Increase In Total Pulmonary Resistance Research Articles

Blunted hypoxic pulmonary vasoconstriction in apnoea divers.

What is the central question of this study? Does the hyperbaric, hypercapnic, acidotic, hypoxic stress of apnoea diving lead to greater pulmonary vasoreactivity and increased right heart work in apnoea divers? What is the main finding and its importance? Compared with sex- and age-matched control subjects, divers experienced significantly less change in total pulmonary resistance in response to short-duration isocapnic hypoxia. With oral sildenafil (50mg), there were no differences in total pulmonary resistance between groups, suggesting that divers can maintain normal pulmonary artery tone in hypoxic conditions. Blunted hypoxic pulmonary vasoconstriction might be beneficial during apnoea diving. Competitive apnoea divers dive repetitively to depths >50m. During the final portions of ascent, divers experience significant hypoxaemia. Additionally, hyperbaria during diving increases thoracic blood volume while simultaneously reducing lung volume and increasing pulmonary artery pressure. We hypothesized that divers would have exaggerated hypoxic pulmonary vasoconstriction, leading to increased right heart work owing to their repetitive hypoxaemia and hyperbaria, and that the administration of sildenafil would have a greater effect in reducing pulmonary resistance in divers. We recruited 16 divers (Divers) and 16 age- and sex-matched non-diving control subjects (Controls). Using a double-blinded, placebo-controlled, cross-over design, participants were evaluated for normal cardiac and lung function, then their cardiopulmonary responses to 20-30 min of isocapnic hypoxia (end-tidal partial pressure of O2 =50mmHg) were measured 1 h after ingestion of 50mg sildenafil or placebo. Cardiac structure and cardiopulmonary function were similar at baseline. With placebo, Divers had a significantly smaller increase in total pulmonary resistance than Controls after 20-30min isocapnic hypoxia (change -3.85±72.85vs. 73.74±91.06dyns cm-5 , P=0.0222). With sildenafil, Divers and Controls had similar blunted increases in total pulmonary resistance after 20-30 min of hypoxia. Divers also had a significantly lower systemic vascular resistance after sildenafil in normoxia. These data indicate that repetitive apnoea diving leads to a blunted hypoxic pulmonary vasoconstriction. We suggest that this is a beneficial adaption allowing for increased cardiac output with reduced right heart work and thus reducing cardiac oxygen utilization in hypoxaemic conditions.

Mechanisms Involved in the Stimulatory and Inhibitory Effects of 5-Hydroxytryptamine on Vagal Mechanosensitive Afferents in Rat Lung.

Mechanosensitive vagal afferents in the lung, rapidly and slowly adapting receptors (RARs and SARs, respectively), play an important role in eliciting the reflexes that regulate the normal airway function. A profound bronchoconstrictive effect of 5-hydroxytryptamine (5-HT) has been extensively reported in various animal species, but its influence on the SAR and RAR activity is not known. This study investigated the effect of 5-HT on these receptors, and the possible mechanisms involved. Single-fiber activities of these afferents were measured in anesthetized, open-chest, and mechanically ventilated rats. Our results showed that intravenous injection of 5-HT evoked a consistent and pronounced stimulation of phasic RARs. In contrast, 5-HT generated an inconsistent and paradoxical action on SARs: no effect in 29% (5 of 17) of the SARs; stimulation in 35% (6 of 17); and inhibition in the remainder. These responses of both RARs and SARs to 5-HT were reproducible and dose-dependent. After the injection of a high dose of 5-HT (16 μg/kg), the receptor responses slowly reached a peak (after ∼8 s) and returned toward the baseline in ∼20 s, accompanied by a consistent increase in total pulmonary resistance and a decrease in dynamic lung compliance in a temporal pattern very similar to the increased receptor activity. When these changes in lung mechanics induced by 5-HT were prevented by pretreatment with salbutamol, a β2 adrenergic receptor agonist, the delayed responses of both RARs and SARs to 5-HT were also abolished, except that the immediate stimulatory effect on a subset of RARs, the silent RARs, was not affected. In conclusion, 5-HT generated a delayed stimulatory effect on RARs and a paradoxical effect on SARs, which resulted primarily from the 5-HT-induced changes in mechanical properties of the lung.

Reflex bronchoconstriction evoked by inhaled nicotine aerosol in guinea pigs: role of the nicotinic acetylcholine receptor.

Inhaled cigarette smoke stimulated vagal bronchopulmonary C fibers via an action of nicotine on neuronal nicotinic acetylcholine receptor (nAChR). Recent studies have reported that nicotine at high concentrations can also activate the transient receptor potential ankyrin 1 receptor (TRPA1) expressed in these sensory nerves. This study was performed to characterize the airway response to inhaled nicotine aerosol and to investigate the relative roles of nAChR and TRPA1 in this response. Guinea pigs were anesthetized and mechanically ventilated; one tidal volume of nicotine aerosol (2% solution) was diluted by an equal volume of air and delivered directly into the lung via a tracheal cannula in a single breath. Our results showed the following: 1) Inhalation of nicotine aerosol triggered an immediate and pronounced bronchoconstriction; the increase in total pulmonary resistance reached a peak of 588 ± 205% (mean ± SE) in 10-40 s, which gradually returned to baseline after 1-5 min. 2) Pretreatment with either atropine (iv) or mecamylamine (aerosol) almost completely abolished the nicotine-induced bronchoconstriction; the mecamylamine pretreatment did not block the bronchoconstriction and bradycardia evoked by electrical stimulation of the distal end of one sectioned vagus nerve, indicating its minimal systemic effects. 3) Pretreatment with HC-030031, a selective TRPA1 antagonist, abolished the bronchoconstriction induced by allyl isothiocyanate, a selective TRPA1 agonist, but did not attenuate the nicotine-evoked bronchoconstriction. In conclusion, inhalation of a single breath of nicotine aerosol evoked acute bronchoconstriction mediated through the cholinergic reflex pathway. This reflex response was triggered by activation of nAChR, but not TRPA1, located in airway sensory nerves. NEW & NOTEWORTHY Recent reports revealed that nicotine at high concentration activated transient receptor potential ankyrin 1 receptor (TRPA1) expressed in vagal bronchopulmonary sensory nerves. This study showed that inhalation of a single breath of nicotine aerosol consistently evoked acute bronchoconstriction that was mediated through the cholinergic reflex pathway and triggered by activation of nicotinic acetylcholine receptor, but not TRPA1, located in these nerves. This is new and important information considering the recent rapid and alarming rise in the prevalence of e-cigarette use for nicotine inhalation.

Bronchoconstriction induced by increasing airway temperature in ovalbumin-sensitized rats: role of tachykinins

This study was carried out to determine the effect of allergic inflammation on the airway response to increasing airway temperature. Our results showed the following: 1) In Brown-Norway rats actively sensitized by ovalbumin (Ova), isocapnic hyperventilation with humidified warm air (HWA) for 2 min raised tracheal temperature (Ttr) from 33.4 ± 0.6°C to 40.6 ± 0.1°C, which induced an immediate and sustained (>10 min) increase in total pulmonary resistance (Rl) from 0.128 ± 0.004 to 0.212 ± 0.013 cmH2O·ml(-1)·s (n = 6, P < 0.01). In sharp contrast, the HWA challenge caused the same increase in Ttr but did not generate any increase in Rl in control rats. 2) The increase in Rl in sensitized rats was reproducible when the same HWA challenge was repeated 60-90 min later. 3) This bronchoconstrictive effect was temperature dependent: a slightly smaller increase in peak Ttr (39.6 ± 0.2°C) generated a significant but smaller increase in Rl in sensitized rats. 4) The HWA-induced bronchoconstriction was not generated by the humidity delivered by the HWA challenge alone, because the same water content delivered by saline aerosol at room temperature had no effect. 5) The HWA-evoked increase in Rl in sensitized rats was not blocked by atropine but was completely prevented by pretreatment either with a combination of neurokinin (NK)-1 and NK-2 antagonists or with formoterol, a β2 agonist, before the HWA challenge. This study showed that increasing airway temperature evoked a pronounced and reversible increase in airway resistance in sensitized rats and that tachykinins released from the vagal bronchopulmonary C-fiber endings were primarily responsible.

Impaired preload reserve during exercise limits exercise capacity in the better Fontan patients

Background: Factors controlling cardiac output in a Fontan circulation are still poorly understood. This study aimed at evaluating changes in exercise hemodynamics using a novel cardiac magnetic resonance (CMR) methodology during mild, moderate and high intensity exercise. Methods: Ten Fontan patients (6 male, age 20±4 years, NYHA I-II) underwent CMR at rest and during supine exercise on a programmable cycle ergometer. Systemic ventricular volumes were obtained at rest (heart rate 72±14 bpm) and during mild (100±10 bpm), moderate (122±15 bpm) and high intensity (144±15 bpm) exercise. Images were acquired using an ungated, free-breathing real-time CMR sequence (12-18 contiguous 8mm slices). Software was developed to allow for synchronization of short and long-axis images with compensation for respiratory phase translation. Endocardial borders were delineated using a bi-plane model. Simultaneously, radial and pulmonary artery pressures were measured. Results: Cardiac output (CO) increased from rest to moderate intensity exercise, but failed to increase further during high intensity exercise (6.8±1.6 vs 10.0±3.2 vs 11.8±3.2 vs 12.5±3.1 l/min; P<0.0001). The increase in CO depended on a 106±49% increase in heart rate as stroke volume (SV) decreased during high intensity exercise (95±19 vs 100±21 vs 96±20 vs 87±16 ml; P<0.0001). End-diastolic volume (EDV) decreased during high intensity exercise (169±38 vs 174±39 vs 170±38 vs 162±36 ml; P=0.002), whereas end-systolic volume (ESV) did not change during exercise (74±31 vs 74±31 vs 73±32 vs 75±32 ml; P=0.715). Ejection fraction (EF) decreased during exercise (57±10 vs 58±10 vs 59±11 vs 55±11%, P=0.037). Pulmonary artery pressures (9±3 vs 14±4 vs 17±4 vs 21±5 mmHg; P<0.0001) and mean arterial pressures (81±7 vs 92±7 vs 100±6 vs 106±4 mmHg; P<0.0001) increased during exercise. Total pulmonary resistance increased during high intensity exercise (P=0.004) whereas systemic vascular resistance decreased during exercise (P=0.003). Arteriovenous oxygen difference increased from 5.5±1.2 to 9.6±1.9 ml/100ml (P=0.001). Conclusions: A decreasing SV and EDV despite a blunted heart rate response during exercise reflect a limited ventricular preload which is presumably related to the increase in total pulmonary resistance. The decreased preload reserve in a Fontan circuit is an important determinant limiting exercise capacity.

Sildenafil improves exercise hemodynamics in Fontan patients

Background: Reduced preload reserve is a fundamental limitation of the Fontan circulation. Sildenafil may increase exercise capacity in patients with Fontan physiology, but the underlying mechanism is still unclear. Using a novel exercise cardiac magnetic resonance (CMR) methodology, we tested the hypothesis that sildenafil would improve exercise hemodynamics in Fontan patients. Methods: Ten Fontan patients (6 male, age 20±4 years) underwent CMR at rest and during supine exercise on a programmable cycle ergometer before (baseline) and after a single dose of sildenafil (50 mg oral). Systemic ventricular volumes were obtained at rest and during mild (104±11 bpm), moderate (127±16 bpm) and high intensity (147±15 bpm) exercise. Bi-plane cine images were acquired using an ungated, free-breathing real-time CMR sequence (12-18 contiguous 8mm slices) and analyzed using software developed enabling retrospective gating for cardiac phase and respiratory translation. Endocardial borders were delineated using a bi-plane model. Simultaneously, radial and pulmonary artery pressures (PAPs) were measured. Results: Under resting conditions as compared with baseline, sildenafil reduced PAPs (9±3 to 8±3 mmHg, P=0.029) and increased heart rate (72±14 to 82±13 bpm, P<0.0001) and cardiac output (6.8±1.6 to 8.1±2.1 L/min, P=0.006). Total pulmonary resistance (TPR) (1.49±0.86 to 1.13±0.66 mmHg.min/L; P=0.010) and systemic vascular resistance (SVR) (11.05±2.43 to 8.65±1.90 mmHg.min/L; P<0.0001) decreased. During exercise sildenafil resulted in improved hemodynamics. PAPs (mean difference -1.0±0.7 mmHg, P=0.010) and mean arterial pressures (mean difference -7.1±1.5 mmHg, P<0.0001) decreased, whilst cardiac output (mean difference +1.4±0.7 L/min, P=0.001), ejection fraction (mean difference +4.6±2.5%, P=0.003) and stroke volume (mean difference +6.7±4.8 ml, P=0.012) all increased. TPR (mean difference -0.34±0.21 mmHg.min/L, P=0.004) and SVR (mean difference -1.38±0.28 mmHg.min/L, P<0.0001) decreased. The decrease in SVR between exercise stages was similar before and after sildenafil (interaction P=0.137). However, in contrast to the increase in TPR before sildenafil, TPR did not increase between stages after sildenafil (interaction P=0.033). Conclusion: In patients with Fontan physiology, sildenafil improves cardiac output during exercise which is presumably related an improved response of the pulmonary vasculature, especially during exercise. This implies that pulmonary vasodilation is a potential physiological target for improving exercise hemodynamics, the clinical significance of which warrants further study.

Effect of Three Resuscitation Procedures on Respiratory and Metabolic Adaptation to Extra Uterine Life in Newborn Calves

The purpose of this study was to evaluate the effects of three resuscitation procedures on respiratory and metabolic adaptation to extra-uterine life during the first 24h after birth in healthy newborn calves. Twenty-four newborn calves were randomly grouped into four categories: six calves did not receive any specific resuscitation procedure and were considered as controls (C); six received pharyngeal and nasal suctioning immediately after birth by use of a hand-powered vaccum pump (SUC); six received five litres of cold water poured over their heads immediately after birth (CW) and six were housed in a calf pen with an infrared radiant heater for 24h after birth (IR). Calves were examined at birth, 5, 15, 30, 45 and 60min, 2, 3, 6, 12 and 24h after birth and the following measurements were recorded: physical and clinical examination, arterial blood gas analysis, pulmonary function tests using the oesophageal balloon catheter technique, arterial and venous blood acid-base balance analysis, jugular venous blood sampling for determination of metabolic, haematological and passive immune transfer variables.SUC was accompanied by improved pulmonary function efficiency and by a less pronounced decrease in body temperature. The “head shaking movement” and the subsequent temporary increase in total pulmonary resistance as well as the greater lactic acidosis due to CW were accompanied by more efficient, but statistically non-significant, pulmonary gas exchanges. IR allowed maintenance of higher body temperature without requiring increased catabolism of energetic stores. IR also caused a change in breathing pattern which contributed to better distribution of the ventilation and to slightly improved gas exchange. The results indicate that use of SUC, CW and IR modified respiratory and metabolic adaptation during the first 24h after birth without side-effects. These resuscitation procedures should be recommended for their specific indication, i.e. cleansing of fetal fluid from upper airways, hypothermal stimulation of breathing and prevention of heat losses.

N-Omega-Nitro-L-Arginine Methyl Ester Increases Airway Responsiveness to Serotonin but Not to Acetylcholine in Cats in vivo

Background: We previously reported that N^ω-nitro-L-arginine methyl ester (L-NAME) enhances airway responsiveness to inhaled serotonin in cats treated with atropine and propranolol. Objective: To further elucidate the role of nitric oxide (NO) in airway responsiveness, we investigated whether L-NAME induces airway hyperresponsiveness to serotonin and acetylcholine (ACh) in animals with intact innervation. Methods: Cats were anesthetized with pentobarbital sodium (50 mg/kg, i.p.), and mechanically ventilated. To assess airway responsiveness, we measured increase in total pulmonary resistance (R_L) produced by delivering serotonin or ACh aerosol to the airway, and determined PC₂₀₀ (the concentration which caused a 200% increase in R_L). Results: The following results were obtained: (1) Airway responsiveness to serotonin was significantly enhanced by the administration of L-NAME (100 mg/kg) in animals treated with atropine and propranolol. (2) Airway responsiveness to serotonin was also significantly enhanced by L- NAME in animals with intact innervation. (3) In contrast, airway responsiveness to ACh was not changed by the addition of L-NAME in cats with intact innervation. Conclusion: These results suggest that NO modulates nonspecific airway responsiveness in animals with intact innervation, presumably by a reflex mechanism.

Role of nitric oxide and septide-insensitive NK(1) receptors in bronchoconstriction induced by aerosolised neurokinin A in guinea-pigs.

The tachykinin, neurokinin A (NKA), contracts guinea-pig airways both in vitro and in vivo, preferentially activating smooth muscle NK(2) receptors, although smooth muscle NK(1) receptors may also contribute. In vitro evidence suggests that NKA activates epithelial NK(1) receptors, inducing the release of nitric oxide (NO) and subsequent smooth muscle relaxation. A number of selective NK(1) receptor agonists have been reported to activate both smooth muscle and epithelial NK(1) receptors, however septide appears only to activate smooth muscle NK(1) receptors. The aim of the present study was to investigate whether NKA-induced bronchoconstriction in guinea-pigs in vivo may be limited by NO release via NK(1) receptor activation, and whether selective NK(1) receptor agonists may activate this mechanism differently. Aerosolized NKA caused an increase in total pulmonary resistance (RL) that was markedly reduced by the NK(2) receptor antagonist, SR 48968, and abolished by the combination of SR 48968 and the NK(1) receptor antagonist, CP-99, 994. The increase in RL evoked by NKA was potentiated by pretreatment with the NO synthase (NOs) inhibitor, L-NAME, but not by the inactive enantiomer D-NAME. Potentiation by L-NAME of NKA-induced increase in RL was reversed by L-Arginine, but not by D-Arginine. Pretreatment with L-NAME did not affect the increase in RL induced by the selective NK(2) receptor agonist, [beta-Ala(8)]NKA(4-10), and by the selective NK(1) receptor agonist, septide, whereas it markedly potentiated the increase in RL caused by a different NK(1) selective agonist, [Sar(9),Met(O(2))(11)]SP. Dose-response curves showed that septide was a more potent bronchoconstrictor than [Sar(9),Met(O(2))(11)]SP to cause bronchoconstriction. Pretreatment with the NK(1) receptor antagonist, CP-96,994, abolished the ability of L-NAME to increase bronchoconstriction to aerosolized NKA. Bronchoconstriction to aerosolized NKA was increased by L-NAME, after pretreatment with the NK(3) receptor antagonist, SR 142801. The present study shows that in vivo bronchoconstriction in response to the aerosolized naturally occurring tachykinin, NKA, is limited by its own ability to release relaxant NO via NK(1) receptor activation. This receptor is apparently insensitive to septide, thus justifying, at least in part, the high potency of septide to cause bronchoconstriction in guinea-pigs.

PACAP Reverses Airway Hyperresponsiveness Induced by Ozone Exposure in Guinea Pigs

Background: We previously demonstrated that pituitary adenylate cyclase activating peptide (PACAP) inhibits airway smooth muscle contraction and plasma extravasation. Objective: We thus hypothesized that PACAP may regulate airway responsiveness through these effects and examined the effects of exogenously applied PACAP on the airway hyperresponsiveness induced by ozone exposure. Methods: Ozone exposure was carried out in awake, spontaneously breathing guinea pigs using 3 ppm for 2 h. Airway responsiveness to histamine was determined before and 30 and 90 min after the termination of ozone exposure for 2 h in anesthetized animals. Extravasation of Evans blue was measured before and 90 min after the termination of ozone exposure. Either PACAP (10^–6 mol/kg) or vehicle was administered intravenously 60 min after exposure. The airway responsiveness was expressed as the concentration of histamine required to produce a 200% increase in total pulmonary resistance (PC₂₀₀). Results: Ozone exposure caused a significant decrease in PC₂₀₀ (n = 5, p < 0.05) 30 min after ozone exposure which persisted 90 min thereafter, thus suggesting that ozone caused airway hyperresponsiveness. PACAP significantly suppressed the increase in airway hyperresponsiveness induced by ozone 90 min after exposure (n = 5, p < 0.05). In contrast, this peptide did not have any effect on plasma extravasation. Conclusion: We thus conclude that PACAP decreases ozone-induced airway responsiveness, and, therefore, intravenously administered PACAP may be useful in reversing airway hyperresponsiveness.

Inhibition of bronchoconstriction by pituitary adenylate cyclase activating polypeptide (PACAP 1–27) in guinea‐pigs in vivo

1. We studied the inhibitory effect of pituitary adenylate cyclase activating polypeptide (PACAP 1-27) on the increase in total pulmonary resistance (RL) caused either by allergen or histamine in anaesthetized, ventilated guinea-pigs. 2. PACAP 1-27 given via i.v. infusion (0.045-4.5 nmol kg-1 min-1) dose-dependently reduced the increase in RL caused by inhaled ovalbumin and histamine. At the highest dose, PACAP 1-27 prevented the increase in RL caused by ovalbumin and histamine completely. Infusion of PACAP 1-27 and the beta 2-adrenoceptor agonist, salbutamol (0.045-4.5 nmol kg-1 min-1) inhibited the increase in RL similarly, but salbutamol increased the heart rate more than PACAP 1-27. 3. PACAP 1-27 and salbutamol given via inhaled aerosol (0.1 mM, 20 breaths) significantly reduced the increase in RL caused by histamine infused i.v., whereas aerosolised sterile saline did not. Both PACAP 1-27 and salbutamol caused bronchodilator effects within 1 min of drug inhalation and these effects remained throughout the 20 min of study. 4. Because PACAP 1-27 produced significant bronchodilatation and rapid onset of sustained action in vivo and without pronounced cardiovascular side effects, we conclude that this peptide may have therapeutic potential as a bronchodilator.

Cigarette smoke-induced bronchoconstriction: cholinergic mechanisms, tachykinins, and cyclooxygenase products.

The mechanisms underlying cigarette smoke-induced bronchoconstriction were studied by using selective blockade of muscarinic acetylcholine receptors, neurokinin receptors and production of eicosanoids of the cyclooxygenase pathway in anesthetized guinea pigs. Inhalation of three breaths of cigarette smoke (University of Kentucky research series 2R1; 2.45 mg of nicotine and 35.3 mg of tar per cigarette) reproducibly induced an immediate bronchoconstriction; total pulmonary resistance increased from 0.24 +/- 0.02 to 1.44 +/- 0.21 cmH2O.ml-1.s (P < 0.01) and dynamic lung compliance decreased from 0.53 +/- 0.03 to 0.39 +/- 0.06 ml/cmH2O (P < 0.05) in 10-15 breaths after the smoke inhalation. Atropine pretreatment (50 micrograms/kg i.v.) prevented the immediate decrease in dynamic lung compliance and reduced the immediate increase in total pulmonary resistance by approximately 55%. The atropine-resistant bronchoconstriction occurring immediately after smoke inhalation was completely blocked by a pretreatment with a combination of CP-99994 (0.3 mg/kg i.v.) and SR-489668 (0.3 mg/kg i.v.), the antagonists of neurokinin-1 and neurokinin-2 receptors, respectively. However, a delayed and sustained bronchoconstriction still persisted and reached a plateau in 45-55 breaths after smoke inhalation challenge. This delayed response was completely prevented by pretreatment with indomethacin (5 mg/kg i.v.). We conclude that the smoke-induced bronchoconstriction in guinea pigs consists of an early phase induced by both a cholinergic reflex and tachykinin release, probably evoked by the activation of bronchopulmonary C fibers, and a late phase caused by the action of arachidonic acid metabolite(s) of the cyclooxygenase pathway.

Changes in total pulmonary resistance and PCO2 between wakefulness and sleep in normal human subjects

We investigated the possible role of an increase in total pulmonary resistance in the sleep-related hypoventilation that occurs in healthy subjects. Eight nonsnoring volunteers were studied during quiet wakefulness and stage IV sleep. Airflow was measured via a nasal mask with a low dead space, and breathing pattern, end-tidal PCO2 (PETCO2), and a continuous estimate of total pulmonary resistance were estimated. From wakefulness to sleep, mean inspiratory resistance increased from 5.5 +/- 2.4 (SD) to 8.1 +/- 4.3 cmH2O.l-1.s, PETCO2 increase from 38.7 +/- 3.0 to 40.7 +/- 3.5 Torr, and ventilation decreased from 7.12 +/- 1.15 to 6.47 +/- 1.68 l/min. In five of the eight subjects, low levels of continuous positive airway pressure were applied during stage IV sleep to reverse any increase in resistance. In these subjects, continuous positive airway pressure reduced mean inspiratory resistance from 9.3 +/- 4.3 +/- 3.0 cmH2O.l-1.s but had little effect on mean PETCO2 (from 39.8 +/- 4.0 to 39.6 +/- 4.0 Torr) and mean ventilation (from 6.79 +/- 1.93 to 6.91 +/- 1.80 l/min). These findings suggest that in nonsnoring subjects reductions in alveolar ventilation cannot be accounted for by an increase in airway resistance.

Ozone exposure suppresses epithelium-dependent relaxation in feline airway

We examined the effect of exposure to ozone on the epithelium-dependent relaxation (EpDR) of bronchioles evoked by electrical field stimulation (EFS) in a feline model with hyperresponsive airways induced by exposure to ozone. Airway responsiveness was assessed by measuring the increases in total pulmonary resistance (RL) produced by aerosolized acetylcholine (ACh) in vivo. Airway responsiveness was also measured in vitro in dissected bronchiolar ring preparations. Exposure to ozone (3 ppm, 2h) significantly increased the airway responsiveness in vivo. The concentration of ACh required increasing RL to 200% of the baseline value, decreased from 1.97 mg/ml (GSEM 1.94) to 0.12 mg/ml (GSEM 1.77, p < 0.01) after exposure to ozone. EFS evoked atropine-, guanethidine-, and tetrodotoxin-resistant relaxations in the control bronchiolar rings precontracted by 5-hydroxytryptamine. Such relaxation was significantly suppressed by the mechanical denudation of epithelium, confirming that it was epithelium dependent. The amplitude of the EpDR was significantly suppressed in the animals exposed to ozone. These results suggest that EpDR is present in cats, and that its inhibition may contribute to the development of airway hyperresponsiveness.

Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide

In pulmonary inflammatory processes such as pneumonia there is diminished hypoxic pulmonary vasoconstriction (HPV). We investigated whether the attenuated HPV in pneumonia is a due to excess nitric oxide (NO) release. Sprague-Dawley rats were anesthetized, and a slurry (0.06 ml) of infected agar beads (containing 6 x 10(5) Pseudomonas aeruginosa organisms) or control (sterile) beads was then injected into a distal bronchus through a tracheotomy. After the establishment of a chronic P. aeruginosa pneumonia (7-10 days later) animals were instrumented for hemodynamic monitoring, and the response to exposure to hypoxic gas (fraction of inspired O2 = 0.08) was recorded before and after the administration of NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg), an inhibitor of NO synthesis. The hypoxic pressor response, as assessed by the absolute increase in pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR), was reduced in infected animals compared with control animals. The change in PAP and TPR was 8.5 +/- 0.7 and 0.053 +/- 0.007, respectively, in control animals compared with 5.9 +/- 0.5 and 0.041 +/- 0.011 in infected animals. After L-NMMA the increase in PAP and TPR during hypoxia was greater in both control and infected animals. However, treatment with L-NMMA did not affect the difference between control and infected animals. We conclude that excess release of NO does not account for the attenuated hypoxic pressor response in pneumonia.

Involvement of neurogenic inflammation in antigen-induced bronchoconstriction in guinea pigs.

The role of tachykinins released from sensory nerves in bronchoconstriction induced by antigen was studied in sensitized guinea pigs anesthetized with pentobarbital sodium and pretreated with atropine. The combination of NK2 (SR-48968) and NK1 (CP-96,345) tachykinin-receptor antagonists abolished the increase in total pulmonary resistance (RL) evoked by intravenous capsaicin but did not affect the response evoked by intravenous histamine. A small dose of aerosolized ovalbumin (OVA, 0.1%) produced a small increase in RL that was further increased and markedly prolonged by the neutral endopeptidase (NEP) inhibitor phosphoramidon; this bronchoconstrictor effect of OVA was markedly reduced by the NK2-receptor antagonist and was abolished by the combination of the NK1 and NK2-receptor antagonists together. When a larger dose of OVA (0.5%) was used, a maximal bronchoconstrictor response was obtained. Phosphoramidon did not potentiate this response significantly. The combination of NK1- and NK2-receptor antagonists blunted the response at 5 min only slightly but markedly attenuated the later (10-20 min) response. These results show that tachykinins released from sensory nerves play a significant role in antigen-induced bronchoconstriction in guinea pigs. This effect is exaggerated when the normal modulation of neuropeptides by NEP is inhibited and is mediated predominantly by NK2-receptor activation, with a smaller contribution by NK1 receptors.

Capsaicin Increases Airflow Resistance in Guinea PigsIn Vivoby Activating both NK2and NK1Tachykinin Receptors

The role of NK1 tachykinin receptors in the increase in total pulmonary resistance (RL) produced by release of endogenous tachykinins was investigated in anesthetized guinea pigs pretreated intravenously with atropine (1 mumol/kg) by using the novel nonpeptide antagonists of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptors. SR 48968 (0.3 mumol/kg) and CP-96,345 (2 mumol/kg) given intravenously completely blocked the response to the selective NK2 receptor agonist [beta Ala8]neurokinin A(4-10) and NK1 receptor agonist [Sar9,Met(O2)11]substance P, respectively. The response to neurokinin A was reduced dose-dependently, but not abolished, by SR 48968, and it was completely prevented by a combination of SR 48968 and CP-96,345. The response to capsaicin was reduced, but not blocked, by SR 48968, and it was completely abolished by the combination of the two antagonists. The combination of SR 48968 and CP-96,345 did not affect the increase in RL evoked by histamine. Thus, NK1, as well as NK2, receptor activation contributes to the noncholinergic increase in RL evoked by capsaicin and ascribed to release of endogenous tachykinins from sensory nerves.

Intrinsic microbicidal activity and pulmonary hypertension in isolated newborn piglet lungs.

The lung appears to be one of the dominant sites of bacterial clearance from the blood of infant piglets. Part of the lung bacterial clearance involves activation of an oxygen radical bactericidal mechanism that may be central to induction of acute pulmonary hypertension. The present study determined whether this bactericidal activity was intrinsic to resident lung cells. Isolated piglet lung preparations perfused with blood-free salt solution were used to delineate the amount of group B streptococci (GBS) extracted and killed upon transit through pulmonary vasculature. Approximately 45% of infused GBS was deposited in the lung during a single pulmonary transit, whereas nearly 40% of the organisms sequestered in the lung were killed within a 30-min period. Pretreatment with dimethylthiourea, a scavenger of hydroxyl radical that inhibits GBS-induced pulmonary hypertension, attenuated both bacterial uptake and killing to similar extents. Along with its deposition in the lung, GBS also induced concentration-dependent increases in total pulmonary resistance, which were related principally to increases in upstream arterial resistance. Lung weight also increased in a concentration-dependent manner. Both the increase in total pulmonary resistance and lung weight were temporally related to elevation in perfusion medium content of the stable thromboxane degradation product, thromboxane B2. Pretreatment with indomethacin, a prostaglandin H synthase inhibitor, or sodium(E)-3[4-(1-imidazolyl-methyl)phenyl]-2-propenoic acid a thromboxane synthase inhibitor, reduced GBS-induced pulmonary hypertension and edema. These results suggest that, in isolated piglet lungs, GBS evokes an intrinsic bactericidal response residing within lung cells, probably pulmonary intravascular macrophages, which may be responsible for the initiation of pulmonary hemodynamic changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the PAF Antagonist WEB 2086 on PAF-induced Physiologic Alterations and on IgE Anaphylaxis in the Rabbit

The inhibitory effects of the specific platelet-activating factor (PAF) antagonist WEB 2086 on the in vivo PAF- and antigen-induced respiratory, circulatory, and hematologic alterations in the rabbit were investigated. WEB 2086 (600 micrograms/kg) given 5 min before challenge with 0.6 micrograms/kg of PAF completely inhibited the PAF-induced bronchoconstriction, period of rapid, shallow breathing, bradycardia, increase in right ventricular pressure, and hypotension. The PAF-induced thrombocytopenia, leukopenia, and basopenia were also prevented by WEB 2086 pretreatment. In contrast, the inhibitory effects of WEB 2086 on IgE anaphylaxis were much more limited. No significant inhibition of the responses in tidal volume, breathing frequency, hypotension, or bradycardia was observed in sensitized rabbits pretreated with 1 or 6 mg/kg of WEB 2086. However, WEB 2086 significantly inhibited the increase in total pulmonary resistance. Although the peak changes in dynamic lung compliance and right ventricular pressure were not or were only slightly inhibited by WEB 2086, a more rapid recovery to baseline was observed in rabbits receiving the PAF antagonist. No significant inhibition of the thrombocytopenia, leukopenia, and basopenia accompanying antigen challenge was observed in WEB 2086-pretreated rabbits. Pretreatment with the PAF antagonist prevented anaphylactic lethality. Thus, PAF appears to play a role in the lethality and the maximum increase in total pulmonary resistance of IgE systemic anaphylaxis but does not appear to be a major mediator of the other physiologic alterations, including systemic hypotension.

Dibutyryl-cAMP Blocks Endotoxin-induced Lung Injury in Rats

We investigated the effect of dibutyryl-cAMP pretreatment on endotoxin-induced hemodynamic changes and lung vascular injury in rats. In catheter-implanted, unanesthetized rats, intraperitoneal injection of Salmonella enteritidis endotoxin (2 mg/kg) decreased cardiac output and systemic blood pressure while increasing total pulmonary vascular resistance. Db-cAMP (1 mg given intraperitoneally every 30 min), although not significantly affecting cardiac output and systemic blood pressure, blocked the increase in total pulmonary resistance caused by endotoxin. Ninety minutes after intraperitoneal endotoxin injection, perfused lungs from endotoxin-treated rats exhibited increased pulmonary vascular permeability, as assessed by increased extravascular accumulation of 125I-albumin and water. Db-cAMP treatment in vivo markedly attenuated the increases in lung albumin leak index and wet-to-dry weight ratio caused by endotoxin without affecting lung microvascular pressures. This protective action of db-cAMP is not due to its effect on prostaglandin or leukotriene synthesis since endotoxin-stimulated increases in lung tissue 6-keto-prostaglandin F1 alpha, thromboxane B2 and leukotriene C4 were not inhibited. We conclude that db-cAMP blocks endotoxin-induced lung injury in the rat by a mechanism independent of eicosanoid products and speculate that agents that increase intracellular cAMP may be therapeutically useful in acute lung vascular injury.