Pulmonary Receptors Research Articles

Dependence of pulmonary neuronal M2 muscarinic receptors on cyclooxygenase is altered by previous viral infection

Dependence of pulmonary neuronal M2 muscarinic receptors on cyclooxygenase is altered by previous viral infection

901-113 Endothelin Receptor Antagonists in a Beagle Model of Pulmonary Hypertension: Contribution to Possible Potential Therapy?

The idealvasodilator for pulmonary hypertension (PH) would decrease pulmonary arterial pressure with minimal systemic hypotension. The present study was undertaken to investigate the pharmacologic effect of endothelin receptor antagonists on cardiopulmonary hemodynamics in an animal model of PH. We recently developed a beagle model of PH which allows accurate determination of cardiopulmonary hemodynamics and which is associated with elevated plasma endothelin-1 concentrations similar to PH in humans. Twelve beagles (PH, n = 6; and Control, n = 6) were studied during baseline conditions and during right atrial infusion of FR139317 (the ETA receptor antagonist). RES-701–1 (the ETB receptor antagonist). nitroglycerin, and prostaglandin E1. PH was induced in experimental animals 8 weeks after an injection of 3 mg/kg dehydromonocrotaline. The table showed hemodynamic values of PH beagles at baseline and during drug infusion. FR139317 lowered pulmonary and systemic arterial pressure both in pulmonary hypertensive and control animals, with a significantly greater effect on pulmonary arterial pressure in pulmonary hypertensive animals. RES-701-1 increased pulmonary arterial pressure only in PH. Nitroglycerin depressed pulmonary and systemic arterial tone equally well in controls and animals with PH. Prostaglandin El produced a greater decrease in systemic arterial pressure in pulmonary hypertensive than in normal animals, despite same effect on pulmonary arterial pressure in both. Baseline FR139317 200μg/kg/min RES-701-1 100μg/kg/min Nitroglycerin 10μg/kg/min Plastaglandin El 0.4μg/kg/min MSAP (mmHg) 106 ± 5 101 ± 7 109 ± 6 87 ± 6 * 93 ± 7 * MPAP (mmHg) 33.2 ± 59 26.8 ± 3.7 * 36.2 ± 6.4 27.0 ± 5.1 * 27.8 ± 4.1 * SVR (dynes/s/cm 5 ) 4685 ± 439 4581 ± 608 4771 ± 597 3767 ± 229 * 3718 ± 120 * PVR(dynes/cm 5 ) 1237 ± 441 867 ± 164 * 1319 ± 299 856 ± 207 * 870 ± 243 * * Significant difference between baseline and drug infusions at P < 0,05 levels. MSAP: mean systemic arterial pressure. MPAP: mean pulmonary arterial pressure, SVR: systemic vascular resistance, PVR: pulmonary vascular resistance ETA receptor antagonists decrease pulmonary arterial pressure in a beagle model and therefore may be clinically useful for therapy of pulmonary hypertension.

Vagal cooling and the origin of pulmonary reflexes in cats.

Cooling the vagus nerve is often used to study respiratory reflexes mediated by pulmonary receptors (2,5). Its use is based on the finding that at low temperatures (e.g. 4°C) unmyelinated fibres still transmit impulses whereas transmission in myelinated fibres is fully blocked. This allows distinguishing reflex effects caused by C-fibres from those caused by slowly and rapidly adapting pulmonary receptors (SAR and RAR) (2). The aim of the present study was to investigate whether vagal cooling can also be used to distinguish between reflex effects caused by SAR and RAR. Cooling a nerve fibre increases its refractory period in the cooled area. During this period an afferent impulse in this fibre cannot pass the cold block. As a consequence, the frequency of impulses arriving at the brain stem respiratory centres is reduced. SAR have higher discharge frequencies than RAR. Therefore, the relative reduction in impulse frequency by cooling is larger for SAR than for RAR (5). Our hypothesis is that during vagal cooling the effects of stimulating SAR start to disappear at a higher temperature than the effects of stimulating RAR. In the present study two clearly distinct temperature ranges were identified. It is argued that in the first range (14–10°C) the reflex effects caused by SAR were strongly reduced and in the second (8–4°C) the reflex effects caused by RAR.KeywordsVagus NerveUnmyelinated FibreAfferent ImpulseReflex EffectHigh Discharge FrequencyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Heterogeneous activity of pulmonary vagal receptors during high-frequency oscillation ventilation.

The purpose of the study was to examine the response of vagal pulmonary slowly adapting stretch receptors (SAR) to high-frequency oscillation ventilation (HFO) in rabbits by analyzing the afferent activity recorded in vagal single-fiber preparations. The vagal afferent activity was recorded during short runs of HFO with a stroke volume of 2-3 ml/kg applied at oscillation frequencies (fosc) of 5, 10, 15, 20, and 25 Hz and each frequency at three levels of mean airway pressure (P(aw)), namely, 1, 3, and 8 cm H2O. The receptor discharge rates during HFO were compared with those during quiet spontaneous breathing as well as during static lung inflations and deflations. The majority of SAR was stimulated by HFO, however, the SAR discharge patterns during HFO were less homogeneous than during static lung inflations. The heterogeneity of SAR responses to HFO became pronounced with increasing P(aw) and fosc. From the results, we conclude that HFO elicits heterogeneous discharge patterns of SAR, but the previously reported heterogeneity of responses of rapidly adapting receptors was even greater. This heterogeneity of vagal activity is probably the result of heterogeneous mechanical conditions within the lungs during HFO and may, in turn, give rise to the various types of respiratory reflex responses to HFO.

Two types of P neurons in the medullary dorsal respiratory cellular group in cats

Electrophysiological properties of P neurons localized in the medullary dorsal respiratory cellular group and of vagal afferent fibers innervating these neurons were studied in acute experiments on nembutal-anesthetized cats with preserved spontaneous respiration. P neurons were shown to form a non-homogeneous cellular population. They generated phasic discharges during the whole inspiration period, but differed in their responses to lung inflation. These findings allowed us to classify P neurons as slowly adapting and rapidly adapting units, probably activated by slowly and rapidly adapting pulmonary receptors, respectively. Sensitivity of the slowly adapting P neurons to activation by the corresponding receptors and the mechanisms underlying the participation of the two types of P neurons in the reflex feedback between the respiratory center and lungs are discussed.

Histamine degradative uptake by cultured human pulmonary vascular endothelial cells utilizes an inflammatory cell diamine oxidase

Neutrophil-endothelial interactions, altered clearance properties of the lung toward vasoactive mediators, and damaging effects of histamine that target the lung represent prominent elements of the inflammatory response at the systemic level. The pulmonary vasculature is unusual in that, unlike other tissues and vascular beds, it normally does not metabolize circulating histamine in vivo, although histamine-metabolizing enzyme activities have been detected in disrupted lung tissue. We have therefore explored the capability of human pulmonary artery endothelial cells in culture to express the receptor-mediated histamine degradative uptake system we previously defined in systemic endothelial cells (Haddock, R. C., Mack, P., Leal, S., and Baenziger, N. L. (1990) J. Biol. Chem. 265, 14395-14401). Pulmonary endothelial cells display all components of this system: histamine methyltransferase generating the proximal cell-associated metabolite tele-methylhistamine and receptors binding diamine oxidase which generates the distal product methylimidazoleacetic acid that is accumulated by the cells. A diamine oxidase released from human neutrophil granules by activation with Ca2+ ionophore binds pulmonary and systemic endothelial cell and fibroblast diamine oxidase receptors and, thereby, participates in histamine degradative uptake. This enzyme utilizes cell-associated tele-methylhistamine as a substrate, preferentially generating methylimidazoleacetic acid in addition to reactive oxygen species. Thus the enzymatic and interactive cellular machinery for histamine clearance is inherently present as a functional unit in two major human pulmonary cell types. It interacts with products of inflammatory host defense cells, and pulmonary endothelial-neutrophil interactions via this pathway may influence the progression of inflammation.

Downregulation of pulmonary atrial natriuretic peptide receptors in rats exposed to chronic hypoxia.

We hypothesized that a downregulation in pulmonary atrial natriuretic peptide (ANP) receptors helps raise plasma ANP levels during chronic hypoxia. We measured in vivo pulmonary uptake and plasma clearance of 125I-ANP and in vitro pulmonary binding kinetics of 125I-ANP in normoxic and chronically hypoxic rats. Exposure to 21 days of hypobaric (0.5 atm) hypoxia did not decrease specific binding of 125I-ANP in the kidney, but pulmonary binding decreased 35 and 75% after 1 and 3 days of hypoxia, respectively, and increased 200% after 3 days of normoxic recovery from 21 days of hypoxia. The total binding capacity for ANP to lung membrane fractions from normoxic rats, chronically hypoxic rats, and rats that had recovered from hypoxia was 488 +/- 59, 109 +/- 17, and 338 +/- 48 fmol/mg, respectively (P < 0.05 for hypoxic vs. normoxic or recovered lung membranes). The area under the 125I-ANP plasma concentration curve for normoxic and hypoxic rats and normoxic rats that were infused with the ANP C-receptor ligand C-ANF-(4-23) was 3,292 +/- 216, 5,022 +/- 466, and 8,205 +/- 1,059 disintegrations.min-1.ml-1, respectively [P < 0.05 for hypoxic vs. normoxic or C-ANF-(4-23)-infused rats]. We conclude that pulmonary ANP clearance is reduced during chronic hypoxia secondary to a downregulation in pulmonary ANP clearance receptors. Reduced pulmonary clearance of ANP may represent an adaptation that contributes to increased plasma ANP levels during chronic hypoxia.

Reflex effects of lung inflation on tracheomotor tone observed during apnea produced by the Hering-Breuer reflex

Reflex effects of static pressure lung inflation (SLI) on tracheomotor tone (TT) were studied during apnea produced by the Hering-Breuer expiratory-facilitatory reflex. Anesthetized dogs were placed on cardiopulmonary bypass, and diaphragm electromyogram was used as an indicator of central nervous system inspiratory output. Tracheomotor tone (TT) was reflexly produced by chemoreceptor stimulation. The volume and frequency of the ventilator [phasic lung inflation (PLI)] were adjusted to produce nearly a maximum reflex decrease in TT. The increase in TT observed while PLI was withheld (0 mmHg tracheal pressure) for 1-2 min was used as the control response. SLIs were interspersed among sets of PLIs. Although SLI produced apnea, TT returned toward the control TT recorded during 0 mmHg tracheal pressure. TT observed during apnea was reflexly sensitive to further increases in SLI and to changes in chemoreceptor stimulation, which also affected the time course of the tracheomotor responses. These results suggest that the reflex decrease in TT produced by SLI and the Hering-Breuer expiratory-facilitatory reflex are mediated by different central mechanisms but may be from the same or different pulmonary receptors.

Laryngeal and tracheobronchial cough in anesthetized dogs

Tussigenic sensitivity of laryngeal and tracheobronchial regions to mechanical and chemical stimuli was compared in 22 urethan-alpha-chloralose-anesthetized dogs. In addition, the contribution of myelinated and unmyelinated vagal fibers in mediating laryngeal and tracheobronchial cough was investigated. The intensity of cough was evaluated from changes in esophageal pressure. Whereas all mechanical stimulations and citric acid inhalations into tracheobronchial region elicited cough, only 56.7% of mechanical stimulation and 33.3% of citric acid challenges to larynx were effective. The intensity of tracheobronchial cough was significantly higher than that of laryngeal cough. When mechanical stimulation was conducted under visual control (bronchofiberscope), cough elicitability was found to be higher from tracheal bifurcation and main stem bronchi (62.5-87.5%) than from any laryngeal structure (0-42.9%). During partial block of vagal conduction (cooling to 6 degrees C), mechanical and citric acid tracheobronchial stimulations failed to elicit cough and mechanical laryngeal stimulation was effective only in 1 of 10 dogs. Intensity of cough was strongly decreased when mechanical stimulation followed capsaicin administration into trachea (0.3 ml; 100 micrograms/ml) or intravenously (10 micrograms/kg). We conclude that, in anesthetized dogs, stimulation of tracheobronchial region is more effective and prompt in eliciting cough than stimulation of larynx, myelinated vagal afferent fibers play an important role in mediating mechanically and citric acid-induced tracheobronchial cough and mechanically induced laryngeal cough, and stimulation of tracheobronchial and pulmonary capsaicin-sensitive receptors strongly inhibits mechanically induced cough.

Responses of neurons in the nucleus tractus solitarius to stimulation of heart and lung receptors in the rat.

To characterize central integration of reflex responses to stimulation of mechanically and chemically sensitive receptors in the heart and lung, male rats (350 to 425 g) were anesthetized (pentobarbital, 50 mg/kg IP) and paralyzed (gallamine triethiodide, 25 mg/kg IV) and then they underwent bilateral sinoaortic denervation. Extracellular activity of neurons in the nucleus tractus solitarius (NTS) was recorded in response to bolus intra-atrial saline (50, 100, 200, or 300 microL) or phenylbiguanide (PBG, 16 micrograms/kg in 100 microL) administered in random sequence. Changes in mean arterial pressure (MAP), mean right atrial pressure, and right atrial systolic pressure (RASP) were measured as correlates of stimulus intensity, and heart rate (HR) and renal sympathetic nerve activity (RSNA) were used to assess efferent reflex effects of cardiac and pulmonary receptor stimulation. NTS neurons with possible afferent input from stretch and chemically sensitive receptors were identified by an excitatory evoked response to electrical stimulation of the ipsilateral vagus nerve (1 Hz, 500 microA, 1-millisecond duration). Thirty-eight vagus nerve-evoked NTS units with onset latencies of 25.3 +/- 0.9 milliseconds displayed excitatory or inhibitory responses to saline or PBG injections or to both interventions. Saline administration elicited volume-dependent transient increases in MAP and RASP, which were followed by reflex decreases in MAP, HR, and RSNA. PBG injections also evoked hypotension, bradycardia, and sympathoinhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhalation of resuspended road dust, but not ammonium nitrate, decreases the expression of the pulmonary macrophage Fc receptor

Pulmonary macrophages (PM) play a key role in the immune defenses of the lung. When stimulated, PM express Fc receptors (FcR) that regulate the immune response. PM were assayed for FcR expression following subchronic inhalation exposure of adult Fischer 344 rats to either 90 μg/m 3 nitrate (NH 4NO 3), 300 μg/m 3 road dust, or clean air, for 4 h/day, 4 days/week, for 8 weeks. PM were lavaged from the lungs and attached to glass coverslips for 18 h. PM FcR were labelled with rat IgG conjugated with cyanine-3. For each exposure, FcR were determined with a Meridian ACAS 570 confocal cytometer by imaging the fluorescence of 50 cells. We found that the IgG binding to FcR (in arbitrary fluorescence units, FU, per cell) for PM from road dust exposed rats was less (835 ± 39.3 FU/cell) than that for PM from both ammonium nitrate or clean air-exposed rats (1115 ± 58.0 FU/cell and 1123 ± 46.6 FU/cell, respectively). While acid incubation conditions in vitro (pH 5.5 for 30 min to simulate the acid environment of ammonium nitrate inhalation) resulted in a 16% decrease in IgG binding ( P < 0.05), IgG binding to PM from acid aerosol exposed rats was no different than the IgG bound to PM from clean air-exposed rats. PM exposed to road dust in vivo expressed 25% fewer FcR ( P < 0.05). Three-dimensional images of PM failed to show any major alterations in FcR distribution. These preliminary results indicate cellular recognition of antibody-immune complexes may be impaired by subchronic exposure to road dust, which could decrease the immune response of road dust exposed animals.

Functional Ontogeny of Pulmonary Vascular DA1 Dopamine Receptors in the Isolated Perfused Rabbit Lung

Using an in situ isolated salt-perfused rabbit lung preparation, we investigated the functional ontogeny of pulmonary vascular dopamine receptors. In rabbits from 1 to 23 d of age, we measured pulmonary vascular vasodilatory responses to the peripheral vascular dopamine receptor (DA1) agonist, fenoldopam, and sodium nitroprusside during prostaglandin F2 alpha-induced pulmonary vasoconstriction. In separate experiments, the lungs were pretreated with the DA1 receptor blocker, SCH 23390, before prostaglandin F2 alpha, fenoldopam, and sodium nitroprusside. Lungs from rabbits at one of 6 age groups (n = 6-8 per group) were ventilated and perfused. After a stabilization period, prostaglandin F2 alpha was infused into the pulmonary inflow catheter in a concentration range to yield a sustained rise in mean pulmonary artery pressure (4.9 +/- 0.2 mm Hg). Fenoldopam was injected into the pulmonary artery at doses of 0.01, 0.1, 1.0, and 10 micrograms/g after a recovery period, sodium nitroprusside (0.2 micrograms/g) was injected into the pulmonary artery, and the resultant changes in vascular pressure were recorded. Across all age groups, with and without DA1 receptor blockade, sodium nitroprusside-induced vasodilation was similar (-2.7 +/- 0.2 mm Hg) and was considered reference vasodilation. The fenoldopam vasodilation response was considered a percentage of the sodium nitroprusside reference. Response to fenoldopam varied significantly (p < 0.05 by analysis of variance) across the six age groups, with a maximum at 3-5 d of age. Pretreatment with SCH 23390, a selective DA1-blocking agent, significantly attenuated fenoldopam vasodilation in all but the youngest animals (age 0-2 d), in which no blockade effect was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term exposure to norepinephrine results in down-regulation and reduced mRNA expression of pulmonary beta-adrenergic receptors in guinea pigs.

We studied the down-regulation of beta 2-adrenoceptors in guinea pig lung after chronic exposure to a beta-agonist. Guinea pigs were exposed to either norepinephrine (NE) or vehicle for 7 days. The density and affinity of beta-adrenoceptors were determined by Scatchard analysis of [125I]cyanopindolol binding in a lung membrane preparation and beta 1- and beta 2-adrenoceptor subtypes were studied in the presence of 0.1 microM ICI 118,551, a selective beta 2-adrenoceptor antagonist, or 0.1 microM CGP 20712 A, a selective beta 1-adrenoceptor antagonist, respectively. beta 2-Adrenoceptor mRNA was examined by Northern blot analysis. The tissue distribution of beta 2-adrenoceptors and of beta 2-adrenoceptor mRNA in lung after NE infusion were determined using receptor autoradiography and in situ hybridization, respectively. The functional significance of the decrease in beta 2-adrenoceptor was tested by measuring the relaxation response to a beta 2-agonist in isolated parenchymal strips. NE treatment resulted in decreases of 75 +/- 9%, 84 +/- 4%, and 66 +/- 9% of total beta-, beta 1-, and beta 2-adrenoceptors in the lung, compared with control animals. The administration of NE had only minimal effects on the dissociation constant (Kd) of the receptor for the radioligand. beta 2-Adrenoceptors mRNA was decreased by 46 +/- 13% after NE treatment. There was a correspondence between the distribution of beta 2-adrenoceptors and beta 2-adrenoceptor mRNA localization in both control and NE-treated guinea pigs. NE treatment reduced alveolar beta 2-adrenoceptors by 70 +/- 3% and its mRNA expression by 78 +/- 5%.(ABSTRACT TRUNCATED AT 250 WORDS)

Reflex control of the tracheal vasculature of sheep.

Arteries to the cervical trachea were perfused at constant flow in anesthetized sheep. Perfusion pressures (PP), blood pressure (BP), and changes in tracheal smooth muscle tone (Ptr) were measured. Stimulation of pulmonary C-fiber receptors decreased PP (-6.5%) and BP (-16.8%) and increased Ptr (+61.5%), changes prevented by vagotomy and therefore reflex. Stimulation of cardiac receptors and slowly adapting pulmonary stretch receptors decreased PP (-7.9%) and BP (-21.0) and increased Ptr (+19.0%), changes reversed by vagotomy and therefore reflex. Stimulation and inhibition of slowly adapting pulmonary stretch receptors had no vagal-dependent effect on PP and BP, but inflation decreased (-20.3%) and deflation increased Ptr (+35.2%), effects abolished by vagotomy and therefore reflex. Systemic hypoxia increased PP and BP before and after vagotomy (+12.2 and +40.3%), effects greatly reduced by cutting the carotid body nerves; it increased Ptr (+29.8%), an effect abolished by vagotomy and cutting the carotid body nerves. Systemic hypercapnia increased PP (+16.9%), BP (+20.5%), and Ptr (+36.2%), the first two responses being unaffected by vagotomy and the last almost abolished. Stimulation of carotid body chemoreceptors by KCN increased PP (+22.5%), BP (+104.7%), and Ptr (+8.5%), all responses prevented by cutting the carotid body nerves. Responses to intravenous injections of KCN were similar.

Rat renal, aortic and pulmonary endothelin-I receptors: effects of changes in sodium and water intake.

1. In the present study we investigated, first, the effects of high Na+ intake and, second, the effects of water deprivation on plasma endothelin-1 concentration and urinary endothelin-1 excretion and on endothelin receptors in membranes of renal glomeruli and papillae and of aortic smooth muscle and lung tissue from 32 female Sprague-Dawley rats. 2. After 5 weeks of high Na+ intake (n = 8) urinary Na+ excretion was 10.5 +/- 1.3 compared with 1.6 +/- 0.2 mmol/24 h in controls. Body weight, plasma osmolarity, plasma endothelin-1 concentration (23 +/- 6 versus 28 +/- 3 fmol/ml) and urinary endothelin-1 excretion (6.1 +/- 1.3 versus 4.7 +/- 0.3 pmol/24 h) remained unchanged. 3. The characteristics of endothelin-1 receptors in glomeruli, papillae, aortic smooth muscle and lung tissue from salt-loaded rats were not different from those of controls. 4. After 48 h water deprivation (n = 8) body weight had decreased, whereas packed cell volume and plasma and urine osmolarities had increased compared with controls (n = 8) (P < 0.05). Plasma endothelin-1 concentration (40 +/- 6 versus 21 +/- 2 fmol/ml) was higher (P < 0.01) and urinary endothelin-1 excretion (1.0 +/- 0.2 versus 2.8 +/- 0.3 pmol/24 h) was lower than in controls (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes of Pulmonary Glucocorticoid Receptor and Phospholipase A2in Sheep with Acute Lung Injury after High Dose Endotoxin Infusion

In a sheep model of acute lung injury induced by an Escherichia coli endotoxin (5 micrograms/kg) with chronic lung lymph fistula (n = 15), we measured the changes in glucocorticoid receptor (GCR) binding capacity in lung tissue by means of radioligand binding assay. The content of cortisol and the activity of phospholipase A2 (PLA2) were also measured. The results showed that the maximal binding capacity (Bmax) of GCR in lung cytoplasma decreased continuously 2 h (113 +/- 3 versus 66 +/- 2 fmol/mg protein, p < 0.01), 4 h (105 +/- 6 versus 52 +/- 3 fmol/mg protein, p < 0.01), and 6 h (105 +/- 5 versus 37 +/- 2 fmol/mg protein, p < 0.01) after endotoxin infusion. Its affinity decreased markedly (p < 0.05) at 6 h after the infusion. The contents of cortisol in plasma elevated at 0.5 h and remained at a high level until 4 h after the infusion. PLA2 activity rose from 97 +/- 25 to 188 +/- 12 U (p < 0.05), 99 +/- 13 to 285 +/- 25 U (p < 0.01), and 106 +/- 14 to 354 +/- 32 U (p < 0.01) at 2, 4, and 6 h after endotoxin infusion, respectively. There was a negative correlation between the Bmax of GCR and PLA2 activity (r = -0.87, p < 0.01). The findings indicate that there was a secondary GCR abnormality and a higher PLA2 activity during endotoxin-induced lung injury. The glucocorticoid hypofunction caused by reduced GCR binding capacity may accelerate the pathologic response of acute lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related changes in pulmonary muscarinic receptor binding properties

The goal of this study was to elucidate mechanisms responsible for age-related reductions in responsiveness to cholinergic muscarinic stimulation in guinea pigs, by examining the binding properties of muscarinic receptors and their coupling to guanine nucleotide regulatory proteins as a function of animal age. In addition, the binding constants of three selective muscarinic receptor antagonists pirenzepine, [11-((2-[(diethylamino)methyl]-1-piperidinyl)-acetyl)-5, 11-dihydro-6H-pyrido(2,3)(1,4)benzodiazepine-6-on], and 4-diphenylacetoxy-N-methylpiperidine methobromide were examined. We found that there were no changes in either the receptor density or the affinity of the muscarinic receptor with age. There was a significant reduction in the affinity constant for the high-affinity agonist binding site in the old tissues (7.63 +/- 0.08) compared with the young tissues (8.31 +/- 0.10). Guanine nucleotides lowered agonist affinity for the receptor in young lungs, however, they had no effect on agonist binding in old tissues. Antagonist competition binding curves in young tissues revealed that 73% of the receptors are of the M2 type, with 27% being of the M3 subtype. In contrast, antagonist competition binding curves in the old tissues revealed that 37% of the receptors were of the M2 subtype, 30% were M3, and 33% were of the M1 subtype. Our studies provide evidence that the loss of sensitivity to cholinergic muscarinic stimulation in the senescent lung may be due to changes in both muscarinic receptor subtypes and receptor coupling to G proteins.

Cardiac but not pulmonary receptors mediate depressor response to IV phenyl biguanide in conscious rabbits

Phenyl biguanide (PBG) stimulates pulmonary and cardiac receptors in the cat and rabbit. Previous reports have suggested that pulmonary receptors mediate the reflex respiratory responses and cardiac receptors mediate the reflex hypotension and bradycardia. Using selective denervation of the lung (LDX) and intrapericardial procaine to block cardiac nerves (CDX), we investigated the specific role of pulmonary and cardiac receptors in the reflex response to PBG infusion (60 micrograms/kg iv) in the conscious rabbit. Breathing frequency, arterial pressure, heart rate, and renal sympathetic nerve activity (RSNA) were recorded before and after LDX and CDX. Before LDX and CDX, PBG infusion produced tachypnea, hypotension, and bradycardia. This was accompanied by a withdrawal of RSNA to a level not different from that evoked by ganglionic blockade. These responses were preserved after LDX but were abolished after CDX with intrapericardial procaine. Intrapericardial infusion of PBG produced no response. These results indicate that in conscious rabbits both the respiratory and cardiovascular responses to PBG infusion are mediated by cardiac receptors not accessible from the epicardial surface. Furthermore, the reflex hypotension is mediated largely by withdrawal of sympathetic nerve activity resulting in a decreased peripheral resistance.

Identification of vagal sensory receptors in the rat lung: are there subtypes of slowly adapting receptors?

1. We studied the characteristics of pulmonary sensory receptors whose afferent fibres are in the left vagus nerve of opened-chest rats. The activity of these receptors was recorded during mechanical ventilation approximating eupnoea, as well as during deflation, stepwise inflations and constant-pressure inflations of the lungs. Data were also collected from closed-chest rats and analysed separately. 2. Ninety-four per cent of receptors were located in the ipsilateral lung or airways with the remainder in the contralateral lung. 3. Not only were slowly adapting receptors (SARs) the most abundant pulmonary receptors but 21% of them were either exclusively or predominantly active during the deflationary phase of the ventilatory cycle. Deflationary units were found in opened- and closed-chest rats. The average conduction velocity for all fibres innervating SARs averaged 29.7 m s-1. 4. We found rapidly adapting receptors (RARs) to be extremely rare in the rat. Their activity was sparse and irregular. The conduction velocities of fibres innervating RARs averaged 12.3 m s-1. 5. Far more abundant than RARs in the remaining population of pulmonary fibres were C fibres. They were observed to have an average conduction velocity of 2.1 m s-1, base-level activity which was irregular and a high pressure threshold of activation and were stimulated by intravenous capsaicin injection. 6. Notable differences exist between pulmonary receptors in rats and those reported in other species. The variations include the abundant existence of intrapulmonary SARs with exclusively deflationary modulation and the rarity of RARs. We also encountered C fibres which have not previously been described systematically in the rat.

Control of pulmonary vasomotility in congestive heart failure

Although enhanced sympathetic tone is a well-known component of the autonomic imbalance of heart failure, its influence on pulmonary vasomotility is undefined. We investigated the pulmonary circulation in 12 patients with congestive heart failure in NYHA functional class III and in a control group of 10 normal subjects. Sympathetic influence on pulmonary vessels was studied through adrenergic activation by the arithmetic test and the cold pressor test. A rubber balloon was distended in the inferior vena cava to reduce transpulmonary flow and its influence on vascular tone. In normal individuals the arithmetic test caused pulmonary vasodilation, probably because of the mechanical effect of a largely enhanced flow: in fact, caval obstruction unmasked a neurogenic vasoconstrictor response to the arithmetic test by simply reducing the amount of cardiac output increase. In patients with heart failure, cardiac output and pulmonary arteriolar resistance remained steady during the arithmetic test, no matter what the condition of the venous return was. The cold pressor test was always a vasoconstrictor stimulus, but only in normal subjects was vasoconstriction potentiated by reducing, with caval obstruction, transpulmonary flow and its vasodilatory influence. From these data an attenuation of the sympathetic influence on pulmonary vessels in congestive heart failure seems to be likely. This might be explained as the result of modifications of pulmonary vessels rather than of reduced sympathetic excitability since circulating catecholamine levels varied to similar extents in the two groups during the tests. In congestive heart failure interstitial edema and vascular wall imbibition might increase pulmonary vessel tone and decrease vascular receptor availability. Lower reactivity to sympathetic stimuli, particularly to the vasoconstrictor ones, would ensue.