 were 79% and 62%, respectively. These findings suggest that the response to intensive therapy in CF exacerbations is variable and that improvements in pulmonary function after 1 week of therapy may be used to predict the subsequent duration of therapy in the majority of CF patients with pulmonary exacerbations.

Acute Disease↗

PubMed1992

Assessment of signal transduction mechanisms regulating airway smooth muscle contractility.

Agonist-receptor interactions regulate airway smooth muscle tone through activation of guanine nucleotide binding proteins (G proteins) which are coupled to second-messenger pathways that mediate changes in the tissue's contractile state. Various methods have been applied to identify the structure/function characteristics of G proteins and their role in signal transduction in airway smooth muscle, including the use of exotoxins, nonhydrolyzable analogs of guanosine-triphosphate (GTP), antibodies to purified G proteins, and membrane reconstitution studies. In elucidating mechanisms of airway smooth muscle relaxation, considerable progress has been made in identifying the molecular basis for receptor/G protein coupling and other regulatory processes leading to both the activation and down-regulation of the adenylate cyclase/adenosine 3',5'-cyclic monophosphate system. Further, with respect to airway smooth muscle contraction, various approaches have been used to evaluate the role of membrane phosphoinositide turnover and the mechanisms of action of the bifurcating signal transduction pathways associated with the production and metabolism of inositol 1,4,5-trisphosphate and 1,2-diacylglycerol, and activation of protein kinase C. This review identifies much of the information gained to date on the above signal transduction pathways, with an emphasis placed on various methodological approaches used to determine membrane and transmembrane signaling processes in airway smooth muscle.

Adenylyl Cyclases↗

PubMed1992

Maturation of inositol 1,4,5-trisphosphate receptor binding in rabbit tracheal smooth muscle.

The mechanisms underlying maturational changes in agonist-mediated airway contractility remain to be identified. Since the signal transduction process coupled to airway contraction involves the Ca(2+)-mobilizing action of the second messenger, inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], the present study examined 1) whether Ins(1,4,5)P3 binding to its intracellular receptor varies with age in rabbit tracheal smooth muscle (TSM), and 2) whether Ca2+ exerts a modulatory effect on Ins(1,4,5)P3 receptor binding that is age dependent. [3H]Ins(1,4,5)P3 binding was assayed in crude TSM membrane preparations isolated from 2-week-old and adult rabbits. Monophasic Scatchard plots were obtained, reflecting a single binding site, with Hill coefficients of 0.988-0.996. The mean +/- SE values for receptor density (Bmax) and binding affinity [i.e., the dissociation constant (Kd)] were similar in the adult and immature tissues, wherein Bmax = 211 +/- 6 238 +/- 60 fmol/mg protein, respectively; and Kd = 14.1 +/- 0.2 and 11.6 +/- 1.2 nM, respectively. Addition of Ca2+ (10(-8)-10(-3) M) significantly modulated Ins(1,4,5)P3 binding, with opposing maturational effects. In adult tissues, Ca2+ produced dose-dependent inhibition of Ins(1,4,5)P3 binding to 59.5% control, whereas Ins(1,4,5)P3 binding in response to Ca2+ was significantly enhanced in the 2-week-old tissues to 183% control. Collectively, these observations demonstrate that the inherent basal binding characteristics of the Ins(1,4,5)P3 receptor are similar in maturing TSM, but that Ca2+ exerts opposite modulatory actions on Ins(1,4,5)P3 receptor binding in immature and adult tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1991

Role of endothelin 1 in regulating rabbit airway contractility.

Endothelin 1 (ET-1) is a potent vasoconstrictor peptide recently isolated from vascular endothelial cells. Because its role and mechanisms of action in regulating airway contractility remain to be identified, we examined the contractile effects of ET-1 in isolated rabbit tracheal smooth muscle (TSM) segments. In TSM under passive tension, ET-1 elicited dose-dependent contractions with a mean +/- SE -log 50% of maximal response value of 7.82 +/- 0.13 vs. a value of 5.61 +/- 0.07 -log M for acetylcholine (ACh). In TSM half-maximally contracted with ACh, however, ET-1 exerted dual and opposing contractile effects. Lower doses of ET-1 (less than or equal to 10(-9) M) produced a 74.2 +/- 16.6% decrease in active TSM tension. This relaxant response to ET-1 was associated with an accelerated accumulation of prostaglandin (PG) I2 and PGE2 and was attenuated by cyclooxygenase inhibition with indomethacin (10(-5) M). The combination of indomethacin and removal of the airway epithelium completely inhibited the TSM relaxant response to ET-1. In contrast, higher doses of ET-1 (greater than 10(-9) M) induced airway contractions that were attenuated by the Ca2+ channel blockers nifedipine (10(-5) M) and diltiazem (10(-5) M) and ablated in Ca2(+)-free buffer. Moreover, ET-1-induced TSM contractions were inhibited by the protein kinase C (PK-C) antagonists 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, and staurosporine.(ABSTRACT TRUNCATED AT 250 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Mechanisms of action of endothelin 1 in maturing rabbit airway smooth muscle.

Maturational differences in the effects and mechanisms of action of endothelin 1 (ET-1) on airway contractility were investigated in tracheal smooth muscle (TSM) segments isolated from 2-wk-old and adult rabbits. In TSM under passive tension, ET-1 elicited dose-dependent contractions, with a potency of action that was significantly greater (P less than 0.001) in the 2-wk-old vs. adult tissues (i.e., mean +/- SE - log 50% of maximal response values: 8.59 +/- 0.17 vs. 7.79 +/- 0.15 - log M, respectively). In TSM half-maximally contracted with acetylcholine (ACh), however, ET-1 elicited dual and opposing dose-dependent effects. At lower doses (less than or equal to 10(-9) M), ET-1 induced TSM relaxation that was significantly greater in the adult vs. 2-wk-old TSM segments (i.e., approximately 100 vs. 26.5% decrease in active tension, respectively). The relaxant responses were associated with significantly enhanced (P less than 0.001) ET-1-induced release of prostaglandins E2 and I2 in the adult tissues. At higher doses (greater than 10(-9) M), ET-1 induced TSM contractions that were 1) attenuated to a relatively greater extent by the Ca2+ channel blocker, nifedipine (10(-5) M) in the 2-wk-old tissues and 2) associated with significantly (P less than 0.001) enhanced ET-1-stimulated accumulation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] in the immature TSM. Moreover, the TSM contractions were inhibited by the protein kinase C (PKC) antagonist, H-7, and the latter effect was more potent in the immature TSM. Collectively, these findings demonstrate that ET-1 exerts a potent duality of action in rabbit TSM which varies significantly with maturation, wherein 1) age-dependent differences in airway relaxation are associated with changes in the evoked release of bronchodilatory prostaglandins and 2) maturational differences in airway contraction are associated with changes in Ins(1,4,5)P3 accumulation and extracellular Ca2+ mobilization, coupled to differences in PKC activation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1991

Use of TAO without methylprednisolone in the treatment of severe asthma.

The antimicrobial agent troleandomycin (TAO) has been shown to be effective in reducing corticosteroid requirements in patients with corticosteroid-dependent asthma. To our knowledge, the efficacy of TAO without concomitant use of corticosteroids has never been documented. We report the case of a 12-year-old patient with corticosteroid-dependent asthma who has remained asymptomatic and without any evidence of pulmonary deterioration during treatment with TAO without concomitant use of corticosteroids.

Adolescent↗

PubMed1989

Mechanisms of protein kinase C regulation of airway contractility.

To elucidate the role of protein kinase C (PK-C) in regulating airway contractility, the effects of PK-C activation with phorbol esters, 12-deoxyphorbol 13-isobutyrate (DPB), and phorbol 12-myristate 13-acetate (PMA), and with the diacylglycerol analogue 1-oleoyl-2-acetate-rac-glycerol (OAG) were separately evaluated in isolated rabbit tracheal smooth muscle (TSM) segments. The latter agents produced dual and opposing contractile effects, with DPB being the most potent. Lower doses of DPB (less than or equal to 10(-6) M) elicited significant increases in isometric tension in both untreated TSM, as well as in TSM half-maximally precontracted with methacholine. These potentiated TSM contractions were inhibited by the Ca2+ channel blockers, nifedipine (10(-4) M) and diltiazem (10(-5) M). In contrast, higher doses of DPB (greater than or equal to 10(-6) M) induced airway relaxation, which was ablated by preinhibition of the electrogenic Na+-K+ pump with ouabain (5 x 10(-6) M) or K+-free buffer. Indeed, in separate experiments DPB (10(-7) M) was found to significantly potentiate the functional activity of the Na+-K+ pump, an effect occurring independent of inhibition of Na+-H+ exchange with amiloride (10(-4) M) or extracellular Ca2+ influx with nifedipine (10(-4) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Expiratory volume clamping: a new method to assess respiratory mechanics in sedated infants.

During breathing under sedation via a two-way valve, airflow (V), volume (delta V), and airway pressure (P) were recorded in eight normal (N) infants, seven with reversible obstructive airway disease (ROAD), and seven with chronic lung disease (CLD). Intermittently, expiratory volume clamping (EVC) was applied, involving selective occlusion of the expiratory valve for three to five breaths. The latter produced cumulative increases in delta V that, due to progressive recruitment of the Hering-Breuer reflex, were accompanied by increasing expiratory plateaus in P (i.e., apneas). The resultant passive inflation delta V-P relationships were closely approximated by the expression: delta V = aP2 + bP + c, wherein a represented the pressure-related changes in chord compliance (Crs), b the Crs at P = 0, and c the difference between the dynamic end-expiratory and relaxation volumes of the respiratory system. Relative to N, the ROAD and CLD infants had significantly reduced weight-specific values of a/kg, their b/kg values were increased, whereas the c/kg measurements did not significantly vary. Moreover, for each subject we determined the net Crs/kg obtaining at P = 20 cmH2O (i.e., Crs20/kg), an estimate of the net deflation compliance; the passive respiratory time constant (tau rs) based on the slope of the expired delta V/V relationship; and the respiratory system conductance (Grs/kg). Relative to N, the mean Crs20/kg was significantly reduced only in the infants with CLD and, due to increases in tau rs, both patient groups depicted significantly diminished values of Grs/kg, suggesting the presence of airways obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomechanical Phenomena↗

PubMed1987

Respiratory influence of peripheral chemoreceptor stimulation in maturing rabbits.

To evaluate whether the influence of peripheral chemoreceptor (PCR) stimulation is centrally modulated by hypoxia, the respiratory effects of sodium cyanide (NaCN) infusion were compared during room air and 10% O2 inhalation in 18 lightly anesthetized, tracheotomized rabbits of varying postnatal age (1-33 days). During normoxia, noncumulative infusions of NaCN (5-400 micrograms/kg body wt) produced dose-dependent ventilatory (VE) stimulation. Maximal VE stimulation (VEmax) and ventilatory sensitivity to NaCN [i.e., log dose producing 50% of VEmax (log ED50)] did not significantly vary with age, with the average VEmax and log ED50 values amounting to 238% above base line and 1.564 micrograms/kg, respectively. During hypoxia, after initial stimulation (average: 152%), VE progressively decreased and stabilized to 67% above the normoxic base-line level. In contrast to normoxia, subsequent NaCN administration during steady-state hypoxia produced dose-dependent VE depression, occasionally manifested by abrupt apnea. The NaCN effect during hypoxia was significantly related to age (P less than 0.05), as well as to the estimated change in CO2 production during hypoxia (P less than 0.01). Both the respiratory depressant effects of hypoxia alone and in combination with NaCN were abolished after denervation of the peripheral chemoreceptors. These findings demonstrate that while PCR stimulation during normoxia produces ventilatory stimulation, the influence of enhanced PCR input during hypoxia is centrally modulated to produce ventilatory depression.

Aging↗