Reactive Oxygen Species-Dependent Calpain Activation Contributes to Airway and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease.

Aims: Airway and pulmonary vascular remodeling is an important pathological feature in the pathogenesis of chronic obstructive pulmonary disease (COPD). Tobacco smoke (TS) induces the production of large amounts of reactive oxygen species (ROS) in COPD lungs. We investigated how ROS lead to airway and pulmonary vascular remodeling in COPD. Results: We used in vitro bronchial and pulmonary artery smooth muscle cells (BSMCs and PASMCs), in vivo TS-induced COPD rodent models, and lung tissues of COPD patients. We found that H2O2 and TS extract (TSE) induced calpain activation in BSMCs and PASMCs. Calpain activation was elevated in smooth muscle of bronchi and pulmonary arterioles in COPD patients and TS-induced COPD rodent models. Calpain inhibition attenuated H2O2- and TSE-induced collagen synthesis and proliferation of BSMCs and PASMCs. Exposure to TS causes increases in airway resistance, right ventricular systolic pressure (RVSP), and thickening of bronchi and pulmonary arteries. Calpain inhibition by smooth muscle-specific knockout of calpain and the calpain inhibitor MDL28170 attenuated increases in airway resistance, RVSP, and thickening of bronchi and pulmonary arteries. Moreover, smooth muscle-specific knockout of calpain did not reduce TS-induced emphysema in the mouse model, but MDL28170 did reduce TS-induced emphysema in the rat model. Innovation: This study provides the first evidence that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling in TS-induced COPD. Calpain might be a novel therapeutic target for the treatment of COPD. Conclusion: These results indicate that ROS-induced calpain activation contributes to airway and pulmonary vascular remodeling and pulmonary hypertension in COPD.

Bronchial artery chemoembolization combined with radioactive iodine-125 seed implantation in the treatment of advanced nonsmall cell lung cancer.

OBJECTIVE: The aim of this study was to investigate the short-term efficacy and safety of bronchial artery chemoembolization (BACE) combined with radioactive iodine-125 seed implantation in the treatment of nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty-two Stage III-IV NSCLC patients were divided into Groups A and B. Thirty cases were treated with BACE combined with radioactive iodine-125 seed implantation in the Group A and 32 cases were treated with BACE alone in the Group B until disease progression. Efficacy, incidence rate of adverse drug reactions, and survival rate were compared between the two groups. RESULTS: The local control rates and effective rates of Groups A and B were 90% and 59.3% and 74% and 40.6%, respectively, with P < 0.05 for each. The progression-free survival of the study group and the control group was 12.6 and 8.2 months, respectively; the median survival time of the Groups A and B was 644 and 544 days, and the difference was statistically significant (P = 0.034). CONCLUSION: BACE combined with radioactive iodine-125 seed implantation was safe and effective in the treatment of advanced NSCLC, with an efficacy superior to that of single BACE.

Bronchial and non-bronchial systemic arteries: value of multidetector CT angiography in diagnosis and angiographic embolisation feasibility analysis.

INTRODUCTION: The aim of this study is to evaluate the diagnostic performance of multidetector CT angiography (CTA) in depicting bronchial and non-bronchial systemic arteries in patients with haemoptysis and to assess whether this modality helps determine the feasibility of angiographic embolisation. MATERIALS AND METHODS: Fifty-two patients with haemoptysis between January 2010 and July 2011 underwent both preoperative multidetector CTA and digital subtraction angiography (DSA) imaging. Diagnostic performance of CTA in depicting arteries causing haemoptysis was assessed on a per-patient and a per-artery basis. The feasibility of the endovascular treatment evaluated by CTA was analysed. Sensitivity, specificity, and positive and negative predictive values for those analyses were determined. RESULTS: Fifty patients were included in the artery-presence-number analysis. In the per-patient analysis, neither CTA (P = 0.25) nor DSA (P = 1.00) showed statistical difference in the detection of arteries causing haemoptysis. The sensitivity, specificity, and positive and negative predictive values were 94%, 100%, 100%, and 40%, respectively, for the presence of pathologic arteries evaluated by CTA, and 98%, 100%, 100%, and 67%, respectively, for DSA. On the per-artery basis, CTA correctly identified 97% (107/110). Fifty-two patients were included in the feasibility analysis. The performance of CTA in predicting the feasibility of angiographic embolisation was not statistically different from the treatment performed (P = 1.00). The sensitivity, specificity, and positive and negative predictive values were 96%, 80%, 98% and 67%, respectively, for CTA. CONCLUSIONS: Multidetector CTA is an accurate imaging method in depicting the presence and number of arteries causing haemoptysis. This modality is also useful for determining the feasibility of angiographic embolisation for haemoptysis.

Administration of poly(ADP-ribose) polymerase inhibitor into bronchial artery attenuates pulmonary pathophysiology after smoke inhalation and burn in an ovine model.

Poly(ADP-ribose) polymerase (PARP) is well known to be an enzyme that repairs damaged DNA and also induces cell death when overactivated. It has been reported that PARP plays a significant role in burn and smoke inhalation injury, and the pathophysiology is thought to be localized in the airway during early stages of activation. Therefore, we hypothesized that local inhibition of PARP in the airway by direct delivery of low dose PJ-34 [poly(ADP-ribose) polymerase inhibitor] into the bronchial artery would attenuate burn and smoke-induced acute lung injury. The bronchial artery in sheep was cannulated in preparation for surgery. After a 5-7 day recovery period, sheep were administered a burn and inhalation injury. Adult female sheep (n=19) were divided into four groups following the injury: (1) PJ-34 group A: 1h post-injury, PJ-34 (0.003mg/kg/h, 2mL/h) was continuously injected into the bronchial artery, n=5; (2) PJ-34 group B: 1h post-injury, PJ-34 (0.03mg/kg/h, 2mL/h) was continuously injected into bronchial artery, n=4; (3) CONTROL GROUP: 1h post-injury, an equivalent amount of saline was injected into the bronchial artery, n=5; (4) Sham group: no injury, no treatment, same operation and anesthesia, n=5. After injury, all animals were placed on a ventilator and fluid resuscitated equally. Pulmonary function as evaluated by measurement of blood gas analysis, pulmonary mechanics, and pulmonary transvascular fluid flux was severely deteriorated in the control group. However, the above changes were markedly attenuated by PJ-34 infusion into the bronchial artery (P/F ratio at 24h: PJ-34 group A 398±40*, PJ-34 group B 438±41*†‡, Control 365±58*, Sham 547±47; * vs. sham [p<0.05], † vs. control [p<0.05], ‡ vs. PJ-34 group A [p<0.05]). Our data strongly suggest that local airway production of poly(ADP-ribose) polymerase contributes to pulmonary dysfunction following smoke inhalation and burn.

Differential effects of inhaled methacholine on circumferential wall and vascular smooth muscle of third-generation airways in awake sheep.

Evolution and natural selection ensure that specific mechanisms exist for selective airway absorption of inhaled atmospheric molecules. Indeed, nebulized cholinoceptor agonists used in asthma-challenge tests may or may not enter the systemic circulation. We examined the hypothesis that inhaled cholinoceptor agonists have selective access. Six sheep were instrumented under general anesthesia (propofol 5 mg/kg iv, 2-3% isoflurane-oxygen), each with pulsed-Doppler blood flow transducers mounted on the single bronchial artery and sonomicrometer probes mounted on the intrapulmonary third-generation lingula lobe bronchus. Continuous measurements were made of bronchial blood flow (Q(br)), Q(br) conductance (C(br)), bronchial hemicircumference (CIRC(br)), and bronchial wall thickness (WALL TH(br)) in recovered, standing, awake sheep. Methacholine (MCh; 0.125-2.0 µg/kg iv), at the highest dose, caused a 233% rise in Q(br) (P < 0.05) and a 286% rise in C(br) (P < 0.05). CIRC(br) fell to 90% (P < 0.05); WALL TH(br) did not change. In contrast, nebulized MCh (1-32 mg/ml), inhaled through a mask at the highest dose, caused a rise in ventilation and a rise in Q(br) proportional to aortic pressure without change in C(br). CIRC(br) fell to 91% (P < 0.01), and WALL TH(br) did not change. Thus inhaled MCh has access to cholinoceptors of bronchial circumferential smooth muscle to cause airway lumen narrowing but effectively not to those of the systemic bronchovascular circulation. It is speculated that the mechanism is selective neuroparacrine inhibition of muscarinic acetylcholine receptors (M3 bronchovascular cholinoceptors) by prostanoids released by intense MCh activation of epithelial and mucosal cells lining the airway.

Direct delivery of low-dose 7-nitroindazole into the bronchial artery attenuates pulmonary pathophysiology after smoke inhalation and burn injury in an ovine model.

Bronchial circulation plays a critical role in the pathophysiology of burn and smoke inhalation-induced acute lung injury. A 10-fold increase in bronchial blood flow is associated with excessive production of nitric oxide (NO) following smoke inhalation and cutaneous burn. Because an increased release of neuropeptides from the airway has been implicated in smoke inhalation injury, we hypothesized that direct delivery into the bronchial artery of low-dose 7-nitroindazole (7-NI), a specific neuronal NO synthase inhibitor, would attenuate smoke/burn-induced acute lung injury. Eighteen adult female sheep were instrumented for chronic hemodynamic monitoring 5 to 7 days before the injury. The bronchial artery was cannulated via intercostal thoracotomy, while blood flow was preserved. Acute lung injury was induced by 40% total body surface area third-degree cutaneous burn and smoke inhalation (48 breaths of cotton smoke, <40°C) under deep anesthesia. Following injury, animals (35.4 ± 1.1 kg) were divided into three groups: (a) 7-NI group: 1 h after injury, 7-NI (0.01 mg · kg · h, 2 mL · h) was continuously infused into the bronchial artery, n = 6; (b) control group: 1 h after injury, same amount of saline was injected into the bronchial artery, n = 6; (c) sham group: no injury, no treatment, same operation and anesthesia, n = 6. After injury, all animals were ventilated and fluid resuscitated according to an established protocol. The experiment was conducted for 24 h. Injury induced severe pulmonary dysfunction, which was associated with increases in lung edema formation, airway obstruction, malondialdehyde, and nitrate/nitrite. 7-Nitroindazole injection into the bronchial artery reduced the degree of lung edema formation and improved pulmonary gas exchange. The increase in malondialdehyde and nitrate/nitrite in lung tissue was attenuated by treatment. Our data strongly suggest that local airway production of NO contributes to pulmonary dysfunction following smoke inhalation and burn injury. Most mechanisms that drive this pathophysiology reside in the airway.

Application of Aidi injection (艾迪注射液) in the bronchial artery infused neo-adjuvant chemotherapy for stage III A non-small cell lung cancer before surgical operation.

OBJECTIVE: To study the effect of Aidi Injection (艾迪注射液,ADI) applied in the bronchial artery, applied in the bronchial artery infused (BAI) neo-adjuvant chemotherapy for stage III A non-small cell lung cancer (NSCLC) before surgical operation. METHODS: The 60 patients with NSCLC stage III A underwent two courses BAI chemotherapy before tumor incision were assigned to two groups, the treatment and the control groups, using a random number table, 30 in each group. ADI (100 mL) was given to the patients in the treatment group by adding into 500 mL of 5% glucose injection for intravenous dripping once daily, starting from 3 days before each course of chemotherapy, and it lasted for 14 successive days, so a total of 28 days of administration was completed. The therapeutic effectiveness and the adverse reaction that occurred were observed, and the levels of T-lymphocyte subsets, natural killer cell activity, and interleukin-2 in peripheral blood were measured before and after the treatment. RESULTS: The effective rate in the treatment group was higher than that in the control group (70.0% vs. 56.7%, P<0.05). Moreover, as compared with the control group, the adverse reaction that occurred in the treatment group was less and mild, especially in terms of bone marrow suppression and liver function damage (P<0.05). Cellular immune function was suppressed in NSCLC patients, but after treatment, it ameliorated significantly in the treatment group, showing significant difference as compared with that in the control group (P<0.05). CONCLUSION: ADI was an ideal auxiliary drug for the patients in stage III A NSCLC received BAI neo-chemotherapy before surgical operation; it could enhance the effectiveness of chemotherapy, ameliorate the adverse reaction and elevate patients' cellular immune function; therefore, it is worthy for spreading in clinical practice.

Injection of prostaglandin F2alpha into the bronchial artery in sheep increases the pulmonary vascular permeability to protein.

Lung injury and oedema following smoke inhalation are associated with eicosanoid release and the injury is heavily influenced by the tracheobronchial circulation. We hypothesized that injection of a vasoactive eicosanoid, prostaglandin F2alpha (PGF2alpha), into the tracheobronchial circulation would induce a permeability leak in that circulation as measured in lung lymph flow and protein content. PGF2alpha when injected into the bronchial artery increased lung lymph flow, protein content and lymph protein flux (protein times flow). The increase in lymph to plasma protein concentration after injection of PGF2alpha is consistent with an increase in vascular protein permeability since an increase in pressure alone would cause an increase in fluid flow in excess of protein with a fall in protein concentration. Ligation of the bronchial artery 3min after injection of the PGF2alpha largely prevented the late changes suggesting that the protein leak into the lymph was from the bronchial arteries.

Vasoconstrictor responses, and underlying mechanisms, to isoprostanes in human and porcine bronchial arterial smooth muscle.

We investigated the effects of five different isoprostanes (8-iso PGE1, 8-iso PGE2, 8-iso PGF1alpha, 8-iso PGF2alpha and 8-iso PGF2beta) on vasomotor tone in human and porcine bronchial arterial tissues. In the human bronchial arteries, 8-iso PGE2 and 8-iso PGF2alpha evoked powerful constrictions (magnitudes several fold greater than the responses to high millimolar KCl) with negative log concentration causing 50% excitation (EC50) values of 6.8 and 6.5, respectively; 8-iso PGE1 was less potent (EC50 not calculated, since a clear peak contraction was not obtained), while the other isoprostanes were largely ineffective. In the porcine arteries, on the other hand, all three F-ring isoprostanes as well as 8-iso PGE2 evoked constrictor responses, although the peak magnitudes were approximately 50% of the KCl-evoked response; 8-iso PGE2 and 8-iso PGF2alpha were the most potent, with negative log EC50 values of 6.5. We next sought to characterize the signaling pathways underlying the vasoconstrictor responses to 8-iso PGE2, since this was the most potent of the isoprostanes we tested. These responses were largely reversed by the thromboxane A2-selective (TP) prostanoid receptor antagonist ICI 192605 (10-8 m; 4(Z)-6-[(2,4,5 cis)2-(2-chlorophenyl)-4-(2-hydroxy phenyl)1,3-dioxan-5-yl]hexenoic acid) as well as by the nonspecific tyrosine kinase inhibitor genistein (10-5 and 10-4 m), and were reversed approximately 50% by the Rho-kinase inhibitor Y27632 (10-5 m; (+)-(R)-trans-4-(1-aminoethyl)-N-(pyridyl) cyclohexanecarboxamide dihydrochloride). We conclude, therefore, that 8-iso PGE2 constricts bronchial vasculature through the activation of TP receptors, which in turn trigger tyrosine kinase and Rho-kinase activities, resulting in powerful vasoconstriction. These findings are highly relevant to lung transplantation and to exercise-induced asthma.

Bronchovascular responses to intravenous contrast media for helical CT pulmonary angiography.

CT angiography is now commonly used for the diagnosis of pulmonary embolism, but the contrast media used for imaging produces various hemodynamic changes. In this study, we investigated the bronchovascular and hemodynamic responses to intravenous iopromide, a non-ionic contrast agent used for pulmonary CT angiograms, in anesthetized, mechanically ventilated sheep (n = 6). Bronchial blood flow and cardiac output were measured with ultrasonic flow probes. Systemic and pulmonary arterial pressures were continuously monitored. Injections of 0.9% NaCl (120 ml over 30 s) or iopromide (300 mg/ml, 120 ml over 30 s) were given in random order in a peripheral vein with an angiogram infuser and hemodynamic changes were determined. After these parameters returned to baseline, the left pulmonary artery (LPA) was occluded with a snare and the animals were allowed to stabilize. Injections of NaCl and iopromide were repeated in random order as before. There were no significant hemodynamic effects with infusion of NaCl. With intact pulmonary vasculature, NaCl and iopromide did not cause significant changes in arterial blood gases, however, cardiac output (QT, L/min), mean systemic and pulmonary arterial pressures (PSA and PPA, Torr) increased and bronchovascular resistance (BVR, Torr x min/ml), decreased. Following LPA ligation, pH and PO2 significantly decreased over baseline, whereas PCO2 increased. After LPA ligation, iopromide produced a greater decrease in BVR as compared with preligation intact pulmonary vasculature. In conclusion, iopromide caused rapid hemodynamic changes and decreased BVR, likely secondary to osmolar stress. Bronchovascular effects were more pronounced after pulmonary arterial occlusion.

Mechanical and electrophysiological effects of isoprostanes on bronchial arterial smooth muscle.

We investigated the mechanical and electrophysiological responses of human and porcine bronchial arterial smooth muscle to isoprostanes (metabolites of membrane lipid peroxidation). These evoked a constrictor response which was sensitive to blockade of thromboxane receptors, as well as to a non-specific tyrosine kinase inhibitor and an inhibitor of Rho-kinase. The patch clamp technique was used to characterize the K+ and Ca2+ currents in these tissues, and to show that isoprostanes caused a brief enhancement of K+ currents followed by prolonged and marked suppression of the same.

Occurrence of dopaminergic (D(2)) receptors within the rabbit pulmonary circulation.

The pharmacological characteristics and the microanatomical localization of dopamine D(2)-like receptors, or more correctly spiroperidol binding sites, in the rabbit pulmonary circulation were studied using combined marker binding and light microscopy autoradiography with [((3))H]-spiroperidol (spiperone) as marker. The marker was bound to the samples of the pulmonary artery in a manner consistent with the labelling of dopamine D(2)-like receptors with an equilibrium dissociation constant (K(d)) of about 2.4+/-0.07 nmol/l and a maximum density of binding sites of 65+/-4.5 fmol/mg tissue. Samples of bronchial artery show the same results as those of the pulmonary artery. In contrast, binding experiments made with samples of rabbit lung (capillary of the microcirculation), of pulmonary veins and/or of bronchial veins did not allow the evaluation of specific binding.Autoradiography, observed with light microscopy, showed the development of specific silver grains within the whole wall of extraparenchymal branches of the pulmonary artery and/or of the bronchial artery. Development of silver grains was inhibited by compounds active on the dopamine receptors. The greater sensitivity to displacement by domperidone, haloperidol, and bromocriptine than to displacement by N-propyl-nor-apomorphine, quinpirole and clozapine suggests that the binding sites observed in extraparenchymal, large and medium-sized branches of the rabbit pulmonary and bronchial arteries belong, likely, to the dopamine D(2) receptor subtype. Quantitative analysis of images let us count the amount of these receptors in many samples of the pulmonary and/or bronchial arteries.

Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists.

Anandamide acts as a full vanilloid receptor agonist in many bioassay systems, but it is a weak activator of primary afferents in the airways. To address this discrepancy, we compared the effect of different vanilloid receptor agonists in isolated airways and mesenteric arteries of guinea pig using preparations containing different phenotypes of the capsaicin-sensitive sensory nerve. We found that anandamide is a powerful vasodilator of mesenteric arteries but a weak constrictor of main bronchi. These effects of anandamide are mediated by vanilloid receptors on primary afferents and do not involve cannabinoid receptors. Anandamide also contracts isolated lung strips, an effect caused by the hydrolysis of anandamide and subsequent formation of cyclooxygenase products. Although capsaicin is equally potent in bronchi and mesenteric arteries, anandamide, resiniferatoxin, and particularly olvanil are significantly less potent in bronchi. Competition experiments with the vanilloid receptor antagonist capsazepine did not provide evidence of vanilloid receptor heterogeneity. Arachidonoyl-5-methoxytryptamine (VDM13), an inhibitor of the anandamide membrane transporter, attenuates responses to olvanil and anandamide, but not capsaicin and resiniferatoxin, in mesenteric arteries. VDM13 did not affect responses to these agonists in bronchi, suggesting that the anandamide membrane transporter is absent in this phenotype of the sensory nerve. Computer simulations using an operational model of agonism were consistent, with differences in intrinsic efficacy and receptor content being responsible for the remaining differences in agonist potency between the tissues. This study describes differences between vanilloid receptor agonists regarding tissue selectivity and provides a conceptual framework for developing tissue-selective vanilloid receptor agonists devoid of bronchoconstrictor activity.

Membrane currents in canine bronchial artery and their regulation by excitatory agonists.

The bronchial vasculature plays an important role in airway physiology and pathophysiology. We investigated the ion currents in canine bronchial smooth muscle cells using patch-clamp techniques. Sustained outward K(+) current evoked by step depolarizations was significantly inhibited by tetraethylamonium (1 and 10 mM) or by charybdotoxin (10(-6) M) but was not significantly affected by 4-aminopyridine (1 or 5 mM), suggesting that it was primarily a Ca(2+)-activated K(+) current. Consistent with this, the K(+) current was markedly increased by raising external Ca(2+) to 4 mM but was decreased by nifedipine (10(-6) M) or by removing external Ca(2+). When K(+) currents were blocked (by Cs(+) in the pipette), step depolarizations evoked transient inward currents with characteristics of L-type Ca(2+) current as follows: 1) activation that was voltage dependent (threshold and maximal at -50 and -10 mV, respectively); 2) inactivation that was time dependent and voltage dependent (voltage causing 50% maximal inactivation of -26 +/- 22 mV); and 3) blockade by nifedipine (10(-6) M). The thromboxane mimetic U-46619 (10(-6) M) caused a marked augmentation of outward K(+) current (as did 10 mM caffeine) lasting only 10-20 s; this was followed by significant suppression of the K(+) current lasting several minutes. Phenylephrine (10(-4) M) also suppressed the K(+) current to a similar degree but did not cause the initial transient augmentation. None of these three agonists elicited inward current of any kind. We conclude that bronchial arterial smooth muscle expresses Ca(2+)-dependent K(+) channels and voltage-dependent Ca(2+) channels and that its excitation does not involve activation of Cl(-) channels.

The effect of a bradykinin B2 receptor antagonist, NPC-567, on allergen-induced airway responses in a porcine model.

OBJECTIVE AND DESIGN: In order to assess the effect of selective blocking of the bradykinin (BK) B2 receptor in allergic airway reactions, the BK B2 receptor antagonist NPC-567 was administered to sensitized pigs before allergen challenge. MATERIAL: Fourteen specific pathogen-free pigs sensitized to Ascaris suum were used. TREATMENT: NPC-567 (2.5 mg, in 1 ml saline) was delivered as an aerosol twice to six pigs. METHODS: Ascaris antigen (in 2 ml saline) was given as an aerosol to all pigs and airway mechanics were monitored for 8 h. NPC-567 (2.5 mg) was given at t = -30 min (in 1ml saline) and mixed with the antigen at t = 0 to six pigs. RESULTS: Allergen challenge caused an acute reaction with a rapid, significant increase in airways resistance from 4.1 +/- 0.5 cm H2O/l/s to a maximum of 16.2 +/- 3.0 cm H2O/l/s in the control pigs. In the NPC-567-treated pigs, the resistance only increased from 2.9 +/- 0.3 cm H2O/l/s to 6.5 +/- 0.9 cm H2O/l/s (p<0.005 compared to controls). There was also a higher reduction in dynamic lung compliance in the controls than in the treated animals upon allergen challenge. The histamine concentration in urine in the control pigs was markedly elevated after allergen challenge peaking at 15-30 min. This release was inhibited in the NPC-567-treated pigs. CONCLUSIONS: The BK B2 receptor antagonist NPC-567 seems to be effective in inhibiting the acute response to allergen in the pig airways, possibly due to inhibition of mast cell activation via indirect mechanisms. The late obstructive response was reduced as well, probably as a consequence of the reduced mediator release in the acute reaction.

Hypoxic constriction of porcine distal pulmonary arteries: endothelium and endothelin dependence.

To determine the role of endothelium in hypoxic pulmonary vasoconstriction (HPV), we measured vasomotor responses to hypoxia in isolated seventh-generation porcine pulmonary arteries < 300 microm in diameter with (E+) and without endothelium. In E+ pulmonary arteries, hypoxia decreased the vascular intraluminal diameter measured at a constant transmural pressure. These constrictions were complete in 30-40 min; maximum at PO(2) of 2 mm Hg; half-maximal at PO(2) of 40 mm Hg; blocked by exposure to Ca(2+)-free conditions, nifedipine, or ryanodine; and absent in E+ bronchial arteries of similar size. Hypoxic constrictions were unaltered by indomethacin, enhanced by indomethacin plus N(G)-nitro-L-arginine methyl ester, abolished by BQ-123 or endothelial denudation, and restored in endothelium-denuded pulmonary arteries pretreated with 10(-10) M endothelin-1 (ET-1). Given previous demonstrations that hypoxia caused contractions in isolated pulmonary arterial myocytes and that ET-1 receptor antagonists inhibited HPV in intact animals, our results suggest that full in vivo expression of HPV requires basal release of ET-1 from the endothelium to facilitate mechanisms of hypoxic reactivity in pulmonary arterial smooth muscle.

Responsiveness of canine bronchial vasculature to excitatory stimuli and to cooling.

Changes in bronchial vascular tone, in part due to cooling during ventilation, may contribute to altered control of airflow during airway inflammation, asthma, and exercise-induced bronchoconstriction. We investigated the responses of canine bronchial vasculature to excitatory stimuli and cooling. Electrical stimulation evoked contractions in only some (8 of 88) tissues; these were phentolamine sensitive and augmented by N(omega)-nitro-L-arginine. However, sustained contractions were evoked in all tissues by phenylephrine [concentration evoking a half-maximal response (EC(50)) approximately 2 microM] or the thromboxane A(2) mimetic U-46619 (EC(50) approximately 5 nM) and less so by beta,gamma-methylene-ATP or histamine. Cooling to room temperature markedly suppressed ( approximately 75%) adrenergic responses but had no significant effect against U-46619 responses. Adrenergic responses, but not those to U-46619, were accompanied by an increase in intracellular Ca(2+) concentration. Chelerythrine (protein kinase C antagonist) markedly antagonized adrenergic responses (mean maxima reduced 39% in artery and 86% in vein) but had no significant effect against U-46619, whereas genistein (a nonspecific tyrosine kinase inhibitor) essentially abolished responses to both agonists. We conclude that cooling of the airway wall dramatically interferes with adrenergic control of bronchial perfusion but has little effect on thromboxane-mediated vasoconstriction.