Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn

In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O(2) for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg(-1)·dose(-1) times two doses (PPHN-loHC), and six lambs were ventilated with O(2) alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O(2) ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O(2.) We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress.     

D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat

Opioids depress respiration and decrease chest wall compliance. A previous study in this laboratory showed that dopamine-D(1) receptor (D(1)R) agonists restored phrenic nerve activity after arrest by fentanyl in immobilized, mechanically ventilated cats. The reinstated phrenic nerve rhythm was slower than control, so it was not known whether D(1)R agonists can restore spontaneous breathing to levels that provide favorable alveolar gas exchange and blood oxygenation. It was also not known whether the agonists counteract opioid analgesia. In the present study, anesthetized, spontaneously breathing cats were given intravenous doses of fentanyl (18.0 +/- 3.4 microg/kg) that severely depressed depth and rate of respiration, lowered arterial hemoglobin oxygenation (HbO(2)), elevated end-tidal carbon dioxide (ETCO(2)), and abolished the nociceptive hind limb crossed-extensor reflex. Fentanyl (30 microg/kg) also evoked tonic discharges of caudal medullary expiratory neurons in paralyzed mechanically ventilated cats, which might explain decreased chest compliance. The selective D(1)R agonists 6-chloro APB (3 mg/kg) or dihydrexidine (DHD, 1 mg/kg) increased depth and rate of spontaneous breathing after opioid depression and returned HbO(2) and ETCO(2) to control levels. Opioid arrest of the nociceptive reflex remained intact. Pretreatment with DHD prevented significant depression of spontaneous breathing by fentanyl (17.5 +/- 4.3 microg/kg). Tonic firing evoked by fentanyl in expiratory neurons was converted to rhythmic respiratory discharges by DHD (1 mg/kg). The results suggest that D(1)R agonists might be therapeutically useful for the treatment of opioid disturbances of breathing without impeding analgesia.     

Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs

Respiratory muscle blood flow and organ blood flow during endotoxic shock were studied in spontaneously breathing dogs (SB, n = 6) and mechanically ventilated dogs (MV, n = 5) with radiolabeled microspheres. Shock was produced by a 5-min intravenous injection of Escherichia coli endotoxin (0.55:B5, Difco, 10 mg/kg) suspended in saline. Mean arterial blood pressure and cardiac output in the SB group dropped to 59 and 45% of control values, respectively. There was a similar reduction in arterial blood pressure and cardiac output in the MV group. Total respiratory muscle blood flow in the SB group increased significantly from the control value of 51 +/- 4 ml/min (mean +/- SE) to 101 +/- 22 ml/min at 60 min of shock. In the MV group, respiratory muscle perfusion fell from control values of 43 +/- 12 ml/min to 25 +/- 3 ml/min at 60 min of shock. In the SB group, 8.8% of the cardiac output was received by the respiratory muscle during shock in comparison with 1.9% in the MV group. In both groups of dogs, blood flow to most organs was compromised during shock; however, blood flow to the brain, gut, and skeletal muscles was higher in the MV group than in the SB group. Thus by mechanical ventilation a fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during endotoxic shock.     

Responses of the three-toed sloth, Bradypus tridactylus, to some commonly used pharmacologic agents. II. Chloralose and reserpine

1. Chloralose, 50 mg/kg i.v., is a safe effective anesthetic for sloths and reduces incidence of cardiac arrhythmias. 2. However, chloralose blocks baroreflexes and may reduce the sensitivity of beta 1 cardiac receptors. 3. Reserpine, 0.70 mg/kg given i.v. in divided doses, blocks the hypertensive effect of 100 micrograms/kg of tyramine in sloths. 4. Reserpine in this dosage materially reduces arterial pressure and heart rate; these effects last at least 7 days. 5. Reserpine potentiates the hypertensive effects of epinephrine and norepinephrine materially. 6. In sloths reserpine increases cardiac irritability but does not block baroreflexes. 7. As is true with most other drugs sloths are more sensitive to chloralose and reserpine than most common laboratory animals.     

Electrical activation of expiratory muscles increases with time in pentobarbital-anesthetized dogs.

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.     

Ethane production rates and minute ventilation

Ethane quantitated in the expired alveolar gas is a noninvasive measure of free radical activity. This method has been criticized for lack of control of minute ventilation (VE) in spontaneously breathing animals, although ethane, which is poorly soluble in tissues, should not be affected by changes in VE. We measured ethane elimination rates in six strain 13 guinea pigs (GP13) during spontaneous room air breathing and in six room air breathing, pentobarbital-anesthetized, tracheostomized, externally warmed, mechanically ventilated GP13s at various levels of VE. In the ventilated animals, weight0.75/VE (metabolic activity corrected for VE) was a linear function of arterial CO2 tension (PaCO2) drawn from arterial line (r = 0.72, P less than 0.005). However, weight0.75/VE did not correlate with ethane elimination rates (r = 0.12, not significant). The mean (+/- SD) ethane elimination rates in the spontaneously breathing animals was 3.15 +/- 0.96 pmol.min-1.100 g-1 and was not significantly different from the mean rate in the mechanically ventilated animals (3.11 +/- 1.37) over a range of VE's. These data demonstrate that ethane elimination rates are not affected by changes in VE and are unaffected by pentobarbital anesthesia.     

Effects of acetazolamide on cerebrospinal fluid ions in metabolic alkalosis in dogs

We hypothesized that inhibition of carbonic anhydrase in the central nervous system by acetazolamide should limit the rise in cisternal cerebrospinal fluid (CSF) [HCO3-] observed in metabolic alkalosis. To test this hypothesis, isosmotic isonatremic metabolic alkalosis was produced in two groups of anesthetized, paralyzed, and mechanically ventilated dogs (8 in each group). Group II animals received 50 mg/kg of acetazolamide intravenously 1 h before induction of metabolic alkalosis of 5-h duration. Renal effects of acetazolamide were eliminated by ligation of renal pedicles. In both groups cisternal CSF [Na+] remained relatively constant during metabolic alkalosis. In group I CSF [Cl-] decreased 3.6 and 8.2 meq/l, respectively, 2.5 and 5 h after induction of metabolic alkalosis. Respective increments in CSF [HCO3-] were 3.4 and 6.0 meq/l. In acetazolamide-treated dogs, during metabolic alkalosis, increments in CSF [HCO3-] (4.8 and 7.2 meq/l, respectively, at 2.5 and 5 h) and decrements in CSF [Cl-] (9.1 and 13.3 meq/l) were greater than those observed in group I. We conclude that, in dogs with metabolic alkalosis and bilateral ligation of renal pedicles, acetazolamide impairs CSF regulation of HCO3- and Cl- ions; acetazolamide not only failed to impede HCO3- rise but actually appeared to increase it. The mechanisms for these observations are discussed.     

Antihypertensive profile of the angiotensin-converting enzyme inhibitors CI-906 and CI-907

CI-906 and CI-907, new orally active nonsulfhydryl angiotensin-converting enzyme inhibitors, were examined for antihypertensive effects in unanesthetized hypertensive rats and dogs. In two-kidney, one-clip Goldblatt hypertensive rats, single oral daily doses (0.03-30 mg/kg) produced dose-dependent decreases in blood pressure; a single 3 mg/kg oral dose lowered blood pressure to normotensive levels. In spontaneously hypertensive rats, 30 mg/(kg X day) orally administered for 5 consecutive days achieved the same blood pressure decrease as that obtained on the first day in the renal hypertensive rats. In diuretic-pretreated renal hypertensive dogs, a 10 mg/kg oral dose decreased blood pressure by 25%. No adverse side effects were observed with CI-906 and CI-907 in any of the conscious animals. These studies indicate that CI-906 and CI-907 are potent, orally active antihypertensive agents without any apparent limiting side effects.     

Thoracic influence on upper airway patency

Patency of the upper airway (UA) is usually considered to be maintained by the activity of muscles in the head and neck. These include cervical muscles that provide caudal traction on the UA. The thorax also applies caudal traction to the UA. To observe whether this thoracic traction can also improve UA patency, we measured resistance of the UA (RUA) during breathing in the presence and absence of UA muscle activity. Fifteen anesthetized dogs breathed through tracheostomy tubes. RUA was calculated from the pressure drop of a constant flow through the isolated UA. RUA decreased 31 +/- 5% (SEM) during inspiration. After hyperventilating seven of these dogs to apnea, we maximally stimulated the phrenic nerves to produce paced diaphragmatic breathing. Despite absence of UA muscle activity, RUA fell 51 +/- 11% during inspiration. Graded changes were produced by reduced stimulation. In six other dogs we denervated all UA muscles. RUA still fell 25 +/- 7% with inspiration in these spontaneously breathing animals. When all caudal ventrolateral cervical structures mechanically linking the thorax to the UA were severed, RUA increased and respiratory fluctuations ceased. These findings indicate that tonic and phasic forces generated by the thorax can improve UA patency. Inspiratory increases in UA patency cannot be attributed solely to activity of UA muscles.     

Mechanism of arterial hypoxemia following pulmonary thromboembolism in dogs.

Mongrel dogs (29) were anesthetized, paralyzed, and ventilated at a constant minute volume. AaD02 breathing air and 100% O2, venous admixture breathing air (Qva/Qt) and 100% O2 (Qs/Qt), single-breath diffusing capacity for CO (DLCO), and total pulmonary resistance (RL) and pulmonary compliance (CL) were measured before and after pulmonary embolization with autologus in vivo venous thrombi. Nine dogs were heparinized before embolization. In the 20 nonheparinized dogs AaDo2 breathing air increased from 11 to 26 mmHg, Qva/Qt from 4 to 22%, and Qs/At from 5 to 8%. DLCO decreased 24%, RL increased 43%, and CL fell 30%. In the nine heparinized dogs AaDo2 breathing air increased from 8 to 13 mmHg and Qva/Qt from 3 to 8%; Qs/Qt did not change. DLCO decreased 31%; RL and CL did not change significantly. The increase in Qva/Qt of 5% in the heparinized dogs was significantly less (P smaller than 0.001) than the increase of 18% in the nonheparinized dogs. These findings suggest that arterial hypoxemia following thromboembolism is due to ventilation-perfusion inequality caused by changes in lung mechanics.     

Prostaglandins and control of breathing in newborn piglets

To investigate the possible role of prostaglandins in regulation of postnatal breathing, phrenic neural activity (PMO) was recorded as an index of breathing in 42 anesthetized, paralyzed piglets less than 30 days of age (weight 2.4 +/- 0.2 kg, age 9.9 +/- 1.5 days) who were mechanically ventilated with 100% O2 at a fixed tidal volume (8-10 ml/kg). End-tidal CO2 was held constant by an electronic servocontroller which adjusted ventilator rate; ventilator rate was monitored as an index of CO2 production. Rectal temperature was maintained at 39.0 +/- 0.2 degrees C. The effects on PMO of intravenous and brain ventricular injections of NaCl and agents active in the prostaglandin cascade were compared. Intravenous (0.25-1.0 mg/kg, n = 9) and brain (5-33 micrograms/kg, n = 6) indomethacin, a cyclooxygenase inhibitor, doubled PMO within 30 min. Intravenous (1-10 micrograms/kg, n = 6) and brain (1-40 micrograms/kg, n = 6) prostaglandin E1 inhibited PMO by one-half at 10 and 30 min.     

Bronchoconstriction elicited by isocapnic hyperpnea in guinea pigs

We demonstrated spontaneous self-limited bronchoconstriction after eucapnic dry gas hyperpnea in 22 anesthetized, mechanically ventilated guinea pigs pretreated with propranolol (1 mg/kg iv). Eucapnic hyperpnea "challenges" of room temperature dry or humidified gas (5% CO2-95% O2) were performed by mechanically ventilating animals (150 breaths/min, 3-6 ml tidal volume) for 5 min. During a "recovery" period after hyperpnea, animals were returned to standard ventilation conditions (6 ml/kg, 60 breaths/min, 50% O2 in air, fully saturated at room temperature). After dry gas hyperpnea (5 ml, 150 breaths/min), respiratory system resistance (Rrs) increased in the recovery period by 7.7-fold and dynamic compliance (Cdyn) decreased by 79.7%; changes were maximal at approximately 3 min posthyperpnea and spontaneously returned to base line in 10-40 min. This response was markedly attenuated by humidification of inspired air. Four consecutive identical dry air challenges resulted in similar posthyperpnea responses in four animals. Increasing the minute ventilation during hyperpnea (by varying tidal volume from 3 to 6 ml) caused increased bronchoconstriction in a dose-dependent fashion in six animals. Neither vagotomy nor atropine altered the airway response to dry gas hyperpnea. We conclude that dry gas hyperpnea in anesthetized guinea pigs results in a bronchoconstrictor response that shares five similar features with hyperpnea-induced bronchoconstriction in human asthma: 1) time course of onset and spontaneous resolution, 2) diminution with humidification of inspired gas, 3) reproducibility on consecutive identical challenges, 4) stimulus-response relationship with minute ventilation during hyperpnea, and 5) independence of parasympathetic neurotransmission.     

Blood pressure and other physiological responses in awake and anesthetized guinea pigs

The effect of combinations of injectable anesthetics on mean arterial blood pressure, blood gases, heart rate and respiration of the guinea pig (NIH Outbred strain) was investigated. After a 30 minute period in which baseline resting cardiorespiratory measurements were obtained, five groups of six pigmented animals having indwelling carotid cannulas were anesthetized with (a) ketamine hydrochloride (30 mg/kg, im)/xylazine (5 mg/kg, im); (b) sodium pentobarbital (15 mg/kg, ip)/fentanyl-droperidol (0.4 mg/kg, im); (c) diazepam (5mg/kg, ip)/fentanyl citrate (0.32 mg/kg, im); (d) diazepam (5 mg/kg, ip)/alphaxalone-alphadolone acetate (45 mg/kg, im); or (e) 1% alpha-chloralose-40% urethane (0.8 ml/100g, ip). Animals were not respirated artificially and no supplemental doses of anesthetic were given. Resting blood pressure in awake animals was measured over time for as long as cannulas remained patent (109 measurements). Mean resting blood pressure, for this strain of guinea pigs, was determined to be 53.1 +/- 4.2 mmHg. There was no indication that mean arterial blood pressure changed with age in animals varying in weight from 215 g to 550 g. Under diazepam/fentanyl, blood pressure rose significantly above resting level to a mean of 71.1 +/- 6.1 mmHg. With the other four combinations, blood pressure stabilized near, but below pre-anesthesia levels (ketamine/xylazine 47.1 +/- 6.8 mmHg; pentobarbital/fentanyl-droperidol, 46.9 +/- 3.2 mmHg; diazepam/alphaxalone-alphadolone, 47.8 +/- 4.8 mmHg; chloralose-urethane, 51.0 +/- 1.2 mmHg). Under diazepam/alphaxalone-alphadolone and chloralose-urethane, respiration was depressed and blood gas levels deviated from normal to the extent that artificial ventilation would be necessary to maintain an adequate physiological state.     

Diaspirin cross-linked hemoglobin improves oxygen extraction capabilities in endotoxic shock.

We studied the effects of diaspirin cross-linked hemoglobin (DCLHb), a cell-free hemoglobin derived from human erythrocytes, on blood flow distribution and tissue oxygen extraction capabilities in endotoxic shock. Eighteen pentobarbital sodium-anesthetized, mechanically ventilated dogs received 2 mg/kg of E. coli endotoxin, followed by saline resuscitation to restore cardiac filling pressures to baseline levels. The animals were randomly divided into three groups: six served as control, six received DCLHb at a dose of 500 mg/kg (group 1) and six DCLHb at a dose of 1,000 mg/kg (group 2). Cardiac tamponade was then induced by saline injection in the pericardial sac to progressively reduce cardiac index and thereby allow study of tissue oxygen extraction capabilities. DCLHb had a dose-dependent vasopressor effect but did not significantly alter cardiac index or regional blood flow. During cardiac tamponade, critical oxygen delivery was 12.8 +/- 0.7 ml. kg(-1). min(-1) in the control group, but 8.6 +/- 0.9 and 8.2 +/- 0.7 ml. kg(-1). min(-1) in groups 1 and 2, respectively (both P < 0.05 vs. control group). The critical oxygen extraction ratio was 39.1 +/- 3.1% in the control group but 58.7 +/- 12.8% and 60.2 +/- 9.0% in groups 1 and 2, respectively. We conclude that DCLHb can improve whole body oxygen extraction capabilities during endotoxic shock in dogs.     

Effects of anesthetics on cardiovascular responses of the marmot Marmota flaviventris

The effects of pentobarbital (30 mg/kg), urethan (2 g/kg), chloralose/urethan (50 mg/kg, 500 mg/kg), and thiobutabarbital (Inactin, 100 mg/kg) on the mean arterial pressure (BP) and heart period (HP) of Marmota flaviventris were examined. Anesthesia significantly decreased BP by 22-27 mm Hg and HP by 123-151 msec. In a series of paired studies with eight marmots it was found that pentobarbital increased the BP response to phenylephrine and almost abolished the baroreflex HP responses to phenylephrine and nitroglycerin. In another series of animals right carotid occlusion in unanesthetized animals produced greater changes in BP and HP than occlusion of the left carotid. Chloralose/urethan, urethan, or Inactin reduced the reflex BP response to unilateral carotid occlusion by 50% and the HP response by 96%. It was concluded that the anesthetic agents investigated depress baroreflex responses significantly by influencing efferent sympathetic and parasympathetic reflex responses. They, therefore, are not appropriate for cardiovascular studies in acute, anesthetized preparations of the marmot and, perhaps, other hibernating species.     

Liver blood flow during haemorrhagic shock in the dog treated with phenoxybenzamine

The liver blood flow has been extensively studied in hemorrhagic shock, but considerable disagreement exists as to the nature of hemodynamic changes and their controlling mechanism. The present investigation was undertaken in order to determine the effects of hemorrhage and phenoxybenzamine (PBZ) on the participation of hepatic artery (HAF) and portal vein flow (PVF) in total liver blood flow (LBF) changes. The dynamics of LBF (H2 washout method), HAF and PVF (electromagnetic flowmeter) during 3-hours posthemorrhagic hypotension (90 min. = 50-60 mmHg; 90 min. = 25-30 mmHg) and one-hour postretransfusion period were investigated on 20 mongrel dogs under chloralose anesthesia. All animals were divided into 2 groups (control and PBZ-treated--5 mg/kg b.w. 30 minutes following first bleeding). Half an hour following bleeding there occurred a significant decrease of LBF (P less than 0.001) in dogs of both experimental groups. This degree of decrease was due to equal decrease in the PVF and HAF. The infusion of PBZ caused a slight tendency towards increase of LBF, while the subsequent decrease in blood flow values during second hypotensive period in the treated dogs was not so pronounced as in the untreated dogs. Although retransfusion led to an increase of LBF, HAF and PVF in both groups, the restauration was significantly better in PBZ-treated animals. The degree of metabolic acidosis was more pronounced in the untreated dogs than in PBZ-treated.     

Cardiopulmonary function during 7 h of constant-dose halothane and methoxyflurane

Cardiopulmonary effects of prolonged, constant-alveolar-dose halothane (HAL) and methoxyflurane (MOF) in O2 anesthesia on spontaneously breathing dogs were determined. One hour after anesthetic induction, end-tidal concentration was set at 1.04% HAL or 0.28% MOF [each representing 1.2 minimum alveolar concentration (MAC) for dogs] and maintained for 7 h. No time-related changes were associated with MOF. However, HAL significantly (P less than 0.05) elevated cardiac output (Q) from 2 to 7 h by increasing stroke volume; mean aortic pressure (MAP) also increased with time (P less than 0.05 beginning at 5 h). Four of these dogs were studied again at least 3 wk later at a constant end-tidal dose of 1.48% HAL in O2 (1.7 MAC). Q and MAP were lower initially during 1.7 MAC than during 1.2 MAC but not after 2 h of anesthesia. The greater HAL dose initially depressed ventilation and elevated arterial partial pressure of CO2 (PaCO2) compared with the lower dose. PaCO2 continued to increase with duration of 1.7 MAC HAL, as did results of ventilatory gas volume and flow measurements.     

Regional blood flow to canine parietal pleura and internal intercostal muscle

Transcapillary Starling forces in the parietal pleura and the underlying interstitium may potentially contribute to the exchange of fluid across this barrier. However, the extent of blood flow to the parietal pleura has not been measured. Thus, using standard microsphere techniques, we compared blood flow to the parietal pleura, including the subpleural interstitium, with blood flow to the adjacent internal intercostal muscle, as well as with flows to other serous tissues, including mediastinal pleura, pericardium, and parietal peritoneum, in anesthetized dogs that were either breathing spontaneously (n = 9) or ventilated to control arterial PCO2 (n = 5). Blood flow (ml.min-1.g-1) was measured after 20 min of equilibration in four successive body positions: right lateral decubitus, supine, left lateral decubitus, and prone. Overall, flow to parietal pleura was not different in spontaneous [1.07 +/- 0.14 (SE)] and mechanically ventilated animals (0.74 +/- 0.11). Flow to the internal intercostal muscle was significantly less than pleural blood flow, averaging 0.24 +/- 0.03 and 0.16 +/- 0.03 in the same groups, although again there was no effect of ventilation mode. Blood flow to other serous tissues in the thoracic cavity, specifically the mediastinal pleura (0.67 +/- 0.14) and pericardium (0.88 +/- 0.22), was similar to parietal pleural flow, whereas that to the parietal peritoneum was an order of magnitude lower (0.09 +/- 0.02, P less than 0.05). Changing body position had no effect on blood flow to any of the sampled tissues. Blood flow to the dorsal aspect of the chest wall muscle in spontaneously breathing animals tended to be greater than that to lateral or ventral portions of the chest wall.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of digitalis on the diaphragm in anesthetized dogs

We examined the effect of digitalis on diaphragmatic contractility and fatigability in 19 anesthetized mechanically ventilated dogs. The diaphragmatic force was assessed from transdiaphragmatic pressure (Pdi) developed at functional residual capacity against an occluded airway during cervical phrenic nerve stimulation. In a first group of five dogs, Pdi-stimulus frequency relationships were compared before and after administration of ouabain in doses of 0.01, 0.02, and 0.04 mg/kg. In a second group, diaphragmatic fatigue was produced by bilateral phrenic nerve stimulation at 30 Hz. Ten seconds of stimulation and 15 s of mechanical ventilation were repeated for 30 min. The rates of decrease in Pdi were compared between two groups, one of 0.05 mg/kg deslanoside-treated dogs (n = 7) and one of nontreated dogs (n = 7). After ouabain administration Pdi was significantly greater at each frequency in a dose-dependent manner. On the other hand, the rate of decrease in Pdi in the deslanoside group was significantly smaller than that in the nontreated group, whereas deslanoside did not greatly change the Pdi-frequency curves in fresh diaphragm. We conclude that ouabain improves contractility of the fresh diaphragm and that deslanoside has a protective effect against fatigability.     

Effects of papaya seeds extract on the sperm characteristics of dogs

The effect of chloroform extracts from seeds of the papaya plant (Carica papaya) on the spermatic characteristics of dogs was evaluated at doses of 50, 100 and 150 mg/kg, Groups 1, 2, and 3, respectively. Structural and ultrastructural changes in sperm cells and testicular parenchyma were also evaluated, and possible side effects were noted. Significant reductions in sperm concentration and motility were observed starting from Days 60 and 75, respectively, in all treated groups (P<0.05), but no azoospermia was noted. A mild osmotic diarrhea occurred in dogs from Group 3 (150 mg/kg), although blood variables were within the normal range of a clinically healthy dog. Arrested spermatogenesis was observed in the seminiferous tubules of all treated groups, and vacuolization and signs of Sertoli cell degeneration were detected in all treated groups, particularly in Group 3 (150 mg/kg). Selective damage to Sertoli cells induced by the extract occurred in all treated groups independently of the extract concentration. Alteration of the epididymal environment may reduce the motility of sperm cells, considering that their structure was normal. Sperm characteristics in treated animals were considered to be similar to those of sub-fertile dogs. However, these effects may be temporary, and dogs may recover normal sperm characteristics when the extract is withdrawn.