RESUMEN
We hypothesized that the temporary blunted ventilatory response to hypoxia seen in chronically hypoxic rats could be related to the increased amount of dopamine found in their carotid bodies. Rats, kept 2-3 wk in 10% O2, showed reduced nonisocapnic ventilatory responses to 21-12% inspiratory O2 fraction compared with control rats. Stimulus-response curves to almitrine, which simulates the action of hypoxia on the carotid body, were also depressed in chronically hypoxic rats. Responses to hypoxia and almitrine were significantly correlated in the two groups of rats. Dopamine depressed ventilation during normoxia, hypoxia, and almitrine stimulation in both groups, an action abolished by the dopamine-2 antagonist domperidone. Domperidone slightly increased responses to hypoxia and almitrine in control rats but had a greater enhancing effect in chronically hypoxic rats, such that there was no longer a difference between the responses of the two groups.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Domperidona/farmacología , Antagonistas de Dopamina , Hipoxia/fisiopatología , Piperazinas/farmacología , Respiración/efectos de los fármacos , Almitrina , Animales , Enfermedad Crónica , Masculino , Ratas , Ratas EndogámicasRESUMEN
1. Ventilatory measurements and functional residual capacity (FRC) were recorded from anaesthetized rats and ferrets using a whole body plethysmograph. Simulation of aspects of human chronic obstructive airways disease (COAD) was attempted by making animals acutely hypoxic or hypoxic and hypercapnic by causing them to breath appropriate gas mixtures or by increasing the tracheal resistance or dead-space. Some chronically hypoxic rats, which have muscularized pulmonary arterioles similar to COAD patients, were also studied. 2. In 18 chronically hypoxic (CH) rats and 17 littermate control rats (C), breathing air, doses of almitrine bismesylate caused greater increases in ventilation (VE) in C than in CH rats. FRC, which was initially greater in CH rats, increased significantly in both groups after almitrine. 3. In C rats, breathing hypoxic or hypoxic/hypercapnic gas mixtures caused large increases in VE. Slow infusions of almitrine caused a further increase in VE usually via an increase in tidal volume (VT) but not frequency (f). 4. In two series of rats (n = 9; n = 6) severe and moderate degrees of tracheal obstruction caused a fall in PaO2 and a rise in PaCO2, a fall in VE due to both VT and f and large changes in oesophageal pressure (Poes), which often became positive on expiration. Almitrine infusions usually caused a rise in PaO2, a rise in VT and no change in f; with moderate obstruction, Poes also rose. The results were thought to depend on the balance between improved ventilation and increased O2 demand of the respiratory muscles. 5. Eleven ferrets were made hypoxic and hypercapnic by adding a large dead-space to the trachea. A slow infusion of almitrine caused a significant rise in PaO2 before any significant change in VE was detected; PaCO2 fell at some time during the infusion, but not significantly. The initial significant rise in PaO2, at 2.5 min, was not associated with significant changes in T1 (time of inspiration) and VT/TI. At 5 min VT/TI and PaO2 were all significantly altered. 6. Infusions of almitrine into hypoxic and hypercapnic animals caused improvements in the arterial oxygen tension which were associated with subtle changes in the breathing pattern; inspiratory time and inspiratory flow rate changed in the absence of an increase in total VE. Possible conclusions with respect to the action of almitrine in patients with COAD are discussed.
Asunto(s)
Carnívoros/fisiología , Estimulantes del Sistema Nervioso Central/farmacología , Hurones/fisiología , Hipercapnia/fisiopatología , Hipoxia/fisiopatología , Piperazinas/farmacología , Respiración/efectos de los fármacos , Obstrucción de las Vías Aéreas/fisiopatología , Resistencia de las Vías Respiratorias/efectos de los fármacos , Almitrina , Anestesia , Animales , Masculino , Pletismografía Total , Ratas , Ratas Endogámicas , Tráquea/efectos de los fármacos , UretanoRESUMEN
Ventilation to one lobe of lung was reduced in anaesthetized open-chest cats and dogs to simulate the ventilation/perfusion (V/Q) mismatching of chronic lung disease. Blood flow to this lobe fell less than ventilation; thus lobar V/Q diminished. In seven cats almitrine (0.5 mg/kg + 10 micrograms/kg per min, i.v.) caused a rise in pulmonary artery pressure (PPA), increased flow through the hypoventilated lobe in six out of seven cats and both increased or decreased lobar vascular resistance (PVR); the lobar V/Q ratio therefore fell. Arterial and lobar venous oxygen tension (PO2) fell. In five dogs almitrine caused a rise in PPA and PVR but lobar flow changes were variable. Arterial and lobar venous PO2 fell. With fixed ventilation, almitrine failed to improve V/Q matching; there was no improvement in gas exchange in the hypoventilated lobe. In eight dogs the hypoventilated lobe was perfused at constant flow with right atrial blood (i.e. while V/Q was held constant). Almitrine caused a rise in perfusion pressure, vasoconstriction, followed, in five out of eight dogs, by vasodilatation. In six similar cat preparations, vasoconstriction but not vasodilatation was clearly shown. In two cats dilatation after almitrine was demonstrated during ventilation with Nitrogen. In all experiments there was no significant effect of the solvent. Thus the dual action of almitrine seen in other species was seen in a proportion of cats and dogs. Results do not support the view that improved arterial gas tensions in patients after almitrine are attributable to diversion of blood flow away from hypoxic lung. Alternative mechanisms are discussed.
Asunto(s)
Enfermedades Pulmonares Obstructivas/fisiopatología , Piperazinas/farmacología , Relación Ventilacion-Perfusión/efectos de los fármacos , Almitrina , Animales , Gatos , Perros , Oxígeno/sangre , Piperazinas/sangre , Circulación Pulmonar/efectos de los fármacos , Especificidad de la Especie , Resistencia Vascular/efectos de los fármacosRESUMEN
Electrical stimulation of the central end of the vagal communicating branch in the thorax at frequencies between 2 and 20 Hz elicited, after a latency of 7.2 +/- 0.8 s, large-amplitude colonic contractions. 5 Hz stimulation gave near maximal contractions and, because vomiting was more likely to occur at higher stimulus frequencies, was used as the standard stimulus for subsequent experiments. At this frequency the peak colonic contraction was 6.5 +/- 0.9 kPa. Following atropine the characteristics of the response to central vagal stimulation differed from that seen before atropinization. The latency was longer (45.7 +/- 8.2 s) and the amplitude greatly attenuated (0.7 +/- 0.2 kPa). Cooling the vagus nerves to 2 degrees C at a level either above or below the site of stimulation completely abolished both the cholinergic and the atropine-resistant colonic responses to central vagal stimulation. These results are consistent with the vagus containing two motor pathways to the colon which are reflexly stimulated by a vagal afferent input. The functional significance of these reflexes is discussed.
Asunto(s)
Carnívoros/fisiología , Colon/fisiología , Hurones/fisiología , Reflejo/fisiología , Nervio Vago/fisiología , Animales , Frío , Colon/inervación , Femenino , Motilidad Gastrointestinal , Masculino , Factores de TiempoRESUMEN
Reactivity of lung vessels to acute hypoxia was found increased or decreased in chronically hypoxic (CH) rats by different authors. We examined severity and duration of hypoxia and age as possible explanations. Isolated blood-perfused lungs of CH rats ventilated with low-O2 mixtures were compared with control (C) rats. Juvenile CH rats (10 or 12% O2, 3 weeks) showed increased reactivity; reactivity of mature CH rats (10% O2, 3 weeks) was not significantly different from controls. Reactivity declined with age in CH but not C rats. Juvenile and mature rats exposed to 10% O2 for 48 h showed reduced reactivity; after 3 weeks but not 48 h hypoxia, pulmonary arterioles are narrowed by new muscle. The pressure/flow relationship differed in CH from C rats in that resistance and critical closing pressure (CCP) were greater during normoxia. Hypoxia caused increased resistance and CCP in C rats but mainly an increase in CCP in CH rats. The difference may be attributable to muscularisation of collapsible alveolar vessels in chronic hypoxia.
Asunto(s)
Hipoxia/fisiopatología , Circulación Pulmonar , Vasoconstricción , Enfermedad Aguda , Animales , Presión Sanguínea , Enfermedad Crónica , Masculino , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
A rat model was used to assess the viscosity factor in pulmonary hypertension of high altitude. Rats exposed to 10% O2 for three weeks developed increased pulmonary vascular resistance (p.v.r.) and polycythaemia; the haematocrit (Hct) was 50-60%, values similar to those in normal men at high altitudes. The contribution of high Hct to the increased p.v.r. was assessed in isolated perfused lungs of chronically hypoxic rats perfused with their own high Hct blood, or normal Hct blood from control rats. Pressure/flow relationships were measured over a wide range and the slope (P/Q) of this relationship and its extrapolated intercept on the pressure axis were increased by high Hct blood. A return to low Hct blood did not restore initial conditions although a second perfusion with high Hct blood again increased p.v.r. and intercept. Lack of reversibility was attributed to changes with time in blood or lung. In a second experiment designed to eliminate time changes, chronically hypoxic or litter-mate control rats were each perfused with only one blood, their own or each other's and P/Q relations were rapidly measured. The P/Q slope and pressure intercept increased progressively in the following groups: control rats perfused with their own blood (Hct 34%), control rats perfused with chronically hypoxic blood (Hct 56%), chronically hypoxic rats perfused with control blood (Hct 35%) and chronically hypoxic rats perfused with chronically hypoxic blood (Hct 53%). To exclude factors in chronically hypoxic blood other than high Hct which might increase p.v.r., control rats were perfused with blood of different Hct obtained by centrifugation. High Hct again increased p.v.r. There was a significant relationship in all rats between pulmonary artery pressure (Ppa), which takes into account both P/Q slope, intercept and Hct. There was substantial batch variation which may reflect sensitivity to hypoxia. In chronically hypoxic rats with high Hct blood, Ppa varied from 29-47 mmHg; with low Hct blood the range was 26-38 mmHg. Comparable values for control rats were 21-29 and 17-20 mmHg. We conclude that the polycythaemic blood of chronic hypoxia contributes substantially to pulmonary hypertension. Where it is excessive, it may prejudice tissue blood flow.
Asunto(s)
Altitud , Hipertensión Pulmonar/etiología , Policitemia/complicaciones , Animales , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Hematócrito , Hipertensión Pulmonar/fisiopatología , Hipoxia/complicaciones , Técnicas In Vitro , Masculino , Arteria Pulmonar , Ratas , Ratas Endogámicas , Resistencia VascularRESUMEN
Pulmonary vascular actions of almitrine bismesylate were studied in ferrets, rats, cats and dogs in conditions which simulated those of patients with hypoxic lung disease. All or part of a lung was made hypoxic or hypoventilated so that affected vessels were constricted. Rats were made chronically hypoxic (10%, O2, normobaric chamber). In vivo and isolated preparations were used. In all preparations and species almitrine bismesylate caused vasoconstriction in normoxia, constriction followed by dilation in hypoxia or hypoventilation. In hypoventilated lung there is ventilation/perfusion mismatching which was not improved by almitrine bismesylate . Ventilatory measurements in chronically hypoxic/hypercapnic rats showed that almitrine bismesylate increased tidal volume but not frequency. It is uncertain whether vascular (Q) or small ventilatory (V) changes are the cause of the improved gas tensions and V/Q matching in patients with chronic obstructive lung disease receiving almitrine bismesylate .