COMPARATIVE EFFECTS OF DOPAMINE AND DOBUTAMINE ON THE PULMONARY HAEMODYNAMIC RESPONSE TO HYPOXIA IN DOGS VENTILATED WITH A HYPOXIC GAS MIXTURE

1. The effects of dopamine and dobutamine on the pulmonary haemodynamic response to hypoxia were studied in nine anaesthetized dogs under hypoxaemia induced by ventilation with hypoxic gas mixture. 2. From the present study, only dopamine infusion reduced arterial oxygenation during hypoxic hypoxaemia, whereas catecholamine maintained it at the same level during normoxaemia. 3. A redistribution of perfusion to the pulmonary vasculature may be related to a reduction of arterial oxygenation with dopamine infusion during hypoxic hypoxaemia. 4. It is presumed that an increase in pulmonary blood flow would emphasize an inhibition of hypoxic pressor response in the pulmonary vasculature, which may not be a direct effect of dopamine.     

INFLUENCE OF BODY TEMPERATURE ON RESPONSES TO HYPOXIA AND HYPERCAPNIA: IMPLICATIONS FOR SIDS

1. This paper reviews current knowledge regarding interactions between body temperature and the respiratory responses to hypoxia and/or hypercapnia, with special emphasis on how these interactions might predispose towards sudden infant death syndrome (SIDS). 2. Use has been made of an adult rat model in which body core temperature is fixed by means of an intra-abdominal heat exchanger. Initial studies indicated that hyperthermia (T_b～ 41° C) enhanced the ventilatory response to hypercapnia, whereas hypothermia (T_b～35°C) interacted with hypoxia to depress respiration. 3. Studies involving hypothalamic lesions in urethane-anaesthetized rats have implicated the posterior hypothalamic area in the hypoxia/hypothermia interaction. Further studies are directed towards examining the role played by more caudal areas, including the raphe nuclei. 4. It has been shown that not only does the hypoxial hypothermia interaction depress breathing but it also reduces, or sometimes eliminates, the ventilatory response to hypercapnia, which under normal circumstances provides one of the most powerful excitatory inputs to the respiratory centres. This implies that an expected reversal of the respiratory depression by build up of CO₂ levels may not occur, which in turn has important implications for SIDS. 5. The literature dealing with the effects of hyperthermia on hypoxic and hypercapnic responses is also reviewed. It is concluded that environmental heat stress may only become a significant problem when it accompanies a febrile infection, under which circumstances it may seriously compromise thermo-regulatory ability and alter breathing responses to chemical stimuli.     

EFFECTS OF NEUROTOXIN-INDUCED BRAINSTEM LESIONS ON THE RESPIRATORY RESPONSES OF CONSCIOUS RATS

Respiration was recorded in unanaesthetized rats breathing air, or CO2 in air, 4-8 days after injection into the rostral brainstem at the level of the dorsal raphe nucleus of either a catecholaminergic neurotoxin, a serotoninergic neurotoxin, or the vehicle (0.5% ascorbic acid) of these drugs. Some rats were pretreated with the noradrenergic neurone protecting agent, desmethylimipramine (DMI). Vehicle injection resulted in an increase in the frequency (f) sensitivity to CO2. In two of four cases, injection of 6-hydroxydopamine caused a similar response but in the remaining cases injections caused increases in inspiratory duration (TI), expiratory duration (TE) and tidal volume (VT) during air-breathing. The serotonergic neurotoxin, 5,7-dihydroxytryptamine, reduced the frequency sensitivity to CO2 significantly. This reduction was not sustained. In all cases air-breathing f was decreased due to a prolongation of TI; in most cases air-breathing VT was increased. The characteristic effect of midline 5,7-dihydroxytryptamine lesions was an increase in the VT sensitivity to CO2. On the basis of the results, it is proposed that noradrenaline is essential to the processes determining basic respiratory rhythm, whereas dopamine and serotonin are important inhibitors in chemoreflex ventilatory patterns.     

EFFECTS OF RESERPINE ON THE CONTENT AND UPTAKE OF DOPAMINE AND NORADRENALINE IN RABBIT ARTERIES

1. Change with time of the content and uptake of dopamine (DA) and noradrenaline (NA) in the renal, superior mesenteric and femoral arteries and abdominal aorta of rabbit after reserpine administration was examined. Endogenous DA and NA were measured by high performance liquid chromatography coupled with electrochemical detector. 2. A single dose of reserpine (3 mg/kg, i.p.) maximally depleted the endogenous DA and NA contents in the four blood vessels 24 h after the administration; the ratios of reductions were 70–90% and approximately 90% of the normal levels, respectively. The DA contents in all four vessels recovered to the normal level within 4 days after reserpine. However, NA content did not recover to the normal levels within 30 days after reserpine except in the mesenteric artery. 3. The activity of dopamine β-hydroxylase (DBH) significantly increased in all four blood vessels 1 h after reserpine. Although the DBH activity returned to the normal level after 3 days in the mesenteric artery, it returned within 24 h in the other three vessels. 4. [³H]-Dopamine and [³H]-NA uptake were almost completely depressed 1 h after reserpine. The [³H]-NA uptake in four vessels recovered to the normal level 2–14 days after reserpine, and [³H]-DA uptake recovered after 30–45 days. Thus, the endogenous DA content in blood vessels was completely restored although DA uptake and NA content were still affected. 5. These results suggested that the recovery of stored DA after reserpine was faster than that of stored NA and the recovery of DA uptake after reserpine was slower than NA uptake. This indicates a possibility that a part of DA pool may be different from NA pool in adrenergic nerve terminals in the blood vessels.     

BODY GROWTH AND POLYCYTHAEMIA IN HYPOXIC ALBINO RATS OF FIRST AND SECOND GENERATION

1. In our study we followed the growth rate and the haematologic changes occurring in albino rats of Wistar strain when living in a hypoxic environment. Two generations of hypoxic rats were observed for changes in their erythrocytes (RBC), haematocrit (Hct) and haemoglobin (Hb): the first generation (H1) and the second generation (H2). A few hours after birth, the H1 rats were placed and raised in a normobaric hypoxic environment (10% O2 in N2). The H2 rats were born and raised in the environment previously described. The control group had a normoxic environment. The H1 and H2 rats had inferior growth rates in respect to their controls, but H2 were found to have a larger growth rate than the H1 group. The RBC, Hct and Hb had values significantly greater for both H1 and H2 when compared with their controls. However, we did find that the values of H2 were significantly lower than H1. We believe that these results are in relation to the degree of development of the adaptive processes to the hypoxic environment of the H2 rats.     

EFFECTS OF CLONIDINE ON VASCULAR RESPONSES IN KIDNEY AND HINDLIMBS OF CATS

1. Cardiovascular reflexes to intravenous adrenaline and histamine and to carotid occlusion were studied in the renal vasculature, and direct effects of nor-adrenaline and clonidine were compared in renal and hindlimb vascular beds in anaesthetized cats. 2. Unlike its reported effects on cardiovascular reflexes in the hindlimbs, clonidine depressed all three reflexes in the kidneys. 3. Noradrenaline caused vasoconstriction when given directly into both renal and hindlimb circulations, but clonidine produced vasoconstriction only in the hindlimb vascular bed. 4. These results suggest that α-adrenoceptors in the renal vasculature may be different from those in the hindlimbs, and that the cardiovascular reflexes in these two areas are under different control.     

CARDIORESPIRATORY AND RENAL RESPONSES TO ARTERIAL CHEMORECEPTOR STIMULATION BY HYPOXIA OR ALMITRINE IN MEN

1. The cardiorespiratory and renal responses to 3h of normobaric whole-body hypoxic hypoxia (F¹O²= 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls. 2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole-body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant. 3. Renal fractional lithium excretion decreased significantly in response to whole-body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes. 4. The data indicate that, in humans, both almitrine and whole-body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics. 5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well-tolerated, whole-body hypoxic hypixia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.     

EFFECTS OF DOPAMINE ON RENAL FUNCTION IN THE RAT ISOLATED PERFUSED KIDNEY

The renal effects of dopamine, the dopamine antagonist spiperone and the combination of dopamine and spiperone were examined in the isolated perfused rat kidney preparation. Studies were carried out at constant perfusion pressure and the following were measured at 10 min intervals for 1 h: perfusate flow; GFR (3H-inulin); urine flow rate; sodium, potassium and kallikrein excretion; perfusate renin concentration; perfusate and urinary-dopamine levels. Low-dose dopamine infusion (6 X 10(-10) mol/min) resulted in significant diuresis, natriuresis and kaluresis but little change in GFR. These effects were blocked by spiperone (10(-10) mol/min) which had no significant effects when infused alone. At a higher dose (10(-8) mol/min) dopamine significantly increased urine flow alone; this too was reversed by spiperone. Dopamine had no significant effects on perfusate flow, renin release or kallikrein excretion. Perfused control kidneys excreted amounts of dopamine (328 pmol/h, s.e.m. = 57, n = 6) far in excess of kidney dopamine content (49 pmol/g, s.e.m. = 6, n = 32). Renal handling of infused dopamine was dose-related; the fraction of the administered dose taken up and/or metabolized by the kidney on the higher dose infusion was considerably less than on the lower dose (40%, s.e.m. = 3 vs. 82%, s.e.m. = 6) while more was excreted (13%, s.e.m. = 3 vs. 2%, s.e.m. = 1). These studies indicate that dopamine at low doses can produce diuresis, natriuresis and kaluresis independently of extrarenal or haemodynamic influences and not mediated by renal renin or kallikrein systems. The kidney also exhibits a saturable capacity for dopamine uptake and/or metabolism.     

ACTION OF ALMITRINE BISMESYLATE ON VENTILATION-PERFUSION MATCHING IN CATS AND DOGS WITH PART OF THE LUNG HYPOVENTILATED

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.     

EFFECTS OF CALCITONIN ON THE SECRETION OF PANCREATIC JUICE INDUCED BY DOPAMINE, SECRETIN AND PANCREOZYMIN

1. Effects of calcitonin on dopamine-, secretin- and pancreozymin-induced pancreatic secretion were investigated in the isolated blood-perfused canine pancreas. 2. The volume of pancreatic secretion induced by pancreozymin given intra-arterially (i.a.) was decreased by an i.a. infusion of 1 u/min of calcitonin, but that induced by dopamine or secretin given i.a. was not affected by calcitonin treatment. 3. Amylase concentration in pancreatic juice either in spontaneous secretion in the resting state or in that of stimulated secretion by pancreozymin was decreased approximately 30% by calcitonin treatment, but amylase concentration in pancreatic juice induced by dopamine or secretin was not affected by calcitonin treatment. 4. Calcitonin had no effect on bicarbonate concentration in pancreatic juice stimulated by these secretagogues. 5. Calcium concentration in pancreatic juice in the resting state was reduced about 36% by calcitonin treatment. Calcitonin caused a decrease in a calcium concentration in the pancreozymin-induced secretion, but did not cause any change in the dopamine- or secretin-induced one. 6. These results suggest that calcitonin may affect the secretory mechanism of the acinar cells but not that of the ductular cells, and that the acinar cells are active even in the resting state.     

VASODILATORY EFFECTS OF MILRINONE ON PULMONARY VASCULATURE IN DOGS WITH PULMONARY HYPERTENSION DUE TO PULMONARY EMBOLISM: A COMPARISON WITH THOSE OF DOPAMINE AND DOBUTAMINE

1. The limited therapeutic role of pulmonary vasodilation reflects lack of their selectivity for the pulmonary vasculature, and many drugs have been evaluated for effectiveness; however, none has gained widespread clinical use. 2. Milrinone (MIL) is a newly synthetized phosphodiesterase inhibitor, which has potent positive inotropic and vasodilatory effects. 3. The present study shows the effects of MIL on the pulmonary circulation in dogs with pulmonary hypertension due to autologous muscle-induced pulmonary embolism, and also demonstrates a comparison with those of dopamine and dobutamine. 4. As MIL showed potent vasodilatory effects on the pulmonary vasculature, it had a potential clinical role in the treatment of pulmonary hypertension.     

EFFECTS OF PHENOXYBENZAMINE ON RESPONSES TO SOME RECEPTOR AGONISTS AND CALCIUM IN VITRO

Noradrenaline-induced contractions of the rabbit and rat isolated aorta and guinea-pig spleen strips were inhibited by concentrations of phenoxybenzamine which did not affect responses to calcium. This may suggest a specific action on alpha-adrenoceptors. However, analysis of noradrenaline concentration-effect curves in guinea-pig spleen indicated that 1 mumol/l phenoxybenzamine should have reduced the available receptor population to 6% of control, but data from radioligand binding experiments on the same tissues using [3H]-prazosin indicated a reduction of the receptor population to only 82% of control. The reduced responsiveness observed in the organ bath study after phenoxybenzamine pretreatment, whilst not apparently related to effects on voltage-dependent calcium channels, could be due to the actions of phenoxybenzamine on other (non-receptor) processes such as receptor-operated calcium channels. Maximal contractile responses to histamine in rabbit isolated aorta but not those in guinea-pig isolated ileal preparations, were depressed by concentrations of phenoxybenzamine which depressed responses to calcium. Phenoxybenzamine produced parallel rightward shifts of curves to carbachol in guinea-pig ileal preparations but only depressed maximal responses to the agonist in higher concentrations which reduced responses to calcium. On the basis of the results obtained with calcium it is possible that the effects of phenoxybenzamine on receptor-mediated responses could be produced through the actions of this antagonist at less specific sites such as voltage-dependent calcium channels for histamine in rabbit aorta and carbachol in guinea-pig ileum. For alpha-receptor mediated responses in aortic and splenic strip preparations and for histamine-mediated responses in guinea-pig ileum, the actions of phenoxybenzamine may reflect an interaction of the antagonist with receptor-operated calcium channels.     

A COMPARISON OF THE CARDIAC ACTIONS OF DOPAMINE AND NORADRENALINE IN ANAESTHETIZED DOGS AND GUINEA-PIG ATRIA

1. The positive chronotropic and inotropic actions of dopamine and noradrena-line have been compared in anaesthetized dogs and isolated guinea-pig atria. 2. Inotropic activity was measured with a strain-gauge arch in vagotomized dogs or estimated from max (dp/dt) in dogs with denervated hearts. 3. The effects of propranolol and haloperidol on the concentration-response curves to both amines were studied in isolated atria. 4. In anaesthetized vagotomized dogs noradrenaline was more potent than dopamine but dopamine appeared to have a selective inotropic action, less apparent with noradrenaline. In denervated hearts, doses of noradrenaline and dopamine which caused similar increases in max (dp/dt) also caused similar increases in heart rate. 5. In isolated atrial preparations, concentrations of dopamine and noradrenaline which produced similar increases in force of contraction also had similar chronotropic effects. 6. Propranolol produced a shift to the right of the concentration-response curves to both dopamine and noradrenaline but the antagonism of noradrenaline was quantitatively greater. Haloperidol had no effect in concentrations below those found to cause general tissue depression. 7. It is concluded that neither dopamine nor noradrenaline show any real difference in their relative inotropic and chronotropic activities in the absence of autonomic innervation.     

EFFECTS OF FIVE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON THE RENAL AND SYSTEMIC RESPONSES TO ARACHIDONATE IN CONSCIOUS DOGS

1. The effects of five different non-steroidal anti-inflammatory drugs (NSAID) on the renal blood flow responses to arachidonate were compared. 2. Arachidonate (5-200 micrograms/kg) injected into the renal arteries of conscious dogs caused dose-related renal vasodilatation with no systemic effects. 3. Aspirin (35 mg/kg), phenylbutazone (12 mg/kg) and ibuprofen (25 mg/kg) all markedly reduced arachidonate-induced renal vasodilatation. 4. In contrast, neither indomethacin (3 mg/kg) or its related drug sulindac sulphide (6 mg/kg) significantly reduced arachidonate-induced renal vasodilatation. 5. All NSAID abolished the hypotensive response to intravenous injection of arachidonate (10 mg). 6. Thus, indomethacin and sulindac did not block the effects of renal artery injections of arachidonate but did abolish the systemic effects. Aspirin, phenylbutazone and ibuprofen greatly reduced responses to both renal artery and intravenous arachidonate. 7. Indomethacin and aspirin both reduced the production of prostaglandin E2 and 6-keto-PGF1 alpha by dog renal cortical microsomes in vitro. 8. Thus, indomethacin and sulindac had different effects to other NSAID on arachidonate-induced renal vasodilatation. The results are compatible with the hypothesis that some sites of prostaglandin production in the kidneys of conscious dogs may be relatively resistant to inhibition by indomethacin and sulindac.     

EFFECT OF POSITIVE FAMILY HISTORY OF HYPERTENSION ON THE BLOOD PRESSURE AND CATECHOLAMINE RESPONSES TO A 6 HOUR ADRENALINE INFUSION

1. The effects of 6 h infusions of adrenaline (INF-A) or dextrose (INF-D) and of post-infusion cold pressor test (CPT) were compared in normal subjects, with (FH +) and without (FH -) a family history of hypertension. 2. Increased urinary excretion rates suggested facilitated noradrenaline (NA) release during and after INF-A in both FH + and FH -. 3. Urinary adrenaline (U ADR) excretion increased during INF-A, as expected, and was also slightly higher after INF-A than INF-D. 4. The effect of INF-A on systolic blood pressure (SBP) was greater in FH — than in FH S but diastolic blood pressure (DBP) did not fall as quickly with nocturnal recumbency after INF-A in FH +. 5. A significantly greater response in plasma NA to CPT was seen in FH + than in FH — after INF-A. A similar trend was also seen after INF-D. 6. Increases in DBP due to CPT were higher in FH + than in FH - after both infusions. 7. This study provides evidence of increased noradrenergic activity during and after INF-A, and also of a difference in response to sympathetic stimulation between FH + and FH -.     

丁基苯酞对低糖低氧引起神经细胞内钙升高的作用

目的:探讨抗脑缺血新药丁基苯酞(NBP) 对脑缺血过程中细胞内游离钙升高的影响及其作用机制。方法:采用低糖低氧损伤胎鼠或新生鼠神经细胞以模拟脑缺血,用Fura-2/AM 作荧光指示剂,观察手性丁基苯酞对神经细胞内游离钙升高的抑制作用,并用内钙释放剂thapsigargin,外源性谷氨酸,高K+ 及钙离子载体A23187 作工具药,对其作用环节进行分析。结果:d-,l-,dl-丁基苯酞能完全抑制低糖低氧造成的神经细胞内钙升高。手性NBP能降低thapsigargin 引起的内质网钙库释放,d-NBP 还对谷氨酸引起的内钙升高表现出抑制作用。结论:丁基苯酞抑制低糖低氧条件下神经细胞内钙升高的作用环节主要是抑制细胞内钙库的释放。     

EFFECTS OF VERAPAMIL AND DILTIAZEM ON DOPAMINE RELEASE IN THE CENTRAL NERVOUS SYSTEM OF SPONTANEOUSLY HYPERTENSIVE RATS

1. The purpose of the present study was to investigate the effects of Ca²⁺-antagonists (verapamil and diltiazem) on dopamine release in the central nervous system in hypertension. 2. Striatal slices obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were prelabelled with [³H]-dopamine, and superfused with Krebs-Ringer solution in vitro. The slices were stimulated electrically at a frequency of 1 Hz. 3. Stimulation-evoked release of [³H]-dopamine from striatal slices was significantly decreased in SHR compared with WKY rats. 4. Exposure of slices to verapamil and diltiazem significantly increased the stimulation-evoked [³H]-dopamine release. The facilitatory effects of the Ca²⁺-antagonists on dopamine release were significantly greater in SHR than in WKY rats. 5. Because central nervous system dopaminergic mechanisms appear to be depressor, the results suggest that the pronounced effects of verapamil and diltiazem on dopamine release in SHR might be involved in the central hypotensive mechanisms of the Ca²⁺-antagonists.     

INTERACTIONS BETWEEN THE CIRCULATORY EFFECTS OF CENTRAL HYPOVOLAEMIA AND ARTERIAL HYPOXIA IN CONSCIOUS RABBITS

1. Eight conscious rabbits were repeatedly subjected to progressive reduction in central blood volume by gradually inflating a thoracic inferior vena caval-cuff so cardiac index (CI) fell at a constant 8.5% of baseline/min. 2. Caval-cuff inflations were performed after 10 min exposure to 100, 21, 12–14 and 8–10% O₂, with and without the addition of 3–4% CO₂, in randomized order. 3. The haemodynamic response to progressive reduction in central blood volume was biphasic. In Phase I, systemic vascular conductance index (SVCI) fell linearly, supporting mean arterial pressure (MAP). When CI had fallen to a critical level, Phase II occurred in which SVCI rose abruptly, MAP plummeted and respiratory drive progressively increased. 4. During Phase I, there were independent linear relationships between Pao₂ (but not Pao₂) and the rates at which SVCI and MAP changed during the progressive fall of CI. The higher the level of Pao₂, the greater was the rate of fall of SVCI and the less the rate of fall of MAP. 5. There was an inverted U-shaped effect of Pao₂, on the level of CI at which Phase II occurred: (a) during hyperoxia (100% O₂), Phase II occurred later than during normoxia (21% O₂); and (b) across the normoxic and hypoxic gas mixtures (21–8% O₂, with and without added CO₂), there was an independent linear relationship between Pao₂ (but not Pao₂ or Pao₂×Pao₂) and the level of CI at which Phase II occurred. That is, the lower the level of Pao₂, the later was the onset of Phase II. This interaction is best explained by an increased level of central sympathetic vasoconstrictor drive during hypoxia.     

中国萝芙木碱Verticillatine对麻醉狗和猫心功能与血流动力学的影响

Verticillatine(Vt)0.5～1.0mg/kg iv,能使麻醉狗的血压下降,心率减慢,cl,LVSP LV dp/dt max,LVWI,TPR降低,作用随剂量增加而加强。冠脉阻力稍降低,但心肌氧利用率和氧耗减少。颈内动脉和股动脉血流增加,阻力减少。给麻醉猫iv Vt和六羟季铵1.0 mg/kg后,BP,LVP和LV dp/dt max降低,但LV dp/dt/p和LVEDP无明显变化。说明Vt能降低心脏后负荷,对前负荷无明显影响。