Citations

Maximal relaxation of airway smooth muscle (ASM) in response to atrial natriuretic peptide (ANP), which stimulates particulate guanylyl cyclase (pGC), is less than that produced by nitric oxide (NO) and other compounds that stimulate soluble guanylyl cyclase (sGC). We hypothesized that stimulation of pGC relaxes ASM only by decreasing intracellular Ca2+concentration ([Ca2+]i), whereas stimulation of sGC decreases both [Ca2+]iand the force developed for a given [Ca2+]i(i.e., the Ca2+sensitivity) during muscarinic stimulation. We measured the relationship between force and [Ca2+]i(using fura 2) under control conditions (using diltiazem to change [Ca2+]i) and during exposure to ANP, diethylamine-NO (DEA-NO), sodium nitroprusside (SNP), and the Sp diastereoisomer of β-phenyl-1, N2-etheno-8-bromoguanosine-3′,5′-cyclic monophosphorothionate ( Sp-8-Br-PET-cGMPS), a cell-permeant analog of cGMP. Addition of DEA-NO, SNP, or Sp-8-Br-PET-cGMPS decreased both [Ca2+]iand force, causing a significant rightward shift of the force-[Ca2+]irelationship. In contrast, with ANP exposure, the force-[Ca2+]irelationship was identical to control, such that ANP produced relaxation solely by decreasing [Ca2+]i. Thus, during muscarinic stimulation, stimulation of pGC relaxes ASM exclusively by decreasing [Ca2+]i, whereas stimulation of sGC decreases both [Ca2+]iand Ca2+sensitivity.

Dyke, Christopher K., Niki M. Dietz, Robert L. Lennon, David O. Warner, and Michael J. Joyner. Forearm blood flow responses to handgripping after local neuromuscular blockade. J. Appl. Physiol. 84(2): 754–758, 1998.—To test the hypothesis that acetylcholine “spillover” from motor nerves contributes significantly to skeletal muscle vasodilation during exercise, we measured the forearm blood flow responses during attempted handgripping after local paralysis of the forearm with the neuromuscular-blocking drug pipecuronium. This compound blocks postsynaptic nicotinic receptors but has no impact on acetylcholine release from motor nerves. The drug was administered selectively to one forearm by using regional intravenous drug administration techniques in five subjects. Pipecuronium reduced maximum forearm grip strength from 40.0 ± 3.2 kg before treatment to 0.0 kg after treatment. By contrast, drug administration had no effect on maximum voluntary contraction in the untreated forearm (41.3 ± 3.3 vs. 41.4 ± 2.7 kg). During 2 min of attempted maximal contraction of the paralyzed forearm, the forearm blood flow increased from only 3.4 ± 0.8 to 4.8 ± 1.2 ml ⋅ 100 ml−1 ⋅ min−1( P < 0.05). Heart rate increased from 63 ± 3 to 73 ± 8 beats/min ( P > 0.05) during attempted contraction, and only three of five subjects showed obvious increases in heart rate. Mean arterial pressure increased significantly ( P < 0.05) from 102 ± 6 to 109 ± 9 mmHg during attempted contractions. When these increases in flow are considered in the context of the marked (10-fold or greater) increases in flow seen in contracting forearm skeletal muscle, it appears that acetylcholine spillover from motor nerves has, at most, a minimal impact on the hyperemic responses to contraction in humans.

The neurotransmitter responsible for neurogenic vasodilation in human skin during body heating is unknown. We sought to determine whether the vasodilating substance nitric oxide (NO) is involved in this phenomenon. Six subjects were heated for 50 min by use of a water-perfused suit while forearm blood flow (FBF) was measured with plethysmography and skin blood flow (SkBF) was measured by the laser-Doppler method in both arms. In one forearm, NG-monomethyl-L-arginine (L-NMMA), an NO synthase blocker, was infused into the brachial artery. Bolus doses of L-NMMA (< or = 4 mg/min) for 5 min were given to blunt NO-mediated vasodilator responses to acetylcholine (ACh, 64 micrograms/min). A continuous infusion of L-NMMA (< or = 1.0 mg/min) was used during body heating to maintain NO synthase blockade. In the forearm receiving L-NMMA, FBF was 1.8 +/- 0.3 ml.100 ml-1.min-1 before drug infusion and rose to 9.5 +/- 1.3 ml.100 ml-1.min-1 with ACh. After L-NMMA infusion, FBF was 1.3 +/- 0.2 ml.100 ml-1.min-1 and rose to 2.6 +/- 0.4 ml.100 ml-1.min-1 with ACh (both P < 0.05 vs. pre-L-NMMA). Similar changes in SkBF were seen with ACh and L-NMMA, confirming that the drugs reached cutaneous vessels. With body heating, oral temperature increased by 1.2 degrees C, heart rate increased by 34 beats/min, and mean arterial pressure remained constant at approximately 75 mmHg. FBF in the treated forearm rose to 11.5 +/- 2.1 vs. 12.6 +/- 1.7 ml.100 ml-1.min-1 in the control forearm (P > 0.05, control vs. treated response).(ABSTRACT TRUNCATED AT 250 WORDS)

Three anesthetics (pentobarbital, halothane, and isoflurane) were studied in six mongrel dogs to systematically compare their effects on chest wall function during spontaneous breathing. Each dog received each anesthetic on separate occasions. Electrical activities of several respiratory muscles were measured with chronically implanted electrodes, and chest wall motion was assessed by high-speed three-dimensional computed tomography scanning. Phasic expiratory muscle activity was markedly depressed by volatile anesthetics halothane and isoflurane compared with pentobarbital. In contrast, inspiratory activity in parasternal intercostal muscles was relatively well preserved during anesthesia with these volatile agents. The contribution of expiratory muscles to tidal volume was diminished during halothane and isoflurane compared with pentobarbital anesthesia. As anesthesia was deepened, expiratory muscle activity was unchanged during pentobarbital anesthesia, enhanced in some dogs during isoflurane anesthesia, and remained absent during halothane anesthesia. Activity in parasternal intercostal muscle was depressed as inspired concentration of halothane or isoflurane was increased, whereas diaphragmatic activity was unchanged. Depression of expiratory muscle activity by halothane persisted when breathing was stimulated by positive end-expiratory pressure, with significant mechanical consequences for chest wall configuration. Many of these findings are in contrast with previous observations in humans and suggest that the dog is not a suitable model for the study of the effects of anesthetic drugs on the pattern of human respiratory muscle activity.

Although the pentobarbital-anesthetized dog is often used as a model in studies of respiratory muscle activity during spontaneous breathing, there is no information regarding the stability of the pattern of breathing of this model over time. The electromyograms of several inspiratory and expiratory muscle groups were measured in six dogs over a 4-h period by use of chronically implanted electrodes. Anesthesia was induced with pentobarbital sodium (25 mg/kg iv), with supplemental doses to maintain constant plasma pentobarbital concentrations. Phasic electrical activity increased over time in the triangularis sterni, transversus abdominis, and external oblique muscles (expiratory muscles). The electrical activity of the costal diaphragm, crural diaphragm, and parasternal intercostal muscles (inspiratory muscles) was unchanged. These changes in electrical activity occurred despite stable plasma levels of pentobarbital and arterial PCO2. They were associated with changes in chest wall motion and an increased tidal volume with unchanged breathing frequency. We conclude that expiratory muscle groups are selectively activated with time in pentobarbital-anesthetized dogs lying supine. Therefore the duration of anesthesia is an important variable in studies using this model.

To determine the relative contribution of rib cage and abdominal muscles to expiratory muscle activity during quiet breathing, we used lumbar epidural anesthesia in six pentobarbital sodium-anesthetized dogs lying supine to paralyze the abdominal muscles while leaving rib cage muscle motor function substantially intact. A high-speed X-ray scanner (Dynamic Spatial Reconstructor) provided three-dimensional images of the thorax. The contribution of expiratory muscle activity to tidal breathing was assessed by a comparison of chest wall configuration during relaxed apnea with that at end expiration. We found that expiratory muscle activity was responsible for approximately half of the changes in thoracic volume during inspiration. Paralysis of the abdominal muscles had little effect on the pattern of breathing, including the contribution of expiratory muscle activity to tidal breathing, in most dogs. We conclude that, although there is consistent phasic expiratory electrical activity in both the rib cage and the abdominal muscles of pentobarbital-anesthetized dogs lying supine, the muscles of the rib cage are mechanically the most important expiratory muscles during quiet breathing.

Both interregional and intraregional mechanisms may cause changes in N2 concentration of expired gas during the phases of the single-breath O2 test (SBO2) that follow dead-space washout. To evaluate the possible importance of each mechanism, we performed the SBO2 in excised canine lungs that were first suspended in air and then immersed in stable foams that simulated the vertical gradient of pleural pressure. The lungs were deflated at constant submaximal flows. The slope of phase III diminished with increasing expiratory flow and increased with foam immersion. The onset of phase IV depended on flow, and a terminal decrease in N2 concentration (phase V) was often observed. Simultaneously measured estimates of regional flows and volumes (J. Appl. Physiol. 65: 1764-1774, 1988) were used to further interpret these results. The onset of phase IV at flows greater than quasi-static signified the onset of flow limitation of dependent regions. The onset of phase V corresponded to flow limitation of nondependent regions.

We have previously demonstrated appreciable inhomogeneity of alveolar pressures measured by a capsule technique in excised canine lobes deflated at submaximal flows (J. Appl. Physiol. 65: 1757-1765, 1988). We further analyzed the results of these experiments by estimating alveolar volumes (VA) and regional flows from regional transpulmonary pressures, assuming that regional pressure-volume relationships were homogeneous. Deflation at submaximal flows of lungs suspended in air caused significant flow-dependent inhomogeneity of VA that increased as lung volume decreased. Immersion of lungs in stable foams that simulated the gradient of pleural pressure modified the pattern of emptying, but not always to a gravity-dependent sequence. Limitation of regional expiratory flow was often asynchronous during both air suspension and foam immersion. There was no evidence of a common regional flow-volume curve. Submaximal deflation is a complex heterogeneous process, with the interregional pattern of emptying determined by the interaction of factors that are both intrinsic and extrinsic to the lungs.

Factors both intrinsic and extrinsic to the lung may cause inhomogeneity of alveolar pressures during deflation. Wilson et al. (J. Appl. Physiol. 59: 1924-1928, 1985) predicted that any such inhomogeneity would be limited by interdependence of regional expiratory flows. To test this hypothesis and to explore how the pleural pressure gradient might affect inhomogeneity of alveolar pressures, we deflated at submaximal flows excised canine lobes that first were suspended in air and then were immersed in foams that simulated the vertical gradient of pleural pressure. Interregional inhomogeneity of regional transpulmonary pressures was measured with use of an alveolar capsule technique. Flow-dependent inhomogeneity of alveolar pressures was present, with differences in alveolar pressure quickly relaxing to a constant limiting value at each flow. Foam immersion increased inhomogeneity at a given flow. We conclude that factors intrinsic to the lung cause significant inhomogeneity of alveolar pressures at submaximal expiratory flows and that this inhomogeneity is enhanced by the extrinsic gradient of pleural pressure. These observations are consistent with the interdependence of flow proposed by Wilson et al.

The objective of this investigation was to determine the minimum transpulmonary pressure (PL) at which the forces of interdependence between the airways and the lung parenchyma can prevent airway closure in response to maximal stimulation of the airways in excised canine lobes. We first present an analysis of the relationship between PL and the transmural pressure (Ptm) that airway smooth muscle must generate to close the airways. This analysis predicts that airway closure can occur at PL less than or equal to 10 cmH2O with maximal airway stimulation. We tested this prediction in eight excised canine lobes by nebulizing 50% methacholine into the airways while the lobe was held at constant PL values ranging from 25 to 5 cmH2O. Airway closure was assessed by comparing changes in alveolar pressure (measured by an alveolar capsule technique) and pressure at the airway opening during low-amplitude oscillations in lobar volume. Airway closure occurred in two of the eight lobes at PL = 10 cmH2O; in an additional five it occurred at PL = 7.5 cmH2O. We conclude that the forces of parenchymal interdependence per se are not sufficient to prevent airway closure at PL less than or equal to 7.5 cmH2O in excised canine lobes.