Kayleen S. Kott

Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits.

1. This study tested the hypothesis that substance P stimulates rapidly adapting receptors (RARs), contributes to the increase in RAR activity produced by mild pulmonary congestion, and evokes an augmented response from RARs when combined with near‐threshold levels of pulmonary congestion. 2. RAR activity, peak tracheal pressure, arterial blood pressure and left atrial pressure were measured in paralysed, anaesthetized and ventilated rabbits. Substance P was given i.v. in one‐half log incremental doses to a maximum of 3 micrograms kg‐1. Mild pulmonary congestion was produced by inflating a balloon in the left atrium to increase left atrial pressure by 5 mmHg. Near‐threshold levels of pulmonary congestion were produced by increasing left atrial pressure by 2 mmHg. 3. Substance P produced dose‐dependent increases in RAR activity. The highest dose given increased the activity from 1.3 +/‐ 0.5 to 11.0 +/‐ 3.1 impulses bin‐1. Increases in left atrial pressure of 5 mmHg increased RAR activity from 3.8 +/‐ 1.4 to 14.7 +/‐ 3.9 impulses bin‐1. Blockade of NK1 receptors with CP 96345 significantly attenuated RAR responses to substance P and to mild pulmonary congestion. 4. Doses of substance P, which alone had no effect, stimulated the RARs when delivered during near‐threshold levels of pulmonary congestion. 5. The findings suggest that substance P augments the stimulatory effect of mild pulmonary congestion on RAR activity, most probably by enhancing hydraulically induced microvascular leak.

Nitric Oxide Contributes to Substance P‐Induced Increases in Lung Rapidly Adapting Receptor Activity in Guinea‐Pigs

1 Substance P induces fluid flux via nitric oxide, and fluid flux stimulates lung rapidly adapting receptors (RARs). We therefore proposed that nitric oxide contributes to substance P‐evoked increases in RAR activity. Since substance P decreases dynamic compliance (Cdyn), which can stimulate RARs, we also determined whether nitric oxide contributed to substance P‐induced effects on pulmonary function. 2 In anaesthetized guinea‐pigs, the effects of substance P on RAR activity, Cdyn, pulmonary resistance (RL), and arterial blood pressure were measured before and after i.v. infusion of NG‐methyl‐l‐arginine (l–NMMA; a nitric oxide synthase inhibitor), or l–NMMA followed by l‐arginine (a nitric oxide precursor which reverses the effects of l–NMMA). 3 Substance P‐evoked increases in RAR activity were blunted by l–NMMA (P= 0.006) but not by l–NMMA–l‐arginine (P= 0.42). 4 Substance P‐evoked decreases in Cdyn were slightly inhibited by l–NMMA (P= 0.02) and slightly enhanced by l‐NMM A–l‐arginine (P= 0.004). However, at the time at which l–NMMA maximally reduced substance P‐induced RAR stimulation (the first 30 s), it did not change substance P‐induced decreases in Cdyn. 5 Substance P‐evoked increases in RL were not changed by l–NMMA (P= 0.10) and were enhanced by l‐NMM A–l‐arginine (P= 0.03). 6 l–NMMA‐evoked increases in mean arterial blood pressure were reversed by l‐arginine. Substance P‐evoked decreases in mean arterial blood pressure were not changed by l–NMMA or by l–NMMA–l‐arginine. 7 We conclude that nitric oxide contributes to substance P‐evoked increases in RAR activity and that the increases are most probably independent of decreases in Cdyn.

Muscle function in hibernating hamsters: A natural analog to bed rest?

Abstract 1. 1. In Experiment I(fall/winter), hamsters exposed to cold and short photoperiod entered hibernation; hamsters exposed to cold and long photoperiod did not. 2. 2. Hibernators had reduced body masses, significantly atrophied skeletal muscles, but increased mass-specific maximum activities of citrate synthase (an indicator of aerobic capacity) and HOAD (an indicator of β-oxidation). 3. 3. In Experiment II (winter/spring), hamsters were similarly exposed to cold and either long or short photoperiods, but none hibernated. 4. 4. No differences occurred in skeletal muscle masses or enzymatic activities of these two nonhibernating groups in Experiment II. 5. 5. Thus, photoperiod per se does not appear to elicit the skeletal muscle changes seen in the hibernating hamsters; nor are these changes comparable to those seen during bed or limb immobilization.

Effect of secondhand cigarette smoke, RSV bronchiolitis and parental asthma on urinary cysteinyl LTE4

Cysteinyl leukotrienes promote airway inflammation, bronchoconstriction and mucus hypersecretion. Cigarette smoking and respiratory syncytial virus (RSV) bronchiolitis are known to increase urinary cysteinyl leukotriene E4 (uLTE4), the end product of the cysteinyl leukotriene biosynthetic pathway. We tested the following hypotheses: (1) Secondhand smoke (SHS) exposure increases uLTE4 in well infants and in those hospitalized for RSV bronchiolitis; (2) Length of hospital stay for those with RSV bronchiolitis correlates with uLTE4; and (3) Infants with parent(s) with asthma will have higher uLTE4. Parental asthma for infants hospitalized with RSV bronchiolitis (n = 79) and Well babies (n = 31) was determined by questionnaire. Urine was analyzed for LTE4, cotinine, and creatinine. SHS exposure was determined by cotinine to creatinine ratio. Chi square, or t‐tests were used to determine significant differences between two groups. A three‐way analysis of variance compared the effects of SHS exposure and parental asthma on uLTE4 in Well versus RSV babies. Independent variables predicting length of hospital stay were determined by stepwise multiple regression. High SHS exposure and RSV significantly increased uLTE4. The SHS induced increase in uLTE4 was seen in infants with no parental asthma but not in those with parental asthma. Length of hospital stay positively correlated with uLTE4. We concluded that SHS exposure may increase the severity of bronchiolitis in RSV‐infected infants by enhancing production of cysLTs in infants with no parental asthma. Pediatr Pulmonol. 2008; 43:760–766.

Continuum of sedation, activation and hypnosis or hallucinosis: A comparison of low dose effects of pentobarbital, diazepam or gamma-hydroxybutyrate in the cat

Abstract The effects of small doses of pentobarbital, diazepam and GHB were investigated. Intact freely moving cats were utilized with chronic cortical, subcortical and nuchal muscle electrodes. Electroencephalogram, reticular unit activity and nuchal electromyogram recordings were obtained and gross behavior was observed. Based on the correlation of these parameters the criteria for sedation, activation and hypnosis were defined. All three drugs induced a progression of states; at low doses sedation, at slightly higher doses, activation and at higher doses, hypnosis was induced by pentobarbital and diazepam, whereas GHB induced hallucinosis. On the basis of these results it is proposed that a dose/time continuum of sedation, activation and hypnosis exists for hypnotic agents and a continuum of sedation, activation and hallucinosis for hallucinogenic agents.

Effect of Perinatal secondhand tobacco smoke exposure on in vivo and intrinsic airway structure/function in non-human primates

Infants exposed to second hand smoke (SHS) experience more problems with wheezing. This study was designed to determine if perinatal SHS exposure increases intrinsic and/or in vivo airway responsiveness to methacholine and whether potential structural/cellular alterations in the airway might explain the change in responsiveness. Pregnant rhesus monkeys were exposed to filtered air (FA) or SHS (1 mg/m(3) total suspended particulates) for 6 h/day, 5 days/week starting at 50 days gestational age. The mother/infant pairs continued the SHS exposures postnatally. At 3 months of age each infant: 1) had in vivo lung function measurements in response to inhaled methacholine, or 2) the right accessory lobe filled with agarose, precision-cut to 600 mum slices, and bathed in increasing concentrations of methacholine. The lumenal area of the central airway was determined using videomicrometry followed by fixation and histology with morphometry. In vivo tests showed that perinatal SHS increases baseline respiratory rate and decreases responsiveness to methacholine. Perinatal SHS did not alter intrinsic airway responsiveness in the bronchi. However in respiratory bronchioles, SHS exposure increased airway responsiveness at lower methacholine concentrations but decreased it at higher concentrations. Perinatal SHS did not change eosinophil profiles, epithelial volume, smooth muscle volume, or mucin volume. However it did increase the number of alveolar attachments in bronchi and respiratory bronchioles. In general, as mucin increased, airway responsiveness decreased. We conclude that perinatal SHS exposure alters in vivo and intrinsic airway responsiveness, and alveolar attachments.

Effects of extended sidestream smoke exposure on components of the C-fiber axon reflex

We have previously shown that young guinea pigs repeatedly exposed to sidestream cigarette smoke (SS) develop decreased airway reactivity of the C-fiber system without changing reactivity to one of its neurotransmitters, substance P (SP). This study was designed to determine whether the decreased reactivity was due to decreased responsiveness to another neurotransmitter, neurokinin A (NKA), decreased lung SP content, decreased affinity or number of NK1 receptors, and/or decreased number of C-fibers. Duncan Hartley guinea pigs were exposed to filtered air (FA) or to SS for 6 h/day, 5 days/week for 5 weeks starting at 1 week of age. SS exposure did not change, (1) airway reactivity to NKA injected into the pulmonary artery of their isolated perfused lungs (n = 6-7 each group), (2) lung SP content as measured by enzyme immunoassay (n = 12 each group), (3) NK1 receptor number or affinity as measured by radioligand binding (n = 7 each group), or (4) SP-immunoreactive nerve profiles of the terminal bronchioles or small airways (n = 6 each group). Thus, SS exposure does not decrease C-fiber system by reducing NKA responsiveness, decreasing SP content, changing NK1 receptors, or decreasing the number of C-fibers.

House-dust mite allergen and ozone exposure decreases histamine H3 receptors in the brainstem respiratory nuclei

Allergic airway diseases in children are a common and a growing health problem. Changes in the central nervous system (CNS) have been implicated in contributing to some of the symptoms. We hypothesized that airway allergic diseases are associated with altered histamine H3 receptor expression in the nucleus tractus solitarius (NTS) and caudal spinal trigeminal nucleus, where lung/airway and nasal sensory afferents terminate, respectively. Immunohistochemistry for histamine H3 receptors was performed on brainstem sections containing the NTS and the caudal spinal trigeminal nucleus from 6- and 12-month-old rhesus monkeys who had been exposed for 5 months to house dust mite allergen (HDMA)+O3 or to filtered air (FA). While histamine H3 receptors were found exclusively in astrocytes in the caudal spinal trigeminal nucleus, they were localized to both neuronal terminals and processes in the NTS. HDMA+O3 exposure significantly decreased histamine H3 receptor immunoreactivity in the NTS at 6 months and in the caudal spinal trigeminal nucleus at 12 months of age. In conclusion, exposing young primates to HDMA+O3 changed histamine H3 receptor expression in CNS pathways involving lung and nasal afferent nerves in an age-related manner. Histamine H3 receptors may be a therapeutic target for allergic asthma and rhinitis in children.