Regional hemodynamic responses to nicotine in conscious and anesthetized dogs: comparative effects of pentobarbital and chloralose

This study was conducted in 12 dogs to evaluate regional hemodynamic responses during intravenous infusion of nicotine (36 micrograms/kg/min) in the conscious state and compare them with those in the same dogs following either pentobarbital (n = 6) or chloralose anesthesia (n = 6). Values for regional blood flow were obtained with 15-microns radioactive microspheres and used to calculate regional vascular conductance. In the conscious state, nicotine increased aortic pressure (+70%) and caused hyperventilation that reduced arterial PCO2 (-44%). These systemic effects were associated with decreases in vascular conductance in the renal cortex (-48%), pancreas (-81%), duodenum (-58%), and cerebral cortex (-55%), whereas no significant change in vascular conductance was evident in spleen, liver, or myocardium. Pentobarbital anesthesia blunted the increases in aortic pressure and respiratory activity and the reductions in vascular conductance in the renal cortex, pancreas, duodenum, and cerebral cortex during nicotine infusion. In contrast, chloralose anesthesia accentuated the increase in aortic pressure and the decrease in vascular conductance in the renal cortex during nicotine infusion, while it converted no change in vascular conductance in the spleen into a decrease and no change in vascular conductance in the myocardium into an increase. Chloralose anesthesia blunted nicotine-induced hyperventilation. These findings demonstrate that general anesthetic agents may have markedly different effects on cardiovascular reflex pathways. They emphasize the importance of considering the particular characteristics of the anesthetic agent used in interpreting results from studies of cardiovascular pharmacology and physiology in anesthetized animals.     

Ventilatory responses to specific CNS hypoxia in sleeping dogs.

Our study was concerned with the effect of brain hypoxia on cardiorespiratory control in the sleeping dog. Eleven unanesthetized dogs were studied; seven were prepared for vascular isolation and extracorporeal perfusion of the carotid body to assess the effects of systemic [and, therefore, central nervous system (CNS)] hypoxia (arterial PO(2) = 52, 45, and 38 Torr) in the presence of a normocapnic, normoxic, and normohydric carotid body during non-rapid eye movement sleep. A lack of ventilatory response to systemic boluses of sodium cyanide during carotid body perfusion demonstrated isolation of the perfused carotid body and lack of other significant peripheral chemosensitivity. Four additional dogs were carotid body denervated and exposed to whole body hypoxia for comparison. In the sleeping dog with an intact and perfused carotid body exposed to specific CNS hypoxia, we found the following. 1) CNS hypoxia for 5-25 min resulted in modest but significant hyperventilation and hypocapnia (minute ventilation increased 29 +/- 7% at arterial PO(2) = 38 Torr); carotid body-denervated dogs showed no ventilatory response to hypoxia. 2) The hyperventilation was caused by increased breathing frequency. 3) The hyperventilatory response developed rapidly (<30 s). 4) Most dogs maintained hyperventilation for up to 25 min of hypoxic exposure. 5) There were no significant changes in blood pressure or heart rate. We conclude that specific CNS hypoxia, in the presence of an intact carotid body maintained normoxic and normocapnic, does not depress and usually stimulates breathing during non-rapid eye movement sleep. The rapidity of the response suggests a chemoreflex meditated by hypoxia-sensitive respiratory-related neurons in the CNS.     

Hypothermia and hypoxia inhibit the Hering-Breüer reflex in the marsupial newborn

The effects of lowering body temperature (T(b)) on metabolic rate, ventilation, and the strength of the Hering-Breüer expiratory promoting reflex (HB reflex; determined from an inhibitory ratio calculated from volumetric measurements of the respiratory rhythm) were examined in 18-day-old ectothermic pouch young of the tammar wallaby during normoxia or hypoxia (10% O(2)). Hypoxia and hypothermia, either singularly or combined, depressed metabolic rate. At all T(b), the hypoxic hyperventilation was associated with a significant hyperpnea. At pouch T(b) (36.5 degrees C) during normoxia, inflation of the lungs with -5 or -10 cmH(2)O extrathoracic pressure induced a significant HB reflex. Exposure to cold reduced the strength of the reflex, almost abolishing it at 28 degrees C. For T(b) above 28 degrees C, the reflex in hypoxia was always less than the corresponding normoxic value. Taken in context with the changes in metabolic state that occurred, these data in the ectothermic marsupial newborn suggest that the decline in the HB reflex during moderate hypothermia is the result of a direct effect of T(b) on vagal mechanisms rather than a temperature-driven decline in metabolic rate that should have acted to strengthen the HB reflex. Therefore, it seems that inputs inhibitory to breathing are more negatively affected during cold than those inputs that are excitatory.     

Renal responses to acute reflex activation of renal sympathetic nerve activity and renal denervation in secondary hypertension

We tested whether the responsiveness of the kidney to basal renal sympathetic nerve activity (RSNA) or hypoxia-induced reflex increases in RSNA, is enhanced in angiotensin-dependent hypertension in rabbits. Mean arterial pressure, measured in conscious rabbits, was similarly increased (+16 +/- 3 mmHg) 4 wk after clipping the left (n = 6) or right (n = 5) renal artery or commencing a subcutaneous ANG II infusion (n = 9) but was not increased after sham surgery (n = 10). Under pentobarbital sodium anesthesia, reflex increases in RSNA (51 +/- 7%) and whole body norepinephrine spillover (90 +/- 17%), and the reductions in glomerular filtration rate (-27 +/- 5%), urine flow (-43 +/- 7%), sodium excretion (-40 +/- 7%), and renal cortical perfusion (-7 +/- 3%) produced by hypoxia were similar in normotensive and hypertensive groups. Hypoxia-induced increases in renal norepinephrine spillover tended to be less in hypertensive (1.1 +/- 0.5 ng/min) than normotensive (3.7 +/- 1.2 ng/min) rabbits, but basal overflow of endogenous and exogenous dihydroxyphenolglycol was greater. Renal plasma renin activity (PRA) overflow increased less in hypertensive (22 +/- 29 ng/min) than normotensive rabbits (253 +/- 88 ng/min) during hypoxia. Acute renal denervation did not alter renal hemodynamics or excretory function but reduced renal PRA overflow. Renal vascular and excretory responses to reflex increases in RSNA induced by hypoxia are relatively normal in angiotensin-dependent hypertension, possibly due to the combined effects of reduced neural norepinephrine release and increased postjunctional reactivity. In contrast, neurally mediated renin release is attenuated. These findings do not support the hypothesis that enhanced neural control of renal function contributes to maintenance of hypertension associated with activation of the renin-angiotensin system.     

Recovery of impaired respiratory activity in cats by thyroliberin analog (PR-546) devoid of hormonal properties

Synthetic analogue thyroliberin (PR-546) devoid of hormonal activity, recovered respiration in conditions of hyperventilation, two-sided vagotomy and hypoxia, caused by the 40-70% bleeding. PR-546 (in doses 100-500 micrograms/kg) intravenously injected was shown to abolish diagram activity decreased effect after hyperventilation. Injection of PR-546 to vagotomized cats in 1.5-2 h, increased breathing rate. The breathing activity resumed after long breaks in respiration as a result of peptide injection. The responses to analogue introductions is similar to the thyroliberin effect.     

Differential control of intrarenal blood flow during reflex increases in sympathetic nerve activity

The role of renal sympathetic nerve activity (RSNA) in the physiological regulation of medullary blood flow (MBF) remains ill defined, yet regulation of MBF may be crucial to long-term arterial pressure regulation. To investigate the effects of reflex increases in RSNA on intrarenal blood flow distribution, we exposed pentobarbital sodium-anesthetized, artificially ventilated rabbits (n = 7) to progressive hypoxia while recording RSNA, cortical blood flow (CBF), and MBF using laser-Doppler flowmetry. Another group of animals with denervated kidneys (n = 6) underwent the same protocol. Progressive hypoxia (from room air to 16, 14, 12, and 10% inspired O(2)) significantly reduced arterial oxygen partial pressure (from 99 +/- 3 to 65 +/- 2, 51 +/- 2, 41 +/- 1, and 39 +/- 2 mmHg, respectively) and significantly increased RSNA (by 8 +/- 3, 44 +/- 25, 62 +/- 21, and 76 +/- 37%, respectively, compared with room air) without affecting mean arterial pressure. There were significant reductions in CBF (by 2 +/- 1, 5 +/- 2, 11 +/- 3, and 14 +/- 2%, respectively) in intact but not denervated rabbits. MBF was unaffected by hypoxia in either group. Thus moderate reflex increases in RSNA cause renal cortical vasoconstriction, but not at vascular sites regulating MBF.     

Respiratory and circulatory activities in carotid body-resected humans.

The respiratory and circulatory activities of patients who underwent carotid body resection (CBR) more than two decades ago were reviewed. No significant ventilatory response to continuous hypoxia was observed. However, in response to stimulation of peripheral chemoreceptors, transient hyperventilation occurred before hypoxemic blood arrived at the central nervous system (single-breath test), which indicated the presence of weak peripheral chemosensitivity. Because of this slight residual peripheral chemosensitivity, which was found shortly after the operation and apparently remained more or less unchanged for greater than 20 years, peripheral chemoreceptor activity, which has been reported in other animal species, does not seem to have returned. Delayed hypoxic hyperventilation reported in dogs and cats with CBR was not observed. Hypoxia significantly depressed the ventilatory response to CO2, but the delayed ventilatory depression with time that has been demonstrated in normal subjects did not occur. In our circulatory studies, hypoxia augmented the heart rate and slightly depressed the stroke volume and total peripheral resistance in the systemic circulation but induced no appreciable changes in arterial blood pressure or cardiac output. We used these results to partition the relative contributions to the overall circulatory response of carotid body stimulation, pulmonary inflation, and other modifying influences. From these calculations, it was inferred that the carotid body reflex plays a dominant role in vascular activities whereas the pulmonary inflation reflex dominates in cardiac activities in humans.     

Low sodium intake does not impair renal compensation of hypoxia-induced respiratory alkalosis.

Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.     

Hering-Breuer reflex in conscious newborn rats: effects of changes in ambient temperature during hypoxia.

In a previous study in conscious normoxic newborn rats, we found that the strength of the Hering-Breuer reflex (HB reflex) was greater (188%) at high (36 degrees C) than at low (24 degrees C) ambient temperature (T(a); D. Merazzi and J. P. Mortola. Pediatr. Res. 45: 370-376, 1999). We now asked what the effect would be of changes in T(a) during hypoxia. Rat pups at 3-4 days of age were studied in a double-chamber airflow plethysmograph. The HB reflex was induced by negative body surface pressures of 5 or 10 cmH(2)O and quantified from the inhibition of breathing during maintained lung inflation. Rats were first studied at T(a) = 32 degrees C in normoxia, followed by hypoxia (10% O(2) breathing). During hypoxia, oxygen consumption (VO(2)) averaged 47%, and HB reflex 115%, of the corresponding normoxic values, confirming that in the newborn, differently from the adult, hypoxia does not decrease the strength of the HB reflex. As hypoxia was maintained, lowering T(a) to 24 degrees C or increasing it to 36 degrees C, on average, had no significant effects on VO(2) and the HB reflex. However, with 5-cmH(2)O inflations, the HB reflex during the combined hypoxia and hyperthermia was significantly stronger than in normoxia. We conclude that in conscious newborn rats during normoxia the T(a) sensitivity of the HB reflex is largely mediated by the effects of T(a) on thermogenesis and VO(2); in hypoxia, because thermogenesis is depressed and VO(2) varies little with T(a), the HB reflex is T(a) independent. The observation that the reflex response to lung inflations during hypoxic hyperthermia can be greater than in normoxia may be of importance in the pathophysiology of apneas during the neonatal period.     

Influence of the stimulation of carotid body chemoreceptors on the gastric mucosal blood flow in artificially ventilated and spontaneously breathing rats.

The cardiovascular effects of the stimulation of arterial chemoreceptors are different in spontaneously breathing and artificially ventilated animals. Respiratory failure and long term sojourn at high altitude coincide frequently with the occurrence of gastric ulceration. In both these situations a profound stimulation of arterial chemoreceptors is present. The purpose of the paper was to investigate the reflex effect of stimulation carotid chemoreceptors on gastric mucosal blood flow in the rat. Arterial chemoreceptors were stimulated by two methods (I) substitution gas mixture of 10% oxygen in nitrogen for room air and (II) direct injection of acid saline ( 0.05 ml, pH = 6.8) into the distal part of left common carotid artery. In artificially ventilated rats stimulation of arterial chemoreceptors caused significant increase in gastric mucosal vascular resistance, accompanied by marked decline in blood flow. This effect was mediated by adrenergic mechanism. On the contrary to artificially ventilated rats, decline of gastric mucosal vascular resistance with concomitant increase in blood flow was found in spontaneously breathing animals. This effect was not abolished either by phentolamine or atropine. As vasodilatatory effect of arterial chemoreceptors stimulation was abolished by bilateral vagotomy, we postulate that non adrenergic and non cholinergic vagal fibers mediate observed vascular changes in gastric mucosa in spontaneously breathing rats. We hypothesize that in artificially ventilated patients with respiratory failure stimulation of arterial chemoreceptors by hypoxemia and or acidosis may contribute to the development of gastric mucosal lesions.     

Possible mechanisms of periodic breathing during sleep

To determine the effect of respiratory control system loop gain on periodic breathing during sleep, 10 volunteers were studied during stage 1-2 non-rapid-eye-movement (NREM) sleep while breathing room air (room air control), while hypoxic (hypoxia control), and while wearing a tight-fitting mask that augmented control system gain by mechanically increasing the effect of ventilation on arterial O2 saturation (SaO2) (hypoxia increased gain). Ventilatory responses to progressive hypoxia at two steady-state end-tidal PCO2 levels and to progressive hypercapnia at two levels of oxygenation were measured during wakefulness as indexes of controller gain. Under increased gain conditions, five male subjects developed periodic breathing with recurrent cycles of hyperventilation and apnea; the remaining subjects had nonperiodic patterns of hyperventilation. Periodic breathers had greater ventilatory response slopes to hypercapnia under either hyperoxic or hypoxic conditions than nonperiodic breathers (2.98 +/- 0.72 vs. 1.50 +/- 0.39 l.min-1.Torr-1; 4.39 +/- 2.05 vs. 1.72 +/- 0.86 l.min-1.Torr-1; for both, P less than 0.04) and greater ventilatory responsiveness to hypoxia at a PCO2 of 46.5 Torr (2.07 +/- 0.91 vs. 0.87 +/- 0.38 l.min-1.% fall in SaO2(-1); P less than 0.04). To assess whether spontaneous oscillations in ventilation contributed to periodic breathing, power spectrum analysis was used to detect significant cyclic patterns in ventilation during NREM sleep. Oscillations occurred more frequently in periodic breathers, and hypercapnic responses were higher in subjects with oscillations than those without. The results suggest that spontaneous oscillations in ventilation are common during sleep and can be converted to periodic breathing with apnea when loop gain is increased.     

Brain hypoxia and control of breathing: neuromechanical control

The effects of graded brain hypoxia on respiratory cycle timing, the lung inflation reflex, and respiratory compensation for an inspiratory flow-resistive load were studied in unanesthetized goats. Two models, inhalation and CO and acute reduction of brain blood flow (BBF) were used to produce comparable levels of brain hypoxia. The lung inflation reflex was assessed as the ratio of inspiratory time of an occluded breath to that of the preceding spontaneous breath (TIoccl/TIspont). Compensation for flow-resistive loading was assessed as the effect of the load upon the airway occlusion pressure response to rebreathing CO2 (delta P 0.1/delta PCO2). Major findings were 1) severe brain hypoxia (HbCO of 60% or BBF of 42%) caused tachypnea due to a 50% or more reduction of expiratory time but only a 20% or less reduction of inspiratory time; 2) moderate carboxyhemoglobinemia (HbCO of 25-30%) enhanced TIoccl/TIspont from 1.5 +/- 0.1 at control to 2.1 +/- 0.1, while severe brain hypoxia (HbCO of 60% and BBF of 42%) reduced the ratio to 1.0 +/- 0.2; and 3) compensation for a flow-resistive load, manifested by increases of delta P 0.1/delta PCO2 of 75-300% in the control state, was abolished at HbCO of 45-50% and BBF of 60%. The data suggest that in unanesthetized animals brain hypoxia elicits tachypnea largely by an effect on the expiratory phase of the bulbopontine timing mechanism. The observed enhancement of the lung inflation reflex and abolition of flow-resistive load compensation are best explained by hypoxic depression of higher than brain stem neural function.     

Effects of hypoxia on genioglossus and scalene reflex responses to brief pulses of negative upper-airway pressure during wakefulness and sleep in healthy men.

Hypoxia can depress ventilation, respiratory load sensation, and the cough reflex, and potentially other protective respiratory reflexes such as respiratory muscle responses to increased respiratory load. In sleep-disordered breathing, increased respiratory load and hypoxia frequently coexist. This study aimed to examine the effects of hypoxia on the reflex responses of 1) the genioglossus (the largest upper airway dilator muscle) and 2) the scalene muscle (an obligatory inspiratory muscle) to negative-pressure pulse stimuli during wakefulness and sleep. We hypothesized that hypoxia would impair these reflex responses. Fourteen healthy men, 19-42 yr old, were studied on two separate occasions, approximately 1 wk apart. Bipolar fine-wire electrodes were inserted orally into the genioglossus muscle, and surface electrodes were placed overlying the left scalene muscle to record EMG activity. In random order, participants were exposed to mild overnight hypoxia (arterial oxygen saturation approximately 85%) or medical air. Respiratory muscle reflex responses were elicited via negative-pressure pulse stimuli (approximately -10 cmH(2)O at the mask, 250-ms duration) delivered in early inspiration during wakefulness and sleep. Negative-pressure pulse stimuli resulted in a short-latency activation followed by a suppression of the genioglossus EMG that did not alter with hypoxia. Conversely, the predominant response of the scalene EMG to negative-pressure pulse stimuli was suppression followed by activation with more pronounced suppression during hypoxia compared with normoxia (mean +/- SE suppression duration 64 +/- 6 vs. 38 +/- 6 ms, P = 0.006). These results indicate differential sensitivity to the depressive effects of hypoxia in the reflex responsiveness to sudden respiratory loads to breathing between these two respiratory muscles.     

Effect of aortic balloon inflation on ventilation and brain stem blood flow in piglets

Increases in brain stem blood flow (BBF) during hypoxia may decrease tissue PCO2/[H+], causing minute ventilation (VE) to decrease. To determine whether an increase in BBF, isolated from changes in arterial PO2 and PCO2, can affect respiration, we obstructed the thoracic aorta with a balloon in 31 intact and 24 peripherally chemobarodenervated, anesthetized, spontaneously breathing newborn piglets. Continuous measurements of cardiorespiratory variables were made before and during 2 min of aortic obstruction. Radiolabeled microspheres were used to measure BBF before and approximately 30 s after balloon inflation in eight intact and five denervated animals. After balloon inflation, there was a rapid increase in mean blood pressure in both the intact and denervated animals, followed within 10 s by a decrease in tidal volume and VE. In the intact animals, the decrease in VE after acute hypertension can be ascribed to a baroreceptor-mediated reflex. After peripheral chemobarodenervation, however, acute hypertension continued to produce a decrease in VE, which cannot be explained by baroreceptor stimulation. In these denervated animals, aortic balloon inflation was associated with an increase in BBF (13.1 +/- 2.7%; P less than 0.05). We speculate that the increase in BBF during hypoxia may contribute to the decrease in ventilation observed after carotid body denervation.     

Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs.

Acute hypoxia increases pulmonary arterial pressure and vascular resistance. Previous studies in isolated smooth muscle and perfused lungs have shown that carbonic anhydrase (CA) inhibition reduces the speed and magnitude of hypoxic pulmonary vasoconstriction (HPV). We studied whether CA inhibition by acetazolamide (Acz) is able to prevent HPV in the unanesthetized animal. Ten chronically tracheotomized, conscious dogs were investigated in three protocols. In all protocols, the dogs breathed 21% O(2) for the first hour and then 8 or 10% O(2) for the next 4 h spontaneously via a ventilator circuit. The protocols were as follows: protocol 1: controls given no Acz, inspired O(2) fraction (Fi(O(2))) = 0.10; protocol 2: Acz infused intravenously (250-mg bolus, followed by 167 microg.kg(-1).min(-1) continuously), Fi(O(2)) = 0.10; protocol 3: Acz given as above, but with Fi(O(2)) reduced to 0.08 to match the arterial Po(2) (Pa(O(2))) observed during hypoxia in controls. Pa(O(2)) was 37 Torr during hypoxia in controls, mean pulmonary arterial pressure increased from 17 +/- 1 to 23 +/- 1 mmHg, and pulmonary vascular resistance increased from 464 +/- 26 to 679 +/- 40 dyn.s(-1).cm(-5) (P < 0.05). In both Acz groups, mean pulmonary arterial pressure was 15 +/- 1 mmHg, and pulmonary vascular resistance ranged between 420 and 440 dyn.s(-1).cm(-5). These values did not change during hypoxia. In dogs given Acz at 10% O(2), the arterial Pa(O(2)) was 50 Torr owing to hyperventilation, whereas in those breathing 8% O(2) the Pa(O(2)) was 37 Torr, equivalent to controls. In conclusion, Acz prevents HPV in conscious spontaneously breathing dogs. The effect is not due to Acz-induced hyperventilation and higher alveolar Po(2), nor to changes in plasma endothelin-1, angiotensin-II, or potassium, and HPV suppression occurs despite the systemic acidosis with CA inhibition.     

Factors that render the kidney susceptible to tissue hypoxia in hypoxemia

To better understand what makes the kidney susceptible to tissue hypoxia, we compared, in the rabbit kidney and hindlimb, the ability of feedback mechanisms governing oxygen consumption (Vo(2)) and oxygen delivery (Do(2)) to attenuate tissue hypoxia during hypoxemia. In the kidney (cortex and medulla) and hindlimb (biceps femoris muscle), we determined responses of whole organ blood flow and Vo(2), and local perfusion and tissue Po(2), to reductions in Do(2) mediated by graded systemic hypoxemia. Progressive hypoxemia reduced tissue Po(2) similarly in the renal cortex, renal medulla, and biceps femoris. Falls in tissue Po(2) could be detected when arterial oxygen content was reduced by as little as 4-8%. Vo(2) remained stable during progressive hypoxemia, only tending to fall once arterial oxygen content was reduced by 55% for the kidney or 42% for the hindlimb. Even then, the fall in renal Vo(2) could be accounted for by reduced oxygen demand for sodium transport rather than limited oxygen availability. Hindlimb blood flow and local biceps femoris perfusion increased progressively during graded hypoxia. In contrast, neither total renal blood flow nor cortical or medullary perfusion was altered by hypoxemia. Our data suggest that the absence in the kidney of hyperemic responses to hypoxia, and the insensitivity of renal Vo(2) to limited oxygen availability, contribute to kidney hypoxia during hypoxemia. The susceptibility of the kidney to tissue hypoxia, even in relatively mild hypoxemia, may have important implications for the progression of kidney disease, particularly in patients at high altitude or with chronic obstructive pulmonary disease.     

Tissue distribution of glycosphingolipids in a case of Fabry's disease

A survey was made of the glycolipid composition of various tissues, including liver, spleen, kidney (cortex and medulla), lymph node, pancreas, prostate gland, heart muscle, thenar muscle, gastrointestinal smooth muscle, frontal cerebral cortex, anterior thalamus, brain stem, a peripheral autonomic ganglion, and renal arterial intima and media, from a patient who died with Fabry's disease. The tissues had been fixed in formalin for 3 yr. Analytical data on trihexosyl ceramide from heart muscle and pancreas indicate a structure identical to trihexosyl ceramide from kidney: galactosylgalactosylglucosyl ceramide. Fatty acid compositions of trihexosyl ceramide and dihexosyl ceramide revealed a wide range of fatty acids, with 16:0, 18:0, 20:0, 22:0, 24:0, and 24:1 predominating. These glycolipids comprised 10-41% of the total lipid in the formalin-fixed organs studied. Trihexosyl ceramide predominated in all tissues and was the only glycolipid found in muscle tissues, lymph node, and arterial tissues. Dihexosyl ceramide was found in kidney, pancreas, liver, spleen, and cerebral tissues. The accumulation of trihexosyl ceramide in cardiac muscle and arterial tissues may account in part for the cardiovascular complications so prominent in Fabry's disease.     

Prostaglandin E2 and thromboxane B2 levels in rats subjected to pancreas transplantation

This work undertakes the study of changes in urinary, plasmatic and tissue levels of Thromboxane B2 (TXB2) as well as in tissue Prostaglandin E2 (PGE2) after pancreas transplantation and the effect of superoxide dismutase (SOD) on these changes. For this purpose, streptozotocine induced diabetic rats were subjected to pancreas transplantation. Experimental groups were classified as follows: Group I: Control; Group II: Animals subjected to 15 min of pancreas arterial flow occlusion followed by reperfusion; Group III: Syngenic pancreas transplantation after 12 hours of organ preservation; Group IV: Same as III, but with additional SOD (13 mg/kg) pretreatment. The results indicate that significant increases of PGE2 and TXB2 levels occur as a consequence of the surgical removal, preservation and implantation of the organ. For TXB2 these increases, immediate in plasma and tissue, are not detected in urine until 24 hours after transplantation of the pancreas. The release of TXB2 and PGE2 was effectively prevented in the SOD treated group supporting the role of oxygen free radicals and lipid peroxidation in the processes of ischemia-reperfusion associated to transplantation of the pancreas.     

Plasma free fatty acids, inhibitor of extrathyroidal conversion of T4 to T3 and thyroid hormone binding inhibitor in patients with various nonthyroidal illnesses.

In order to clarify the role of free fatty acid (FFA) in thyroid hormone abnormalities in patients with nonthyroidal illness, thyroid function, FFA, inhibitor of extrathyroidal conversion of T4 to T3 (IEC) and thyroid hormone binding inhibitor (THBI) were studied in 99 patients with various nonthyroidal illnesses including diabetes mellitus (DM) (n = 35), liver cirrhosis (LC) (n = 33), chronic obstructive pulmonary disease (COPD) (n = 17) and chronic heart failure (CHF) (n = 14). Patients were divided into three groups based on the level of serum T3: Group I (T3 < 50 ng/dl), Group II (50 < or = T3 < 80) and Group III (80 < or = T3). Serum T4, FT3 and the T3/T4 ratio decreased significantly in the order Group III, Group II and Group I (Group III > II > I). The plasma FFA level was 0.91 +/- 0.12 mmol/l in Group I (P < 0.05, vs. Group III), 0.65 +/- 0.06 in Group II and 0.54 +/- 0.04 in Group III, respectively. The incidence of positive IEC was 80.0% in Group I (P < 0.05, vs. Group III), 53.7% in Group II (P < 0.05, vs. Group III) and 34.2% in Group III. However, IEC was not correlated with the serum T3 concentration. The incidence of positive THBI was 80% in Group I (P < 0.05, vs. Group III), 68.3% in Group II and 47.4% in Group III, but THBI was not correlated with the serum T4 level. Positive correlations were observed among FFA, IEC and THBI (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism

Mitochondria play important roles in generation of free radicals, ATP formation, and in apoptosis. We studied the levels of mitochondrial electron transport chain (ETC) complexes, that is, complexes I, II, III, IV, and V, in brain tissue samples from the cerebellum and the frontal, parietal, occipital, and temporal cortices of subjects with autism and age-matched control subjects. The subjects were divided into two groups according to their ages: Group A (children, ages 4-10 years) and Group B (adults, ages 14-39 years). In Group A, we observed significantly lower levels of complexes III and V in the cerebellum (p<0.05), of complex I in the frontal cortex (p<0.05), and of complexes II (p<0.01), III (p<0.01), and V (p<0.05) in the temporal cortex of children with autism as compared to age-matched control subjects, while none of the five ETC complexes was affected in the parietal and occipital cortices in subjects with autism. In the cerebellum and temporal cortex, no overlap was observed in the levels of these ETC complexes between subjects with autism and control subjects. In the frontal cortex of Group A, a lower level of ETC complexes was observed in a subset of autism cases, that is, 60% (3/5) for complexes I, II, and V, and 40% (2/5) for complexes III and IV. A striking observation was that the levels of ETC complexes were similar in adult subjects with autism and control subjects (Group B). A significant increase in the levels of lipid hydroperoxides, an oxidative stress marker, was also observed in the cerebellum and temporal cortex in the children with autism. These results suggest that the expression of ETC complexes is decreased in the cerebellum and the frontal and temporal regions of the brain in children with autism, which may lead to abnormal energy metabolism and oxidative stress. The deficits observed in the levels of ETC complexes in children with autism may readjust to normal levels by adulthood.