The airway nonadrenergic noncholinergic inhibitory nervous system.
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Airway Resistance↗
Biomedical subjects
R J Altiere
Publications and source records attributed to R J Altiere.
Evidence that hypoxic pulmonary vascular remodeling in rats is polyamine dependent.
This study tested the hypothesis that the polyamines, a family of low-molecular-weight organic cations with documented regulatory roles in cell growth and differentiation, are mediators of chronic hypoxia-induced pulmonary vascular remodeling. Relative to room air controls, chronically hypoxic animals (inspired O2 fraction = 0.1; 21 days) exhibited higher pulmonary arterial pressures (measured in room air), thicker medial layers in pulmonary arteries of 50-100 microns diam, increased hematocrits, and right ventricular hypertrophy. In addition, lung contents of the polyamines, putrescine, spermidine, and spermine were greater in hypoxic animals than in controls. alpha-Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, attenuated the hypoxia-induced elevations in lung putrescine and spermidine content and blunted the increases in pulmonary arterial pressure and medial thickness. Neither the increased hematocrit nor right ventricular hypertrophy associated with chronic hypoxia were abrogated by DFMO. In addition, DFMO failed to influence vasoconstrictor responses provoked by acute hypoxic ventilation in isolated, buffer-perfused rat lungs. These observations suggest that depression of polyamine biosynthesis with DFMO blunts the sustained increase in pulmonary arterial pressure by attenuating hypoxia-induced medial thickening.
Amines↗
Polyamine content in rat lung during development of hypoxia-induced pulmonary hypertension.
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Animals↗
Vascular hyperresponsiveness in perfused lungs from monocrotaline-treated rats.
Studies were conducted in isolated, buffer-perfused lungs to determine whether altered pulmonary vascular responsiveness could contribute to the evolution of monocrotaline (MCT)-induced pulmonary hypertension. Adult male rats were given a single subcutaneous injection of either 105 mg/kg MCT or its vehicle and vascular responsiveness to angiotensin II, ventilatory hypoxia (3% O2), and KCl was assessed in isolated, buffer-perfused lungs at 4, 7, and 14 days post-treatment. Relative to preparations derived from control animals, vasopressor responses induced by 0.1 microgram, but not 0.05 microgram angiotensin, were augmented at 4 and 7 days but not at 14 days post MCT. Pulmonary vasoconstriction evoked by hypoxic ventilation was enhanced at 4 days but not at 7 or 14 days posttreatment. Pressor responses induced by 30 and 45 mg KCl were not different in treated animals relative to controls at any time post-MCT administration. MCT provoked perivascular edema, but this factor did not seem to contribute to vascular hyperresponsiveness, since the time course of edema did not parallel the time course of augmented responsiveness. Results of the present study indicate that MCT, by an unknown mechanism, causes an early and transient increase in pulmonary vascular responsiveness to some but not all vasoconstrictors. Because the enhanced responsiveness occurred prior to development of pulmonary hypertension, it is unlikely that this alteration contributes to the sustained elevation in pulmonary arterial pressure.
Angiotensin II↗
Reflex activation of the nonadrenergic noncholinergic inhibitory nervous system in feline airways.
Experiments were undertaken to learn if the nonadrenergic noncholinergic inhibitory nervous system (NANCIS) in feline airways could be activated reflexly either by mechanically stimulating the laryngeal mucosa or by inducing acute bronchospasm with boluses of 5-hydroxytryptamine (5HT) injected intravenously. Mechanical stimulation of the dorsal laryngeal mucosa evoked a biphasic bronchomotor response in anesthetized cats that had received intravenously an infusion of 5HT to raise their basal airway smooth muscle tone. The response consisted of a transient augmentation of bronchoconstriction followed by a prolonged bronchodilation. After muscarinic cholinergic receptor blockade with atropine, the constriction phase of the response disappeared, but the relaxation phase persisted. Bronchodilation elicited by laryngeal stimulation was resistant to beta-adrenergic receptor blockade with propranolol but was abolished by autonomic ganglionic blockade with hexamethonium and blocked reversibly by vagal cooling. The latter interventions, when imposed between successive dose-response curves generated by intravenous 5HT in animals pretreated with atropine and propranolol, did not alter the positions or slopes of the curves. These findings support the conclusion that mechanical stimulation of the larynx reflexly activates not only the well-known vagal cholinergic excitatory pathway to the airways but also the more recently described vagal, nonadrenergic noncholinergic inhibitory pathway. The results further indicate that bronchoconstriction is neither a prerequisite for the bronchodilator component of the laryngeal bronchomotor reflex nor an independent initiating stimulus for NANCIS-mediated reflex bronchodilation.
Airway Resistance↗
Altered pulmonary vascular smooth muscle responsiveness in monocrotaline-induced pulmonary hypertension.
Studies were conducted to determine whether experimental pulmonary hypertension is associated with alterations in pulmonary vascular smooth muscle responsiveness. Adult male rats were given a single s.c. injection of monocrotaline (105 mg/kg) or saline and were sacrificed 4, 7 or 14 days later. Segments of the main trunk and right extrapulmonary artery and an intrapulmonary artery were isolated for determination of vascular reactivity to contractile and relaxant agonists. Monocrotaline treatment caused changes in mechanical properties of pulmonary arteries in that vessels isolated from rats 14 days after monocrotaline administration required greater passive loads to achieve maximal active force development. Cumulative concentration-response curves were generated to potassium chloride, angiotensin II, norepinephrine, isoproterenol and acetylcholine. Vascular contractility was enhanced in main pulmonary artery 4 days after monocrotaline injection but no differences in responsiveness between control and monocrotaline exposed vessels were observed 7 days post-treatment. In contrast, significant decreases in contractility with a specific loss in the response to angiotensin II were observed in pulmonary arteries isolated from rats 14 days after monocrotaline administration. These vessels also were less responsive to the relaxant effects of isoproterenol and acetylcholine when compared to control vessels. These results demonstrate that changes in pulmonary vascular smooth muscle responsiveness occur during evolution of pulmonary hypertension induced by monocrotaline. Enhanced contractility may contribute to inappropriate vasoconstriction early in the development of hypertensive pulmonary vascular disease but does not appear to be involved in sustained elevations in pulmonary artery pressure. Diminished relaxation observed after pulmonary hypertension was well established may contribute to the loss in efficacy of vasodilators in the long-term management of pulmonary hypertension.
Acetylcholine↗
Acetylcholine-induced contractions in isolated rabbit pulmonary arteries: role of thromboxane A2.
Acetylcholine has been reported to produce vasodilation or vasoconstriction in the pulmonary circulation of different species. In rabbit lungs, acetylcholine is a potent vasoconstrictor. The present study was undertaken to examine the contractile effects of acetylcholine in arteries isolated from various regions of the rabbit pulmonary vascular bed and in thoracic aorta. Arteries isolated from within the lung were more responsive than extrapulmonary arteries (main pulmonary artery and aorta) to the contractile effects of acetylcholine. In vessels precontracted with norepinephrine, acetylcholine caused biphasic (relaxation-contraction) concentration-response curves. Atropine inhibited acetylcholine-induced contractions in all vessels, whereas pretreatment with cyclooxygenase or thromboxane synthetase inhibitors abolished contractile responses to acetylcholine only in intrapulmonary arteries. In accordance with these findings, acetylcholine caused a 3-fold increase in thromboxane A2 release from intrapulmonary arteries but not from extrapulmonary arteries. Inhibition of thromboxane synthetase abolished this effect of acetylcholine. Endothelium removal decreased contractile responses in intrapulmonary arteries but it did not decrease contractions in extrapulmonary arteries, suggesting that endothelium may contribute to acetylcholine-induced, thromboxane-mediated contractions in intrapulmonary arteries. Indomethacin did not inhibit contractile responses in endothelium-denuded main pulmonary artery or aorta but it abolished the weak contractile responses in intrapulmonary arteries without endothelium, indicating that arterial smooth muscle also was a source of contractile prostanoid biosynthesis enhanced by acetylcholine. These results demonstrate that acetylcholine contracts rabbit intrapulmonary arteries through generation of thromboxane A2 but that a different mechanism is responsible for mediating weaker acetylcholine-induced contractions in extrapulmonary artery and aorta.(ABSTRACT TRUNCATED AT 250 WORDS)
Acetylcholine↗
Effect of alpha-chymotrypsin on the nonadrenergic noncholinergic inhibitory system in cat airways.
Electrical field stimulation of 5-hydroxytryptamine contracted cat trachea and bronchi in the presence of cholinergic and adrenergic blockade caused relaxation by activating intrinsic nonadrenergic noncholinergic (NANC) inhibitory nerves. Pretreatment of the tissues with the proteolytic enzyme, alpha-chymotrypsin, did not affect NANC inhibitory responses. Relaxations induced by vasoactive intestinal peptide (VIP) were abolished by alpha-chymotrypsin. These results suggest that VIP or related peptides may not act as the NANC inhibitory transmitter in cat airways. However, the possibility remains that peptides not susceptible to degradation by alpha-chymotrypsin may mediate these NANC inhibitory responses.
Animals↗
Suppression of polyamine biosynthesis prevents monocrotaline-induced pulmonary edema and arterial medial thickening.
Previous work in our laboratory has shown that the continuous administration of alpha-difluoromethylornithine (DFMO), a highly specific irreversible inhibitor of ornithine decarboxylase (ODC), which is the rate-limiting enzyme in polyamine biosynthesis, prevented the development of pulmonary hypertension and right ventricular hypertrophy induced in rats 21 days after a single injection of monocrotaline (MCT). We now report that DFMO treatment did not influence the proposed first step of MCT pneumotoxicity, that is, the hepatic metabolism of MCT to toxic pyrrolic metabolites. In contrast, DFMO treatment blunted the development of lung perivascular edema at Day 7, inhibited the respective four- and twofold increases in lung putrescine and spermidine contents at Day 21 without significantly altering spermine content, and prevented the arterial medial thickening at Day 21. It thus appears that increased lung polyamine biosynthesis may be essential for the expression of MCT-induced perivascular edema as well as the development of the medial thickening stage of MCT-induced hypertensive pulmonary vascular disease.
Animals↗
Pulmonary mechanical, ventilatory, and gas exchange abnormalities in rats with monocrotaline-induced pulmonary hypertension.
Recent clinical studies have suggested that peripheral airways dysfunction contributes to the pathogenesis of idiopathic pulmonary hypertension. To determine whether similar peripheral airways defects occur in a common animal model of pulmonary hypertension, pulmonary function tests were performed in adult male rats rendered pulmonary hypertensive with a single subcutaneous injection of monocrotaline. At 20 days post treatment, animals exhibited well-developed right ventricular hypertrophy coincident with significant changes in lung volumes, pulmonary mechanics, and gas exchange function indicative of a severe combined restrictive and obstructive airways disorder. Morphologic changes in alveolar integrity compatible with such a pulmonary defect also were observed in monocrotaline-treated animals. The specific changes in pulmonary function observed in monocrotaline-treated rats were qualitatively similar to abnormalities reported in patients with idiopathic pulmonary hypertension. These results demonstrate that significant pulmonary mechanical, ventilatory, and gas exchange dysfunction is present in rats with monocrotaline-induced pulmonary hypertension and highlight the suitability of this model for investigating a potential contributory role of pulmonary function abnormalities in the pathogenesis of this disorder.
Animals↗
Neurally mediated nonadrenergic relaxation in cat airways occurs independent of cholinergic mechanisms.
Activation of the nonadrenergic noncholinergic (NANC) inhibitory system in cat airways causes coincident release of acetylcholine from vagal nerve terminals. The present study was undertaken to determine if neurally released acetylcholine is involved in initiating or modulating activity in the lung NANC inhibitory system. Electrical field stimulation experiments were performed on isolated segments of cat trachea and bronchi and additional studies were conducted in intact anesthetized, mechanically ventilated cats. In isolated airways, frequency-dependent NANC relaxations of bethanechol contracted tissues were identical to NANC responses of airways contracted with 5-hydroxytryptamine. This result suggested that muscarinic receptor activation did not influence NANC inhibitory system function. In additional studies where agents that inhibited or potentiated the actions of acetylcholine were used, similar results were obtained. Pretreatment of tissues with hexamethonium or atropine did not alter NANC frequency response curves. Contractile responses evoked by field stimulation were potentiated by neostigmine and abolished by hemicholinium treatment; NANC relaxation responses were not significantly affected by either agent. In intact cats, neostigmine pretreatment did not alter the magnitude or duration of vagally mediated NANC bronchodilation. Acetylcholine administered as an aerosol to cats treated with atropine did not mimic the NANC response. These findings suggest that NANC inhibitory system function in cat airways is neither dependent upon nor modulated by neurally released acetylcholine.
Acetylcholine↗
Pulmonary metabolism of exogenous enkephalins in isolated perfused rat lungs.
Metabolism of enkephalins during transit through the pulmonary circulation may be of significance in regulating systemic levels of these opioids. To determine whether Leu- and Met-enkephalin are metabolized by the pulmonary circulation, [3H]Tyr-Leu-enkephalin (10 microM) or [3H]Tyr-Met-enkephalin (10 microM) were each administered to isolated rat lungs perfused in a recirculating manner with a physiologic salt solution and a recently developed high-performance liquid radiochromatographic analytical method was used to identify and quantitate metabolites in the perfusion medium. Both Leu- and Met-enkephalin were metabolized in a curvilinear, time-dependent manner. The principal metabolites were identified as tyrosine and Tyr-Gly-Gly. Neither Tyr-Gly nor Tyr-Gly-Gly-Phe were detected in significant amounts. After a 20-min perfusion, residual Leu- or Met-enkephalin accounted for 28.4 and 21.5%, respectively, of the radioactivity present in the perfusate. In addition, 97% of the initial radioactivity for both Leu- and Met-enkephalin were found in the perfusion medium, indicating that neither the parent compounds nor metabolites were avidly sequestered in pulmonary tissue. The angiotensin converting enzyme inhibitor, captopril (18 microM) blocked the formation of Tyr-Gly-Gly and attenuated slightly the production of tyrosine. Inhibition of aminopeptidase with bestatin (116 microM) blocked the formation of tyrosine and enhanced production of Tyr-Gly-Gly. Inhibition of enkephalinase with thiorphan (0.3 microM) did not appear to affect Met-enkephalin metabolism. These observations indicate that in isolated, buffer perfused rat lungs Leu- and Met-enkephalin are metabolized during pulmonary transit by at least two enzymes, angiotensin converting enzyme and aminopeptidase.
Aminopeptidases↗
alpha-Difluoromethylornithine, an inhibitor of polyamine synthesis, attenuates monocrotaline-induced pulmonary vascular hyperresponsiveness in isolated perfused rat lungs.
Monocrotaline-induced pulmonary hypertension in rats is preceded by an early and prolonged activation of lung ornithine decarboxylase (ODC) and a resultant increase in lung polyamine levels. These changes coincide in time with a transient period of pulmonary vascular hyperresponsiveness to angiotensin II. We therefore tested the hypothesis that enhanced lung ODC activity is necessary for the occurrence of monocrotaline-induced pulmonary vascular hyperresponsiveness. Adult male rats were given a subcutaneous injection of either 105 mg/kg monocrotaline or its vehicle and were treated concurrently with either alpha-difluoromethylornithine (DFMO), a specific, irreversible inhibitor of ODC, or saline. One week post monocrotaline treatment, animals were sacrificed and vascular responsiveness to angiotensin II and KCl was assessed in isolated, buffer perfused lungs. Relative to control preparations, lungs from monocrotaline-treated animals exhibited significantly larger vasoconstrictor responses upon challenge with 0.1 or 0.5 microgram angiotensin II. In contrast, angiotensin II-induced responses in lungs from rats treated with monocrotaline plus DFMO were not different from control. DFMO treatment alone had no impact on angiotensin responses. Vasoconstrictor responses evoked by 30 and 45 mg KCl were not different in lungs from monocrotaline-treated animals relative to control nor were they influenced by concurrent treatment with DFMO. Neither the polyamines (putrescine, spermidine, or spermine) nor DFMO influenced angiotensin II-induced vasoconstriction in normal lungs when added acutely to the perfusate reservoir. These observations suggest that the polyamines, although not serving as regulators of vascular reactivity in the normal pulmonary circulation, are causally related to the evolution of pulmonary vascular hyperresponsiveness observed in lungs from monocrotaline-treated rats.
Angiotensin II↗
Prolonged activation of rat lung ornithine decarboxylase in monocrotaline-induced pulmonary hypertension.
Polyamines are believed to have an essential role in cellular growth and differentiation. Activation of ornithine decarboxylase, the initial rate-limiting enzyme in polyamine biosynthesis, is an early event characteristic of cell growth processes. Monocrotaline-induced pneumotoxicity is associated with cellular hypertrophy and proliferation, most notably pronounced medial thickening of pulmonary arterioles and hypertrophy of right ventricular myocardial cells. We reasoned that polyamines may be causally related to these events and, therefore, elevations in lung and right ventricular ornithine decarboxylase activities might precede development of pulmonary hypertension and right ventricular hypertrophy. To test this hypothesis adult male rats were given monocrotaline (105 mg/kg, s.c.); lung and right and left ventricular ornithine decarboxylase activities, pulmonary artery pressure, and right ventricular hypertrophy were assessed at 1, 4, 7, 10, 14, 16 and 21 days post treatment. Lung ornithine decarboxylase activity was increased approximately 8-fold on day 1 and remained elevated through day 7. Right ventricular ornithine decarboxylase activity was not elevated above control values at any time. Elevated pulmonary artery pressure and right ventricular hypertrophy were not apparent until day 16 and day 14 respectively. Thus, sustained activation of lung ornithine decarboxylase occurred at least 1 week prior to the development of pulmonary hypertension, suggesting that polyamines may play an important role in the pulmonary vascular remodeling that accompanies monocrotaline-induced pneumotoxicity.
Animals↗
VIP as a bronchodilator.
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Blood Pressure↗
Relaxation of cat tracheobronchial and pulmonary arterial smooth muscle by vasoactive intestinal peptide: lack of influence by peptidase inhibitors.
Vasoactive intestinal peptide (VIP) caused concentration-dependent relaxation in precontracted segments of trachea, hilar bronchus, intrapulmonary bronchus and intrapulmonary artery (IPA) isolated from cat lungs. VIP-induced relaxation responses were abolished by preincubation of tissues with the proteolytic enzyme, alpha-chymotrypsin (2 units ml-1). At the concentration employed, alpha-chymotrypsin treatment did not adversely affect tissue viability as isoprenaline and bethanechol continued to relax airways and IPA, respectively. Aprotinin prevented enzymatic degradation of VIP by alpha-chymotrypsin as demonstrated by the ability of VIP to relax tissues incubated with both the peptidase inhibitor and alpha-chymotrypsin. A spectrum of peptidase inhibitors, including aprotinin, leupeptin, bestatin, bacitracin, beta-phenylpropionic acid and captopril, individually or in combination, did not augment the relaxant effects of VIP in isolated pulmonary tissues. These results suggest that local enzymatic degradation may not be a primary route for inactivation of VIP in cat isolated airways and IPA. If VIP acts as a neurotransmitter in these tissues, a mechanism other than enzymatic proteolysis may be responsible for terminating its action.
Airway Resistance↗
Polyamines and the development of monocrotaline-induced pulmonary hypertension.
Previous work in our laboratory has shown that the development of monocrotaline-induced pulmonary vascular disease in rats is preceded by a prolonged activation of lung ornithine decarboxylase (ODC). We now report that significant increases in rat lung adenosylmethionine decarboxylase activity and levels of the diamine putrescine and the polyamines, spermidine and spermine, are produced by a single dose of monocrotaline (MCT). Lung putrescine levels were increased from days 7 through 21, and both spermidine and spermine were first elevated at day 10 following MCT administration. This sustained elevation of lung polyamine levels substantially preceded the development of right ventricular hypertrophy and pulmonary hypertension, which were first evident at days 14 and 16, respectively. Continuous treatment with alpha-difluoromethylornithine, a highly specific enzyme-activated, irreversible inhibitor of ODC activity, prevented the development of MCT-induced pulmonary toxicity. It thus appears that ODC and the polyamines may be important mediators of hypertensive pulmonary vascular disease that develops in response to monocrotaline administration.
Adenosylmethionine Decarboxylase↗
Comparison of vasoactive intestinal peptide and isoproterenol relaxant effects in isolated cat airways.
Vasoactive intestinal peptide (VIP), an endogenous peptide found in mammalian tissues including the lung, is a potent relaxant of smooth muscle. In precontracted segments of cat trachea, hilar bronchus, and intrapulmonary bronchus, concentration-relaxation curves to VIP were compared with those produced by isoproterenol. VIP and isoproterenol were nearly equipotent in causing relaxation of extrapulmonary airways. A decreasing sensitivity to VIP was observed in progressively smaller airways, suggesting regional variation in VIP-induced responses. In contrast, tissues showed no regional differences in response to isoproterenol. Propranolol (10(-6) M), which antagonized relaxation responses to isoproterenol, had no effect on VIP concentration-response curves. Indomethacin (10(-5) M) completely prevented responses to exogenous arachidonic acid but did not inhibit VIP-induced relaxation. Avian pancreatic polypeptide, which has been reported to inhibit vasodilator responses to VIP in the cat, was unable to antagonize airway smooth muscle relaxation induced by VIP. These results demonstrate that VIP is a potent relaxant of cat tracheobronchial smooth muscle in vitro and that the relaxant effects of this peptide are not mediated through beta-adrenergic receptors or by prostaglandins. In view of previous reports on the localization of VIP immunoreactivity in nerves around airways in cat lung, results of the present study suggest that VIP may participate in the regulation of airway tone in this species.
Animals↗