Biomedical subjects

M M Grunstein

Publications and source records attributed to M M Grunstein.

At least 55 records · Page 3Linked to original sources

PubMed1992

Role of endothelin-1 in regulating proliferation of cultured rabbit airway smooth muscle cells.

Increased expression of the potent vasoconstrictor and bronchoactive peptide, endothelin-1 (ET-1), has recently been demonstrated in airway epithelial and endothelial cells of asthmatic patients. To identify its potential role in contributing to airway smooth muscle (ASM) hyperplasia, a characteristic feature of asthmatic airways, the mitogenic action of ET-1 was investigated in cultured rabbit ASM cells. ET-1 elicited significant dose-dependent (10(-12)-10(-6) M) increases in ASM cell number, with a mean potency (i.e., -log mean effective dose) of action of 9.82-log M. ET-1 also acutely stimulated intracellular inositol 1,4,5-trisphosphate accumulation. The latter response was blocked by phospholipase C inhibition with neomycin; however, neomycin had no effect on the promitogenic action of ET-1. By contrast, the ASM cell proliferative response to ET-1 was independently inhibited by pertussis toxin, inhibitors of phospholipase A2, cyclooxygenase, and thromboxane A2 (TxA2) synthesis, as well as blockade of the TxA2 receptor. Moreover, in complementary studies, we found that administration of the stable TxA2 mimetics, carbocyclic TxA2 (CTA2) and U-46619, induced ASM cell proliferation and that ET-1 evoked the release of endogenous TxA2 from the ASM cells. Collectively, these observations provide new evidence that 1) ET-1 is a potent mitogen of ASM cells, 2) the promitogenic effect of ET-1 is associated with activation of a pertussis toxin-sensitive G protein coupled to stimulation of phospholipase A2, and 3) the latter mediates ASM cell proliferation via the release and autocrine mitogenic action of TxA2. The findings support a potential role for ET-1 in mediating the characteristic hyperplasia of ASM in asthma.

Animals↗

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↗

PubMed1992

Role and mechanism of thromboxane-induced proliferation of cultured airway smooth muscle cells.

Thromboxane (Tx)A2 has been reported to play an important role in modulating airway contractility under various conditions associated with airways inflammation. To identify its potential role in contributing to airway smooth muscle (ASM) hyperplasia, a characteristic feature of asthmatic airways, the mitogenic effect and mechanism of action of TxA2 were investigated in cultured rabbit ASM cells. The stable TxA2 mimetics, carbocyclic TxA2 (CTA2) and U-46619, elicited dose-dependent (10(-12) to 10(-6) M) increases in ASM cell number and induced acute augmentation of intracellular inositol 1,4,5-trisphosphate accumulation. The latter action was blocked by neomycin, a phospholipase C inhibitor; however, neomycin had no effect on the promitogenic action of the TxA2 mimetics. In contrast, TxA2-induced ASM cell proliferation was inhibited by inhibitors of phospholipase A2 and 5-lipoxygenase, as well as blockade of the leukotriene (LT)D4 receptor. Moreover, in complementary studies, we found that exogenous administration of LTD4 (10(-14) to 10(-6) M) potently induced ASM cell proliferation and that the TxA2 mimetics evoked the enhanced release of endogenous leukotrienes from the cultured ASM cells. Taken together, these observations provide new evidence that 1) TxA2 stimulates ASM cell proliferation; 2) the promitogenic effect of TxA2 is associated with activation of phospholipase A2; and 3) the latter mediates ASM cell proliferation via the release and autocrine mitogenic action of leukotrienes. The findings support a potential role for TxA2 in contributing to the characteristic increase in ASM cell mass obtained in asthma and other chronic airway diseases.

Animals↗

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

Maturational regulation of inositol 1,4,5-trisphosphate metabolism in rabbit airway smooth muscle.

Airway reactivity has been shown to vary with age; however, the mechanism(s) underlying this process remain unidentified. To elucidate the role of ontogenetic changes in phosphoinositide-linked signal transduction, we examined whether age-related differences in tracheal smooth muscle (TSM) contractility to carbachol (CCh) are associated with developmental changes in the production and metabolism of the second messenger, inositol 1,4,5-trisphosphate (Ins (1,4,5)P3). In TSM segments isolated from 2-wk-old and adult rabbits, both the maximal isometric contractile force and sensitivity (i.e., -logED50) to CCh (10(-10)-10(-4) M) were significantly greater in the immature vs. adult tissues (P less than 0.001). Similarly, Ins(1,4,5)P3 accumulation elicited by either receptor-coupled stimulation with CCh (10(-10)-10(-4) M) or post-receptor-mediated guanine nucleotide binding protein activation of permeabilized TSM with GTP gamma S (100 microM) was also significantly enhanced in 2-wk-old vs. adult TSM. Measurement of the activities of the degradative enzymes for Ins(1,4,5)P3 demonstrated that: (a) mean +/- SE maximal Ins(1,4,5)P3 3'-kinase activity was significantly reduced in the immature vs. adult TSM (i.e., approximately 71.7 +/- 6.0 vs. 137.8 +/- 10.0 pmol/min per mg protein, respectively; P less than 0.005); (b) by contrast, maximal Ins(1,4,5)P3 5'-phosphatase activity was significantly increased in the immature vs. adult TSM (i.e., 27.9 +/- 1.2 vs. 15.6 +/- 1.5 nmol/min per mg protein, respectively; P less than 0.001); and (c) the Km values for Ins(1,4,5)P3 5'-phosphatase were 14- and 19-fold greater than those for Ins(1,4,5)P3 3'-kinase in the 2-wk-old and adult TSM, respectively. Collectively, the findings suggest that the age-related decrease in agonist-induced rabbit TSM contractility is associated with a diminution in Ins(1,4,5)P3 accumulation which is attributed, at least in part, to ontogenetic changes in the relative activities of the degradative enzymes for Ins(1,4,5)P3.

Animals↗

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↗

PubMed1990

Maturation of neuromodulatory effect of substance P in rabbit airways.

The maturation of the neuromodulatory action of substance P (SP) was investigated in tracheal smooth muscle (TSM) segments isolated from rabbits aged 2-24 wk. The tissues were placed in baths containing Krebs-Ringer solution and contracted with electrical field stimulation (ES) with ES frequencies ranging from 1 to 75 Hz. In tissues greater than 1 mo of age, the ES frequency-response relationships were progressively shifted in the presence of a maximally effective neuromodulatory SP dose (10(-7) M) such that by 24 wk of age the mean (+/- SEM) maximal tension (Tmax) significantly increased from 380.4 (+/- 41.9) to 502.3 (+/- 64.2) g/g TSM, and the corresponding mean (+/- SEM) log ES frequency producing 50% of Tmax (log ES50) significantly decreased from 1.209 (+/- 0.069) to 1.055 (+/- 0.046) Hz. By contrast, relative to methacholine, the direct contractile effects of SP did not significantly vary with age. In further analyzing the basis for the above age-related difference in the neuromodulatory action of SP, we found that the magnitude of SP-induced neuromodulation was highly correlated to the tissue's intrinsic sensitivity to ES. Indeed, after accounting for the tissue's sensitivity to ES, the effect of age alone on the magnitude of SP-induced neuromodulation was not statistically significant. These findings provide new evidence that: (a) SP-induced neuromodulation of acetylcholine release at the airway neuromuscular junction is significantly enhanced during postnatal development; and (b) that the latter age-dependent action of SP is based on a close coupling of the magnitude of SP-induced neuromodulation to the tissue's intrinsic sensitivity to neurally mediated contraction.

Age Factors↗

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↗

PubMed1989

The effects of acute hypoxia and hypercapnia on pulmonary mechanics in normal subjects and patients with chronic pulmonary disease.

The influence of progressive hypoxia and hypercapnia on respiratory mechanics was evaluated in 26 subjects (six normal subjects, seven asthmatic subjects, seven patients with IPD, and six patients with COPD). During separate rebreathing runs of progressive isocapnic hypoxia and normoxic hypercapnia, breath-to-breath changes in RL and Cdyn were determined. In five of the six normal subjects, seven of the seven asthmatic subjects, and six of the seven subjects with IPD, RL decreased with both progressive hypoxia and hypercapnia without a change in Cdyn. In the patients with COPD, the effects of hypoxia and hypercapnia on RL and Cdyn were variable. Compared to normal subjects, the changes in RL during hypoxia and hypercapnia were not significantly different in the asthmatic subjects and the patients with IPD. These data provide evidence that acute progressive hypoxia and hypercapnia are associated with significant changes in Raw in both normal subjects and patients with chronic pulmonary disease.

Adult↗

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

Endogenous opioids modulate fetal rabbit lung maturation.

To test the hypothesis that endogenous opioids modulate fetal lung development, separate groups of pregnant rabbits received daily injections of saline, morphine (1 mg/kg body wt), or the opioid antagonist naloxone (0.4 and 5.0 mg) for 10 days during their last trimester of pregnancy. The corresponding groups of fetuses were then delivered prematurely on day 28 of gestation (term approximately 31 days) and evaluated with respect to differences in body weight, lung weight, and the ratios of wet to dry lung weight and lung dry weight to body weight, the static inflation and deflation air and saline pressure-volume (P-V) characteristics of the lungs, and lung morphology. Mean values for body weight, lung weight, and the ratios of lung wet to dry weight and lung dry weight to body weight were not significantly different among the saline control (C), morphine (M)-, and naloxone (NLX)-treated fetuses. On the other hand, the fetal air P-V curves varied significantly (P less than 0.001), wherein the M-treated group depicted increased lung distensibility and alveolar stability on lung deflation, whereas the opposite was obtained in the NLX-treated fetuses. Moreover, morphometric analyses demonstrated that the mean alveolar air space-to-tissue ratio in lungs from M-treated fetuses were significantly greater than that observed either in C or in NLX-treated fetuses (P less than 0.05); however, the air space-to-tissue ratio did not significantly vary between the C and NLX-treated animals. These observations provide new evidence that endogenous opioids enhance fetal lung maturation.

Animals↗

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↗

PubMed1987

Effects of temperature on cholinergic contractility of rabbit airway muscle.

To elucidate the mechanism underlying temperature-induced changes in airway cholinergic contractility, the effects of organ bath cooling were evaluated in isolated rabbit airway smooth muscle (ASM) segments isometrically contracted with methacholine (METH) (10(-8)-10(-3) M) and electrical field stimulation (ES), wherein the ES stimulus frequency was varied between 1 and 100 Hz. Cooling from 37 to 25 degrees C produced systematic increases (P less than 0.01) in isometric tension at various administered doses of METH and at different levels of ES. Since the potentiated contractions to ES significantly exceeded (P less than 0.001) the corresponding increases in METH-induced contractility, we evaluated whether the latter was attributed to temperature-mediated changes in intrinsic airway neuronal acetylcholine (ACh) release. Accordingly, the effects of ASM cooling were independently determined before and after inhibition of the Na+-K+ electrogenic pump with ouabain (10(-5) M), and depletion of intrinsic neuronal ACh stores with hemicholinium-3 (HC-3) (10(-3) M). In the presence of either ouabain or HC-3 the above responses to temperature reduction were reversed, and airway cooling was associated with abrupt relaxation of ASM segments precontracted with METH. In contrast, neither inhibition of cyclooxygenase products with indomethacin (10(-6) M) nor cholinesterase inhibition with neostigmine (10(-3) M) notably influenced the ASM responses to organ bath cooling. Thus these findings demonstrate that 1) both METH-induced and neurally mediated cholinergic contractility are augmented during airway cooling; 2) the potentiated cholinergic responses are attributed to enhanced presynaptic release of ACh at the airway neuromuscular junction.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

PubMed1986

Effect of substance P on neurally mediated contraction of rabbit airway smooth muscle.

The neuromodulatory action of substance P (SP) was investigated in isolated rabbit tracheal smooth muscle (TSM) segments contracted with electrical field stimulation (ES). The tissues were placed in organ baths containing modified Krebs-Ringer solution and stimulated at a constant voltage (8 V; 24.5 mA) and pulse duration (2 ms) with ES frequencies ranging from 1 to 100 Hz. In the presence of SP, there occurred a dose-dependent augmentation of the TSM contractile response to any given ES, with the maximal effect of SP obtained at a dose of 10(-7) M. Accordingly, with the administration of 10(-7) M SP, the ES frequency-response relationship was altered so that 1) the mean (+/- SE) maximal tension (Tmax) induced by ES significantly increased (P less than 0.02) from a base-line value of 273 +/- 53 to 402 +/- 45 g/g TSM; and 2) the mean (+/- SE) log ES frequency producing 50% of Tmax (ES50) significantly decreased from a base-line value of 1.278 +/- 0.069 to 1.102 +/- 0.070 Hz (P less than 0.01). In contrast to these effects on ES-induced contraction, SP administration did not affect the TSM contractile response to administered methacholine chloride (10(-8) to 10(-3) M). On the other hand, the effects of SP on ES-induced contraction were independently blocked by the cholinergic antagonist, atropine (10(-6) M); the neurotoxin, tetrodotoxin (10(-6) g/ml); and the SP antagonist, D-Arg1,D-Pro2,D-Trp7,9,Leu11-SP (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1985

Vasoactive effects of substance P on isolated rabbit pulmonary artery.

The vasoactive properties of substance P (SP) were studied in isolated rabbit pulmonary artery (PA) segments in vitro. In the absence of active base-line tone, noncumulative administration of SP (10(-11) to 10(-4) M) produced dose-dependent increases in PA tension. The peak isometric tension (Tmax) with SP was similar to the Tmax response to epinephrine; however, the doses of the agonist producing a threshold contraction and 25% of Tmax (ED25) were significantly lower for SP. In the presence of active base-line tone, induced by epinephrine or 5-hydroxytryptamine, SP produced transient PA relaxation which was directly related to the magnitude of the precontracted PA tension. Blockade of neurotransmission with tetrodotoxin (1 microgram/ml) and antagonists to alpha 1-adrenergic and histamine receptor binding had no effect on the contractile response to SP. On the other hand, PA contraction to an ED50 dose of SP was 1) inhibited by a mean of 33 +/- 10% (SE) following pretreatment with the cholinesterase inhibitor, neostigmine (10(-6) M) and 2) augmented by 52 +/- 21% with the cholinergic antagonist, atropine (10(-4) M). The latter also completely blocked the relaxation response to SP in precontracted PA. Similarly, removal of the PA endothelium also abolished the relaxation response to SP. In contrast, SP-induced contraction was markedly inhibited by the cyclooxygenase inhibitor, meclofenamate (1 microgram/ml), as well as the SP antagonist, D-Pro2, D-Trp7,9-SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Opposing hemodynamic effects of substance P on pulmonary vasculature in rabbits.

Substance P is a peptide implicated in the control of a variety of physiological processes. Although substance P-containing neurons impinge on the pulmonary vasculature, the effects of substance P on the pulmonary circulation have not been systematically investigated. Rabbits were anesthetized with methohexital sodium and paralyzed with pancuronium bromide. Injection of substance P (0.002-0.10 microgram/kg) in the vena cava produced dose-dependent pulmonary vasoconstriction and systemic vasodilation. Pulmonary arterial pressure reached a peak within 15-20 s and declined toward base line over 10 min. Aortic pressure fell rapidly, reaching minimum at 5-10 s. At higher doses cardiac output fell transiently, resulting in a 65% fall in pulmonary vascular conductance. If repeat substance P dosages were administered 15 min apart, there was no tachyphylaxis. Pulmonary vasoconstriction was inhibited by the cyclooxygenase blocker meclofenamate (10 mg/kg) and the thromboxane synthase inhibitor Dazmegrel (UK-38,485) (2 mg/kg). In contrast, vasoconstriction was enhanced by atropine (2 mg/kg). In Dazmegrel-treated animals in whom pulmonary vasoconstriction was established by epinephrine infusion, low doses of substance P produced vasodilation. Our findings indicate that substance P produces pulmonary vasoconstriction via prostaglandin (particularly thromboxane) generation and pulmonary vasodilation via activation of cholinergic pathways.

Animals↗

PubMed1985

Ontogeny of respiratory control and pulmonary mechanics in newborn rabbits.

Maturation of the respiratory pattern and the active and passive mechanical properties of the respiratory system were assessed in 19 tracheotomized rabbits (postnatal age range: 1-26 days) placed in a body plethysmograph. With maturation both minute ventilation and tidal volume significantly increased, whereas respiratory frequency decreased. When normalized for body weight (kg) both the passive (Rrs X kg) and active (R'rs X kg) resistances of the respiratory system significantly increased with age, whereas the corresponding passive (Crs X kg-1) and active (C'rs X kg-1) compliances significantly decreased. At any given age R'rs X kg only slightly exceeded Rrs X kg, whereas C'rs X kg-1 was significantly lower than Crs X kg-1. Moreover, the maturational increases in Rrs X kg and R'rs X kg exceeded the corresponding decreases in Crs X kg-1 and C'rs X kg-1, resulting in significant age-related increases in both the passive (tau rs) and active (tau'rs) time constants of the respiratory system. Due to the age-related increases in tau'rs, producing a delayed volume response to any given inspiratory driving pressure, the relative volume loss obtained at any time during inspiration was greater in the maturing rabbit. On the other hand, because of concomitant compensatory changes in respiratory pattern, evidenced by increases in inspiratory duration with age, the end-inspiratory tidal volume loss in the maturing animal was maintained generally less than 10% at all postnatal ages. Thus maturational changes in respiratory pattern appear coupled to changes in the active mechanical properties of the respiratory system. The latter coupling serves to optimize the transduction of inspiratory pressure into volume change in a manner consistent with establishing the minimum inspiratory work of breathing during postnatal development.

Age Factors↗